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1. Mapping the landscape of histomorphological cancer phenotypes using self-supervised learning on unannotated pathology slides

Author: Adalberto Claudio Quiros, Nicolas Coudray, Anna Yeaton, Xinyu Yang, Bojing Liu, Hortense Le, Luis Chiriboga, Afreen Karimkhan, Navneet Narula, David A. Moore, Christopher Y. Park, Harvey Pass, Andre L. Moreira, John Le Quesne, Aristotelis Tsirigos, and Ke Yuan
Subjects: Science
Abstract: Abstract Cancer diagnosis and management depend upon the extraction of complex information from microscopy images by pathologists, which requires time-consuming expert interpretation prone to human bias. Supervised deep learning approaches have proven powerful, but are inherently limited by the cost and quality of annotations used for training. Therefore, we present Histomorphological Phenotype Learning, a self-supervised methodology requiring no labels and operating via the automatic discovery of discriminatory features in image tiles. Tiles are grouped into morphologically similar clusters which constitute an atlas of histomorphological phenotypes (HP-Atlas), revealing trajectories from benign to malignant tissue via inflammatory and reactive phenotypes. These clusters have distinct features which can be identified using orthogonal methods, linking histologic, molecular and clinical phenotypes. Applied to lung cancer, we show that they align closely with patient survival, with histopathologically recognised tumor types and growth patterns, and with transcriptomic measures of immunophenotype. These properties are maintained in a multi-cancer study.
Published: 2024
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2. New or enlarging hiatal hernias after thoracic surgery for early lung cancerCentral MessagePerspective

Author: Kimberly J. Song, MD, Rowena Yip, MPH, Michael Chung, MD, Qiang Cai, MD, PhD, Yeqing Zhu, MD, PhD, Ayushi Singh, MD, Erik E. Lewis, MD, David Yankelevitz, MD, Emanuela Taioli, MD, PhD, Claudia Henschke, MD, PhD, Raja Flores, MD, Andrew Kaufman, MD, Dong-Seok Lee, MD, Daniel Nicastri, MD, Andrea Wolf, MD, Kimberly Song, MD, Kenneth Rosenzweig, MD, Jorge Gomez, MD, Mary Beth Beasley, MD, Maureen Zakowski, MD, David F. Yankelevitz, MD, Claudia I. Henschke, PhD, MD, Rebecca Schwartz, MD, Huiwen Chan, Jeffrey Zhu, Sydney Kantor, Shana Adler, Wissam Raad, MD, Zrzu Buyuk, MD, Adie Friedman, MD, Ronald Dreifuss, MD, Stacey Verzosa, MD, Mariya Yakubox, NP, Karina Aloferdova, NP, Patricia Stacey, Simone De Nobrega, Ardeshir Hakami, MD, Harvey Pass, MD, Berne Crawford, MD, Jessica Donnington, MD, Benjamin Cooper, MD, Andre Moreirea, MD, Audrey Sorensen, RN, Leslie Kohman, MD, Robert Dunton, MD, Jason Wallen, MD, Christopher Curtiss, MD, Ernest Scalzetti, MD, Linda Ellinwood, RN, Clifford P. Connery, MD, Emilo Torres, MD, Dan Cruzer, MD, Bruce Gendron, MD, Sonya Alyea, NP, Daniel Lackaye, Lauren Studer, Claudia Henschke, PhD, MD, Rebecca Schwartz, PhD, Betsy Becker, PhD, Artit Jirapatnakul, PhD, Nan You, MS, Huiwen Chan, MPH, MBA, Claudia I. Henschke, David F. Yankelevitz, Rowena Yip, Artit Jirapatnakul, Raja Flores, Andrea Wolf, Daniel M. Libby, James P. Smith, Mark Pasmantier, A.P. Reeves, Steven Markowitz, Albert Miller, Jose Cervera Deval, Heidi Roberts, Demetris Patsios, Shusuke Sone, Takaomi Hanaoka, Javier Zulueta, Juan P. de-Torres, Maria D. Lozano, Ralph Aye, Kristin Manning, Christiana Care, Thomas Bauer, Stefano Canitano, Salvatore Giunta, Enser Cole, Karl Klingler, John H.M. Austin, Gregory D.N. Pearson, Dorith Shaham, Cheryl Aylesworth, Patrick Meyers, Shahriyour Andaz, Davood Vafai, David Naidich, Georgeann McGuinness, Barry Sheppard, Matthew Rifkin, M. Kristin Thorsen, Richard Hansen, Samuel Kopel, William Mayfield, Dan Luedke, Donald Klippenstein, Alan Litwin, Peter A. Loud, Leslie J. Kohman, Ernest M. Scalzetti, Richard Thurer, Nestor Villamizar, Arfa Khan, Rakesh Shah, Xueguo Liu, Gary Herzog, Diana Yeh, Ning Wu, Joseph Lowry, Mary Salvatore, Carmine Frumiento, David S. Mendelson, Michael V. Smith, Robert Korst, Jana Taylor, Michelle S. Ginsberg, Michaela Straznicka, Mark Widmann, Gary Cecchi, Terence A.S. Matalon, Paul Scheinberg, Shari-Lynn Odzer, David Olsen, Fred Grannis, Arnold Rotter, Daniel Ray, David Mullen, Peter H. Wiernik, Edson H. Cheung, Melissa Lim, Louis DeCunzo, Robert Glassberg, Harvey Pass, Carmen Endress, Mark Yoder, Palmi Shah, Laura Welch, Michael Kalafer, Jeremy Green, James Walsh, David Bertsch, Elmer Camacho, Cynthia Chin, James O'Brien, and James C. Willey
Subjects: hiatal hernia, lung cancer, paraesophageal hernia, postoperative complications, thoracic surgery morbidity, Diseases of the circulatory (Cardiovascular) system, RC666-701, Surgery, RD1-811
Abstract: Objective: The study objective was to determine the relationship between lung resection and the development of postoperative hiatal hernia. Methods: Preoperative and postoperative computed tomography imaging from 373 patients from the International Early Lung Cancer Action Program and the Initiative for Early Lung Cancer Research on Treatment were compared at a median of 31.1 months of follow-up after resection of clinical early-stage non–small cell lung cancer. Incidence of new hiatal hernia or changes to preexisting hernias were recorded and evaluated by patient demographics, surgical approach, extent of resection, and resection site. Results: New hiatal hernias were seen in 9.6% of patients after lung resection (5.6% after wedge or segmentectomy and 12.4% after lobectomy; P = .047). The median size of new hernias was 21 mm, and the most commonly associated resection site was the left lower lobe (24.2%; P = .04). In patients with preexisting hernias, 53.5% demonstrated a small but significant increase in size from 21 to 22 mm (P
Published: 2022
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3. Arachidonic acid drives adaptive responses to chemotherapy-induced stress in malignant mesothelioma

Author: Mario Cioce, Claudia Canino, Harvey Pass, Giovanni Blandino, Sabrina Strano, and Vito Michele Fazio
Subjects: Arachidonic acid, cPLA2, NFkB, Chemoresistance, ALDH, Spheroids, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background High resistance to therapy and poor prognosis characterizes malignant pleural mesothelioma (MPM). In fact, the current lines of treatment, based on platinum and pemetrexed, have limited impact on the survival of MPM patients. Adaptive response to therapy-induced stress involves complex rearrangements of the MPM secretome, mediated by the acquisition of a senescence-associated-secretory-phenotype (SASP). This fuels the emergence of chemoresistant cell subpopulations, with specific gene expression traits and protumorigenic features. The SASP-driven rearrangement of MPM secretome takes days to weeks to occur. Thus, we have searched for early mediators of such adaptive process and focused on metabolites differentially released in mesothelioma vs mesothelial cell culture media, after treatment with pemetrexed. Methods Mass spectrometry-based (LC/MS and GC/MS) identification of extracellular metabolites and unbiased statistical analysis were performed on the spent media of mesothelial and mesothelioma cell lines, at steady state and after a pulse with pharmacologically relevant doses of the drug. ELISA based evaluation of arachidonic acid (AA) levels and enzyme inhibition assays were used to explore the role of cPLA2 in AA release and that of LOX/COX-mediated processing of AA. QRT-PCR, flow cytometry analysis of ALDH expressing cells and 3D spheroid growth assays were employed to assess the role of AA at mediating chemoresistance features of MPM. ELISA based detection of p65 and IkBalpha were used to interrogate the NFkB pathway activation in AA-treated cells. Results We first validated what is known or expected from the mechanism of action of the antifolate. Further, we found increased levels of PUFAs and, more specifically, arachidonic acid (AA), in the transformed cell lines treated with pemetrexed. We showed that pharmacologically relevant doses of AA tightly recapitulated the rearrangement of cell subpopulations and the gene expression changes happening in pemetrexed -treated cultures and related to chemoresistance. Further, we showed that release of AA following pemetrexed treatment was due to cPLA2 and that AA signaling impinged on NFkB activation and largely affected anchorage-independent, 3D growth and the resistance of the MPM 3D cultures to the drug. Conclusions AA is an early mediator of the adaptive response to pem in chemoresistant MPM and, possibly, other malignancies.
Published: 2021
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4. Combined Radiomic and Visual Assessment for Improved Detection of Lung Adenocarcinoma Invasiveness on Computed Tomography Scans: A Multi-Institutional Study

Author: Pranjal Vaidya, Kaustav Bera, Philip A. Linden, Amit Gupta, Prabhakar Shantha Rajiah, David R. Jones, Matthew Bott, Harvey Pass, Robert Gilkeson, Frank Jacono, Kevin Li-Chun Hsieh, Gong-Yau Lan, Vamsidhar Velcheti, and Anant Madabhushi
Subjects: radiomics, minimally invasive adenocarcinoma (MIA), ct scan (CT), integrated model analysis, invasive adenocarcinoma (IA), radiologists interpretation, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: ObjectiveThe timing and nature of surgical intervention for semisolid abnormalities are dependent upon distinguishing between adenocarcinoma-in-situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (INV). We sought to develop and evaluate a quantitative imaging method to determine invasiveness of small, ground-glass lesions on computed tomography (CT) chest scans.MethodsThe study comprised 268 patients from 4 institutions with resected (
Published: 2022
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5. Multi-region exome sequencing reveals genomic evolution from preneoplasia to lung adenocarcinoma

Author: Xin Hu, Junya Fujimoto, Lisha Ying, Junya Fukuoka, Kazuto Ashizawa, Wenyong Sun, Alexandre Reuben, Chi-Wan Chow, Nicholas McGranahan, Runzhe Chen, Jinlin Hu, Myrna C. Godoy, Kazuhiro Tabata, Kishio Kuroda, Lei Shi, Jun Li, Carmen Behrens, Edwin Roger Parra, Latasha D. Little, Curtis Gumbs, Xizeng Mao, Xingzhi Song, Samantha Tippen, Rebecca L. Thornton, Humam Kadara, Paul Scheet, Emily Roarty, Edwin Justin Ostrin, Xu Wang, Brett W. Carter, Mara B. Antonoff, Jianhua Zhang, Ara A. Vaporciyan, Harvey Pass, Stephen G. Swisher, John V. Heymach, J. Jack Lee, Ignacio I. Wistuba, Waun Ki Hong, P. Andrew Futreal, Dan Su, and Jianjun Zhang
Subjects: Science
Abstract: There has been a drastic increase in detection of lung nodules, many of which are precancers, preinvasive, minimally invasive or sometimes invasive lung cancers. Here, Hu et al. perform multi-region exome sequencing to discern the evolutional trajectory from precancers to invasive lung cancers.
Published: 2019
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6. Author Correction: Multi-region exome sequencing reveals genomic evolution from preneoplasia to lung adenocarcinoma

Author: Xin Hu, Junya Fujimoto, Lisha Ying, Junya Fukuoka, Kazuto Ashizawa, Wenyong Sun, Alexandre Reuben, Chi-Wan Chow, Nicholas McGranahan, Runzhe Chen, Jinlin Hu, Myrna C. Godoy, Kazuhiro Tabata, Kishio Kuroda, Lei Shi, Jun Li, Carmen Behrens, Edwin Roger Parra, Latasha D. Little, Curtis Gumbs, Xizeng Mao, Xingzhi Song, Samantha Tippen, Rebecca L. Thornton, Humam Kadara, Paul Scheet, Emily Roarty, Edwin Justin Ostrin, Xu Wang, Brett W. Carter, Mara B. Antonoff, Jianhua Zhang, Ara A. Vaporciyan, Harvey Pass, Stephen G. Swisher, John V. Heymach, J. Jack Lee, Ignacio I. Wistuba, Waun Ki Hong, P. Andrew Futreal, Dan Su, and Jianjun Zhang
Subjects: Science
Published: 2021
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7. The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma

Author: Christopher J. Ricketts, Aguirre A. De Cubas, Huihui Fan, Christof C. Smith, Martin Lang, Ed Reznik, Reanne Bowlby, Ewan A. Gibb, Rehan Akbani, Rameen Beroukhim, Donald P. Bottaro, Toni K. Choueiri, Richard A. Gibbs, Andrew K. Godwin, Scott Haake, A. Ari Hakimi, Elizabeth P. Henske, James J. Hsieh, Thai H. Ho, Rupa S. Kanchi, Bhavani Krishnan, David J. Kwaitkowski, Wembin Lui, Maria J. Merino, Gordon B. Mills, Jerome Myers, Michael L. Nickerson, Victor E. Reuter, Laura S. Schmidt, C. Simon Shelley, Hui Shen, Brian Shuch, Sabina Signoretti, Ramaprasad Srinivasan, Pheroze Tamboli, George Thomas, Benjamin G. Vincent, Cathy D. Vocke, David A. Wheeler, Lixing Yang, William T. Kim, A. Gordon Robertson, Paul T. Spellman, W. Kimryn Rathmell, W. Marston Linehan, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Andrew D. Cherniack, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Toshinori Hinoue, Peter W. Laird, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, onathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jr., Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, and Armaz Mariamidze
Subjects: Biology (General), QH301-705.5
Abstract: Summary: Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival. : Ricketts et al. find distinctive features of each RCC subtype, providing the foundation for development of subtype-specific therapeutic and management strategies. Somatic alteration of BAP1, PBRM1, and metabolic pathways correlates with subtype-specific decreased survival, while CDKN2A alteration, DNA hypermethylation, and Th2 immune signature correlate with decreased survival within all subtypes. Keywords: clear cell renal cell carcinoma, papillary renal cell carcinoma, chromophobe renal cell carcinoma, CDKN2A, DNA hypermethylation, immune signature, chromatin remodeling, TCGA, PanCanAtlas
Published: 2018
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8. Driver Fusions and Their Implications in the Development and Treatment of Human Cancers

Author: Qingsong Gao, Wen-Wei Liang, Steven M. Foltz, Gnanavel Mutharasu, Reyka G. Jayasinghe, Song Cao, Wen-Wei Liao, Sheila M. Reynolds, Matthew A. Wyczalkowski, Lijun Yao, Lihua Yu, Sam Q. Sun, Ken Chen, Alexander J. Lazar, Ryan C. Fields, Michael C. Wendl, Brian A. Van Tine, Ravi Vij, Feng Chen, Matti Nykter, Ilya Shmulevich, Li Ding, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Andrew D. Cherniack, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jr., Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, and Armaz Mariamidze
Subjects: Biology (General), QH301-705.5
Abstract: Summary: Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy. : Gao et al. analyze a 9,624 sample TCGA cohort with 33 cancer types to detect gene fusion events. They provide a landscape of fusion events detected, relate fusions to gene expression, focus on kinase fusion structures, examine mutually exclusive mutation and fusion patterns, and highlight fusion druggability. Keywords: fusion, cancer, RNA, translocation, gene fusions
Published: 2018
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9. Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Author: Joel Saltz, Rajarsi Gupta, Le Hou, Tahsin Kurc, Pankaj Singh, Vu Nguyen, Dimitris Samaras, Kenneth R. Shroyer, Tianhao Zhao, Rebecca Batiste, John Van Arnam, Ilya Shmulevich, Arvind U.K. Rao, Alexander J. Lazar, Ashish Sharma, Vésteinn Thorsson, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Andrew D. Cherniack, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, onathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jr., Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, and Armaz Mariamidze
Subjects: Biology (General), QH301-705.5
Abstract: Summary: Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumor-infiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment. : Tumor-infiltrating lymphocytes (TILs) were identified from standard pathology cancer images by a deep-learning-derived “computational stain” developed by Saltz et al. They processed 5,202 digital images from 13 cancer types. Resulting TIL maps were correlated with TCGA molecular data, relating TIL content to survival, tumor subtypes, and immune profiles. Keywords: digital pathology, immuno-oncology, machine learning, lymphocytes, tumor microenvironment, deep learning, tumor-infiltrating lymphocytes, artificial intelligence, bioinformatics, computer vision
Published: 2018
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10. Molecular Characterization and Clinical Relevance of Metabolic Expression Subtypes in Human Cancers

Author: Xinxin Peng, Zhongyuan Chen, Farshad Farshidfar, Xiaoyan Xu, Philip L. Lorenzi, Yumeng Wang, Feixiong Cheng, Lin Tan, Kamalika Mojumdar, Di Du, Zhongqi Ge, Jun Li, George V. Thomas, Kivanc Birsoy, Lingxiang Liu, Huiwen Zhang, Zhongming Zhao, Calena Marchand, John N. Weinstein, Oliver F. Bathe, Han Liang, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Andrew D. Cherniack, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jr., Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, and Armaz Mariamidze
Subjects: Biology (General), QH301-705.5
Abstract: Summary: Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1—master regulators of carbohydrate metabolic subtypes—modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility. : Peng et al. analyze a cohort of 9,125 TCGA samples across 33 cancer types to characterize tumor subtypes based on the expression of seven metabolic pathways. They find metabolic expression subtypes are associated with patient survivals and suggest the therapeutic and predictive relevance of subtype-related master regulators. Keywords: The Cancer Genome Atlas, tumor subtypes, prognostic markers, somatic drivers, master regulator, therapeutic targets, drug sensitivity, carbohydrate metabolism
Published: 2018
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11. Systematic Analysis of Splice-Site-Creating Mutations in Cancer

Author: Reyka G. Jayasinghe, Song Cao, Qingsong Gao, Michael C. Wendl, Nam Sy Vo, Sheila M. Reynolds, Yanyan Zhao, Héctor Climente-González, Shengjie Chai, Fang Wang, Rajees Varghese, Mo Huang, Wen-Wei Liang, Matthew A. Wyczalkowski, Sohini Sengupta, Zhi Li, Samuel H. Payne, David Fenyö, Jeffrey H. Miner, Matthew J. Walter, Benjamin Vincent, Eduardo Eyras, Ken Chen, Ilya Shmulevich, Feng Chen, Li Ding, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Andrew D. Cherniack, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jr., Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, and Armaz Mariamidze
Subjects: Biology (General), QH301-705.5
Abstract: Summary: For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases. : Jayasinghe et al. identify nearly 2,000 splice-site-creating mutations (SCMs) from over 8,000 tumor samples across 33 cancer types. They provide a more accurate interpretation of previously mis-annotated mutations, highlighting the importance of integrating data types to understand the functional and the clinical implications of splicing mutations in human disease. Keywords: splicing, RNA, mutations of clinical relevance
Published: 2018
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12. Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas

Author: Theo A. Knijnenburg, Linghua Wang, Michael T. Zimmermann, Nyasha Chambwe, Galen F. Gao, Andrew D. Cherniack, Huihui Fan, Hui Shen, Gregory P. Way, Casey S. Greene, Yuexin Liu, Rehan Akbani, Bin Feng, Lawrence A. Donehower, Chase Miller, Yang Shen, Mostafa Karimi, Haoran Chen, Pora Kim, Peilin Jia, Eve Shinbrot, Shaojun Zhang, Jianfang Liu, Hai Hu, Matthew H. Bailey, Christina Yau, Denise Wolf, Zhongming Zhao, John N. Weinstein, Lei Li, Li Ding, Gordon B. Mills, Peter W. Laird, David A. Wheeler, Ilya Shmulevich, Raymond J. Monnat, Jr., Yonghong Xiao, Chen Wang, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Michael Miller, Sheila Reynolds, Vesteinn Thorsson, Wei Zhang, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Carrie Cibulskis, Stacey B. Gabriel, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Toshinori Hinoue, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Min Wang, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jr., Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, and Armaz Mariamidze
Subjects: Biology (General), QH301-705.5
Abstract: Summary: DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ∼20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy. : Knijnenburg et al. present The Cancer Genome Atlas (TCGA) Pan-Cancer analysis of DNA damage repair (DDR) deficiency in cancer. They use integrative genomic and molecular analyses to identify frequent DDR alterations across 33 cancer types, correlate gene- and pathway-level alterations with genome-wide measures of genome instability and impaired function, and demonstrate the prognostic utility of DDR deficiency scores. Keywords: The Cancer Genome Atlas PanCanAtlas project, DNA damage repair, somatic mutations, somatic copy-number alterations, epigenetic silencing, DNA damage footprints, mutational signatures, integrative statistical analysis, protein structure analysis
Published: 2018
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13. Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types

Author: Michael Seiler, Shouyong Peng, Anant A. Agrawal, James Palacino, Teng Teng, Ping Zhu, Peter G. Smith, Silvia Buonamici, Lihua Yu, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Andrew D. Cherniack, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jr., Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, and Armaz Mariamidze
Subjects: Biology (General), QH301-705.5
Abstract: Summary: Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over-representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis. : Seiler et al. report that 119 splicing factor genes carry putative driver mutations over 33 tumor types in TCGA. The most common mutations appear to be mutually exclusive and are associated with lineage-independent altered splicing. Samples with these mutations show deregulation of cell-autonomous pathways and immune infiltration. Keywords: splicing, SF3B1, U2AF1, SRSF2, RBM10, FUBP1, cancer, mutation
Published: 2018
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14. Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas

Author: Gregory P. Way, Francisco Sanchez-Vega, Konnor La, Joshua Armenia, Walid K. Chatila, Augustin Luna, Chris Sander, Andrew D. Cherniack, Marco Mina, Giovanni Ciriello, Nikolaus Schultz, Yolanda Sanchez, Casey S. Greene, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Debyani Chakravarty, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Marc Ladanyi, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jr., Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, and Armaz Mariamidze
Subjects: Biology (General), QH301-705.5
Abstract: Summary: Precision oncology uses genomic evidence to match patients with treatment but often fails to identify all patients who may respond. The transcriptome of these “hidden responders” may reveal responsive molecular states. We describe and evaluate a machine-learning approach to classify aberrant pathway activity in tumors, which may aid in hidden responder identification. The algorithm integrates RNA-seq, copy number, and mutations from 33 different cancer types across The Cancer Genome Atlas (TCGA) PanCanAtlas project to predict aberrant molecular states in tumors. Applied to the Ras pathway, the method detects Ras activation across cancer types and identifies phenocopying variants. The model, trained on human tumors, can predict response to MEK inhibitors in wild-type Ras cell lines. We also present data that suggest that multiple hits in the Ras pathway confer increased Ras activity. The transcriptome is underused in precision oncology and, combined with machine learning, can aid in the identification of hidden responders. : Way et al. develop a machine-learning approach using PanCanAtlas data to detect Ras activation in cancer. Integrating mutation, copy number, and expression data, the authors show that their method detects Ras-activating variants in tumors and sensitivity to MEK inhibitors in cell lines. Keywords: Gene expression, machine learning, Ras, NF1, KRAS, NRAS, HRAS, pan-cancer, TCGA, drug sensitivity
Published: 2018
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15. Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Author: Hua-Sheng Chiu, Sonal Somvanshi, Ektaben Patel, Ting-Wen Chen, Vivek P. Singh, Barry Zorman, Sagar L. Patil, Yinghong Pan, Sujash S. Chatterjee, Anil K. Sood, Preethi H. Gunaratne, Pavel Sumazin, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Andrew D. Cherniack, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jr., Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, and Armaz Mariamidze
Subjects: Biology (General), QH301-705.5
Abstract: Summary: Long noncoding RNAs (lncRNAs) are commonly dysregulated in tumors, but only a handful are known to play pathophysiological roles in cancer. We inferred lncRNAs that dysregulate cancer pathways, oncogenes, and tumor suppressors (cancer genes) by modeling their effects on the activity of transcription factors, RNA-binding proteins, and microRNAs in 5,185 TCGA tumors and 1,019 ENCODE assays. Our predictions included hundreds of candidate onco- and tumor-suppressor lncRNAs (cancer lncRNAs) whose somatic alterations account for the dysregulation of dozens of cancer genes and pathways in each of 14 tumor contexts. To demonstrate proof of concept, we showed that perturbations targeting OIP5-AS1 (an inferred tumor suppressor) and TUG1 and WT1-AS (inferred onco-lncRNAs) dysregulated cancer genes and altered proliferation of breast and gynecologic cancer cells. Our analysis indicates that, although most lncRNAs are dysregulated in a tumor-specific manner, some, including OIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergistically dysregulate cancer pathways in multiple tumor contexts. : Chiu et al. present a pan-cancer analysis of lncRNA regulatory interactions. They suggest that the dysregulation of hundreds of lncRNAs target and alter the expression of cancer genes and pathways in each tumor context. This implies that hundreds of lncRNAs can alter tumor phenotypes in each tumor context. Keywords: lncRNA, regulation, modulation, cancer gene, pan-cancer, noncoding RNA, microRNA, RNA-binding proteins, interactome
Published: 2018
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16. Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types

Author: Zhongqi Ge, Jake S. Leighton, Yumeng Wang, Xinxin Peng, Zhongyuan Chen, Hu Chen, Yutong Sun, Fan Yao, Jun Li, Huiwen Zhang, Jianfang Liu, Craig D. Shriver, Hai Hu, Helen Piwnica-Worms, Li Ma, Han Liang, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Yuexin Liu, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Rehan Akbani, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Rupa S. Kanchi, Anil Korkut, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jing Wang, John N. Weinstein, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Pavana Anur, Myron Peto, Paul Spellman, Christopher Benz, Joshua M. Stuart, Christopher K. Wong, Christina Yau, D. Neil Hayes, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, A. Gordon Robertson, Sara Sadeghi, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Andrew D. Cherniack, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Juliann Shih, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Katherine A. Hoadley, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Huihui Fan, Toshinori Hinoue, Peter W. Laird, Hui Shen, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Chad J. Creighton, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Alexander J. Lazar, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, Jonathan Stretch, Maria Synott, John Thompson, James Wilmott, Hikmat Al-Ahmadie, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Rosemary Zuna, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jr., Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, and Armaz Mariamidze
Subjects: Biology (General), QH301-705.5
Abstract: Summary: Protein ubiquitination is a dynamic and reversible process of adding single ubiquitin molecules or various ubiquitin chains to target proteins. Here, using multidimensional omic data of 9,125 tumor samples across 33 cancer types from The Cancer Genome Atlas, we perform comprehensive molecular characterization of 929 ubiquitin-related genes and 95 deubiquitinase genes. Among them, we systematically identify top somatic driver candidates, including mutated FBXW7 with cancer-type-specific patterns and amplified MDM2 showing a mutually exclusive pattern with BRAF mutations. Ubiquitin pathway genes tend to be upregulated in cancer mediated by diverse mechanisms. By integrating pan-cancer multiomic data, we identify a group of tumor samples that exhibit worse prognosis. These samples are consistently associated with the upregulation of cell-cycle and DNA repair pathways, characterized by mutated TP53, MYC/TERT amplification, and APC/PTEN deletion. Our analysis highlights the importance of the ubiquitin pathway in cancer development and lays a foundation for developing relevant therapeutic strategies. : Ge et al. analyze a cohort of 9,125 TCGA samples across 33 cancer types to provide a comprehensive characterization of the ubiquitin pathway. They detect somatic driver candidates in the ubiquitin pathway and identify a cluster of patients with poor survival, highlighting the importance of this pathway in cancer development. Keywords: ubiquitin pathway, pan-cancer analysis, The Cancer Genome Atlas, tumor subtype, cancer prognosis, therapeutic targets, biomarker, FBXW7
Published: 2018
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17. Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

Author: Joshua D. Campbell, Christina Yau, Reanne Bowlby, Yuexin Liu, Kevin Brennan, Huihui Fan, Alison M. Taylor, Chen Wang, Vonn Walter, Rehan Akbani, Lauren Averett Byers, Chad J. Creighton, Cristian Coarfa, Juliann Shih, Andrew D. Cherniack, Olivier Gevaert, Marcos Prunello, Hui Shen, Pavana Anur, Jianhong Chen, Hui Cheng, D. Neil Hayes, Susan Bullman, Chandra Sekhar Pedamallu, Akinyemi I. Ojesina, Sara Sadeghi, Karen L. Mungall, A. Gordon Robertson, Christopher Benz, Andre Schultz, Rupa S. Kanchi, Carl M. Gay, Apurva Hegde, Lixia Diao, Jing Wang, Wencai Ma, Pavel Sumazin, Hua-Sheng Chiu, Ting-Wen Chen, Preethi Gunaratne, Larry Donehower, Janet S. Rader, Rosemary Zuna, Hikmat Al-Ahmadie, Alexander J. Lazar, Elsa R. Flores, Kenneth Y. Tsai, Jane H. Zhou, Anil K. Rustgi, Esther Drill, Ronglei Shen, Christopher K. Wong, Joshua M. Stuart, Peter W. Laird, Katherine A. Hoadley, John N. Weinstein, Myron Peto, Curtis R. Pickering, Zhong Chen, Carter Van Waes, Samantha J. Caesar-Johnson, John A. Demchok, Ina Felau, Melpomeni Kasapi, Martin L. Ferguson, Carolyn M. Hutter, Heidi J. Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Sudha Chudamani, Jia Liu, Laxmi Lolla, Rashi Naresh, Todd Pihl, Qiang Sun, Yunhu Wan, Ye Wu, Juok Cho, Timothy DeFreitas, Scott Frazer, Nils Gehlenborg, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Sam Meier, Michael S. Noble, Gordon Saksena, Doug Voet, Hailei Zhang, Brady Bernard, Nyasha Chambwe, Varsha Dhankani, Theo Knijnenburg, Roger Kramer, Kalle Leinonen, Michael Miller, Sheila Reynolds, Ilya Shmulevich, Vesteinn Thorsson, Wei Zhang, Bradley M. Broom, Apurva M. Hegde, Zhenlin Ju, Anil Korkut, Jun Li, Han Liang, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kwok-Shing Ng, Arvind Rao, Michael Ryan, Jiexin Zhang, Adam Abeshouse, Joshua Armenia, Debyani Chakravarty, Walid K. Chatila, Ino de Bruijn, Jianjiong Gao, Benjamin E. Gross, Zachary J. Heins, Ritika Kundra, Konnor La, Marc Ladanyi, Augustin Luna, Moriah G. Nissan, Angelica Ochoa, Sarah M. Phillips, Ed Reznik, Francisco Sanchez-Vega, Chris Sander, Nikolaus Schultz, Robert Sheridan, S. Onur Sumer, Yichao Sun, Barry S. Taylor, Jioajiao Wang, Hongxin Zhang, Paul Spellman, Joel S. Parker, Matthew D. Wilkerson, Adrian Ally, Miruna Balasundaram, Denise Brooks, Rebecca Carlsen, Eric Chuah, Noreen Dhalla, Robert Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Yussanne Ma, Marco A. Marra, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Karen Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Kane Tse, Tina Wong, Ashton C. Berger, Rameen Beroukhim, Carrie Cibulskis, Stacey B. Gabriel, Galen F. Gao, Gavin Ha, Matthew Meyerson, Steven E. Schumacher, Melanie H. Kucherlapati, Raju S. Kucherlapati, Stephen Baylin, Leslie Cope, Ludmila Danilova, Moiz S. Bootwalla, Phillip H. Lai, Dennis T. Maglinte, David J. Van Den Berg, Daniel J. Weisenberger, J. Todd Auman, Saianand Balu, Tom Bodenheimer, Cheng Fan, Alan P. Hoyle, Stuart R. Jefferys, Corbin D. Jones, Shaowu Meng, Piotr A. Mieczkowski, Lisle E. Mose, Amy H. Perou, Charles M. Perou, Jeffrey Roach, Yan Shi, Janae V. Simons, Tara Skelly, Matthew G. Soloway, Donghui Tan, Umadevi Veluvolu, Toshinori Hinoue, Wanding Zhou, Michelle Bellair, Kyle Chang, Kyle Covington, Huyen Dinh, HarshaVardhan Doddapaneni, Lawrence A. Donehower, Jennifer Drummond, Richard A. Gibbs, Robert Glenn, Walker Hale, Yi Han, Jianhong Hu, Viktoriya Korchina, Sandra Lee, Lora Lewis, Wei Li, Xiuping Liu, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Margi Sheth, Eve Shinbrot, Linghua Wang, Min Wang, David A. Wheeler, Liu Xi, Fengmei Zhao, Julian Hess, Elizabeth L. Appelbaum, Matthew Bailey, Matthew G. Cordes, Li Ding, Catrina C. Fronick, Lucinda A. Fulton, Robert S. Fulton, Cyriac Kandoth, Elaine R. Mardis, Michael D. McLellan, Christopher A. Miller, Heather K. Schmidt, Richard K. Wilson, Daniel Crain, Erin Curley, Johanna Gardner, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Candace Shelton, Troy Shelton, Mark Sherman, Eric Thompson, Peggy Yena, Jay Bowen, Julie M. Gastier-Foster, Mark Gerken, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Niall Corcoran, Tony Costello, Christopher Hovens, Andre L. Carvalho, Ana C. de Carvalho, José H. Fregnani, Adhemar Longatto-Filho, Rui M. Reis, Cristovam Scapulatempo-Neto, Henrique C.S. Silveira, Daniel O. Vidal, Andrew Burnette, Jennifer Eschbacher, Beth Hermes, Ardene Noss, Rosy Singh, Matthew L. Anderson, Patricia D. Castro, Michael Ittmann, David Huntsman, Bernard Kohl, Xuan Le, Richard Thorp, Chris Andry, Elizabeth R. Duffy, Vladimir Lyadov, Oxana Paklina, Galiya Setdikova, Alexey Shabunin, Mikhail Tavobilov, Christopher McPherson, Ronald Warnick, Ross Berkowitz, Daniel Cramer, Colleen Feltmate, Neil Horowitz, Adam Kibel, Michael Muto, Chandrajit P. Raut, Andrei Malykh, Jill S. Barnholtz-Sloan, Wendi Barrett, Karen Devine, Jordonna Fulop, Quinn T. Ostrom, Kristen Shimmel, Yingli Wolinsky, Andrew E. Sloan, Agostino De Rose, Felice Giuliante, Marc Goodman, Beth Y. Karlan, Curt H. Hagedorn, John Eckman, Jodi Harr, Jerome Myers, Kelinda Tucker, Leigh Anne Zach, Brenda Deyarmin, Hai Hu, Leonid Kvecher, Caroline Larson, Richard J. Mural, Stella Somiari, Ales Vicha, Tomas Zelinka, Joseph Bennett, Mary Iacocca, Brenda Rabeno, Patricia Swanson, Mathieu Latour, Louis Lacombe, Bernard Têtu, Alain Bergeron, Mary McGraw, Susan M. Staugaitis, John Chabot, Hanina Hibshoosh, Antonia Sepulveda, Tao Su, Timothy Wang, Olga Potapova, Olga Voronina, Laurence Desjardins, Odette Mariani, Sergio Roman-Roman, Xavier Sastre, Marc-Henri Stern, Feixiong Cheng, Sabina Signoretti, Andrew Berchuck, Darell Bigner, Eric Lipp, Jeffrey Marks, Shannon McCall, Roger McLendon, Angeles Secord, Alexis Sharp, Madhusmita Behera, Daniel J. Brat, Amy Chen, Keith Delman, Seth Force, Fadlo Khuri, Kelly Magliocca, Shishir Maithel, Jeffrey J. Olson, Taofeek Owonikoko, Alan Pickens, Suresh Ramalingam, Dong M. Shin, Gabriel Sica, Erwin G. Van Meir, Hongzheng Zhang, Wil Eijckenboom, Ad Gillis, Esther Korpershoek, Leendert Looijenga, Wolter Oosterhuis, Hans Stoop, Kim E. van Kessel, Ellen C. Zwarthoff, Chiara Calatozzolo, Lucia Cuppini, Stefania Cuzzubbo, Francesco DiMeco, Gaetano Finocchiaro, Luca Mattei, Alessandro Perin, Bianca Pollo, Chu Chen, John Houck, Pawadee Lohavanichbutr, Arndt Hartmann, Christine Stoehr, Robert Stoehr, Helge Taubert, Sven Wach, Bernd Wullich, Witold Kycler, Dawid Murawa, Maciej Wiznerowicz, Ki Chung, W. Jeffrey Edenfield, Julie Martin, Eric Baudin, Glenn Bubley, Raphael Bueno, Assunta De Rienzo, William G. Richards, Steven Kalkanis, Tom Mikkelsen, Houtan Noushmehr, Lisa Scarpace, Nicolas Girard, Marta Aymerich, Elias Campo, Eva Giné, Armando López Guillermo, Nguyen Van Bang, Phan Thi Hanh, Bui Duc Phu, Yufang Tang, Howard Colman, Kimberley Evason, Peter R. Dottino, John A. Martignetti, Hani Gabra, Hartmut Juhl, Teniola Akeredolu, Serghei Stepa, Dave Hoon, Keunsoo Ahn, Koo Jeong Kang, Felix Beuschlein, Anne Breggia, Michael Birrer, Debra Bell, Mitesh Borad, Alan H. Bryce, Erik Castle, Vishal Chandan, John Cheville, John A. Copland, Michael Farnell, Thomas Flotte, Nasra Giama, Thai Ho, Michael Kendrick, Jean-Pierre Kocher, Karla Kopp, Catherine Moser, David Nagorney, Daniel O’Brien, Brian Patrick O’Neill, Tushar Patel, Gloria Petersen, Florencia Que, Michael Rivera, Lewis Roberts, Robert Smallridge, Thomas Smyrk, Melissa Stanton, R. Houston Thompson, Michael Torbenson, Ju Dong Yang, Lizhi Zhang, Fadi Brimo, Jaffer A. Ajani, Ana Maria Angulo Gonzalez, Carmen Behrens, Jolanta Bondaruk, Russell Broaddus, Bogdan Czerniak, Bita Esmaeli, Junya Fujimoto, Jeffrey Gershenwald, Charles Guo, Christopher Logothetis, Funda Meric-Bernstam, Cesar Moran, Lois Ramondetta, David Rice, Anil Sood, Pheroze Tamboli, Timothy Thompson, Patricia Troncoso, Anne Tsao, Ignacio Wistuba, Candace Carter, Lauren Haydu, Peter Hersey, Valerie Jakrot, Hojabr Kakavand, Richard Kefford, Kenneth Lee, Georgina Long, Graham Mann, Michael Quinn, Robyn Saw, Richard Scolyer, Kerwin Shannon, Andrew Spillane, onathan Stretch, Maria Synott, John Thompson, James Wilmott, Timothy A. Chan, Ronald Ghossein, Anuradha Gopalan, Douglas A. Levine, Victor Reuter, Samuel Singer, Bhuvanesh Singh, Nguyen Viet Tien, Thomas Broudy, Cyrus Mirsaidi, Praveen Nair, Paul Drwiega, Judy Miller, Jennifer Smith, Howard Zaren, Joong-Won Park, Nguyen Phi Hung, Electron Kebebew, W. Marston Linehan, Adam R. Metwalli, Karel Pacak, Peter A. Pinto, Mark Schiffman, Laura S. Schmidt, Cathy D. Vocke, Nicolas Wentzensen, Robert Worrell, Hannah Yang, Marc Moncrieff, Chandra Goparaju, Jonathan Melamed, Harvey Pass, Natalia Botnariuc, Irina Caraman, Mircea Cernat, Inga Chemencedji, Adrian Clipca, Serghei Doruc, Ghenadie Gorincioi, Sergiu Mura, Maria Pirtac, Irina Stancul, Diana Tcaciuc, Monique Albert, Iakovina Alexopoulou, Angel Arnaout, John Bartlett, Jay Engel, Sebastien Gilbert, Jeremy Parfitt, Harman Sekhon, George Thomas, Doris M. Rassl, Robert C. Rintoul, Carlo Bifulco, Raina Tamakawa, Walter Urba, Nicholas Hayward, Henri Timmers, Anna Antenucci, Francesco Facciolo, Gianluca Grazi, Mirella Marino, Roberta Merola, Ronald de Krijger, Anne-Paule Gimenez-Roqueplo, Alain Piché, Simone Chevalier, Ginette McKercher, Kivanc Birsoy, Gene Barnett, Cathy Brewer, Carol Farver, Theresa Naska, Nathan A. Pennell, Daniel Raymond, Cathy Schilero, Kathy Smolenski, Felicia Williams, Carl Morrison, Jeffrey A. Borgia, Michael J. Liptay, Mark Pool, Christopher W. Seder, Kerstin Junker, Larsson Omberg, Mikhail Dinkin, George Manikhas, Domenico Alvaro, Maria Consiglia Bragazzi, Vincenzo Cardinale, Guido Carpino, Eugenio Gaudio, David Chesla, Sandra Cottingham, Michael Dubina, Fedor Moiseenko, Renumathy Dhanasekaran, Karl-Friedrich Becker, Klaus-Peter Janssen, Julia Slotta-Huspenina, Mohamed H. Abdel-Rahman, Dina Aziz, Sue Bell, Colleen M. Cebulla, Amy Davis, Rebecca Duell, J. Bradley Elder, Joe Hilty, Bahavna Kumar, James Lang, Norman L. Lehman, Randy Mandt, Phuong Nguyen, Robert Pilarski, Karan Rai, Lynn Schoenfield, Kelly Senecal, Paul Wakely, Paul Hansen, Ronald Lechan, James Powers, Arthur Tischler, William E. Grizzle, Katherine C. Sexton, Alison Kastl, Joel Henderson, Sima Porten, Jens Waldmann, Martin Fassnacht, Sylvia L. Asa, Dirk Schadendorf, Marta Couce, Markus Graefen, Hartwig Huland, Guido Sauter, Thorsten Schlomm, Ronald Simon, Pierre Tennstedt, Oluwole Olabode, Mark Nelson, Oliver Bathe, Peter R. Carroll, June M. Chan, Philip Disaia, Pat Glenn, Robin K. Kelley, Charles N. Landen, Joanna Phillips, Michael Prados, Jeffry Simko, Karen Smith-McCune, Scott VandenBerg, Kevin Roggin, Ashley Fehrenbach, Ady Kendler, Suzanne Sifri, Ruth Steele, Antonio Jimeno, Francis Carey, Ian Forgie, Massimo Mannelli, Michael Carney, Brenda Hernandez, Benito Campos, Christel Herold-Mende, Christin Jungk, Andreas Unterberg, Andreas von Deimling, Aaron Bossler, Joseph Galbraith, Laura Jacobus, Michael Knudson, Tina Knutson, Deqin Ma, Mohammed Milhem, Rita Sigmund, Andrew K. Godwin, Rashna Madan, Howard G. Rosenthal, Clement Adebamowo, Sally N. Adebamowo, Alex Boussioutas, David Beer, Thomas Giordano, Anne-Marie Mes-Masson, Fred Saad, Therese Bocklage, Lisa Landrum, Robert Mannel, Kathleen Moore, Katherine Moxley, Russel Postier, Joan Walker, Michael Feldman, Federico Valdivieso, Rajiv Dhir, James Luketich, Edna M. Mora Pinero, Mario Quintero-Aguilo, Carlos Gilberto Carlotti, Jr., Jose Sebastião Dos Santos, Rafael Kemp, Ajith Sankarankuty, Daniela Tirapelli, James Catto, Kathy Agnew, Elizabeth Swisher, Jenette Creaney, Bruce Robinson, Carl Simon Shelley, Eryn M. Godwin, Sara Kendall, Cassaundra Shipman, Carol Bradford, Thomas Carey, Andrea Haddad, Jeffey Moyer, Lisa Peterson, Mark Prince, Laura Rozek, Gregory Wolf, Rayleen Bowman, Kwun M. Fong, Ian Yang, Robert Korst, W. Kimryn Rathmell, J. Leigh Fantacone-Campbell, Jeffrey A. Hooke, Albert J. Kovatich, Craig D. Shriver, John DiPersio, Bettina Drake, Ramaswamy Govindan, Sharon Heath, Timothy Ley, Brian Van Tine, Peter Westervelt, Mark A. Rubin, Jung Il Lee, Natália D. Aredes, and Armaz Mariamidze
Subjects: Biology (General), QH301-705.5
Abstract: Summary: This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches. : Campbell et al. reveal that squamous cell cancers from different tissue sites may be distinguished from other cancers and subclassified molecularly by recurrent alterations in chromosomes, DNA methylation, messenger and microRNA expression, or by mutations. These affect squamous cell pathways and programs that provide candidates for therapy. Keywords: genomics, transcriptomics, proteomics, head and neck squamous cell carcinoma, lung squamous cell carcinoma, esophageal squamous cell carcinoma, cervical squamous cell carcinoma, bladder carcinoma with squamous differentiation, human papillomavirus
Published: 2018
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18. Identification of autoantibodies to ECH1 and HNRNPA2B1 as potential biomarkers in the early detection of lung cancer

Author: Liping Dai, Jitian Li, Jun-Chieh J. Tsay, Ting-An Yie, John S. Munger, Harvey Pass, William N. Rom, Eng M. Tan, and Jian-Ying Zhang
Subjects: autoantibody, ech1, hnrnpa2b1, lung cancer, serological proteome analysis (serpa), Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Identification of biomarkers for early detection of lung cancer (LC) is important, in turn leading to more effective treatment and reduction of mortality. Serological proteome analysis (SERPA) was used to identify proteins around 34 kD as ECH1 and HNRNPA2B1, which had been recognized by serum autoantibody from 25 LC patients. In the validation study, including 90 sera from LC patients and 89 sera from normal individuals, autoantibody to ECH1 achieved an area under the curve (AUC) of 0.799 with sensitivity of 62.2% and specificity of 95.5% in discriminating LC from normal individuals, and showed negative correlation with tumor size (rs = −0.256, p = 0.023). Autoantibody to HNRNPA2B1 performed an AUC of 0.874 with sensitivity of 72.2% and specificity of 95.5%, and showed negative correlation with lymph node metastasis (rs = −0.279, p = 0.012). By using longitudinal preclinical samples, autoantibody to ECH1 showed an AUC of 0.763 with sensitivity of 60.0% and specificity of 89.3% in distinguishing early stage LC from matched normal controls, and elevated autoantibody levels could be detected greater than 2 y before LC diagnosis. ECH1 and HNRNPA2B1 are autoantigens that elicit autoimmune responses in LC and their autoantibody can be the potential biomarkers for the early detection of LC.
Published: 2017
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19. Inflammasome Modulation by Chemotherapeutics in Malignant Mesothelioma.

Author: Catherine Westbom, Joyce K Thompson, Alan Leggett, Maximilian MacPherson, Stacie Beuschel, Harvey Pass, Pamela Vacek, and Arti Shukla
Subjects: Medicine, Science
Abstract: Malignant mesothelioma (MM) is a fatal disease in dire need of therapy. The role of inflammasomes in cancer is not very well studied, however, literature supports both pro-and anti-tumorigenic effects of inflammasomes on cancer depending upon the type of cancer. Asbestos is a causative agent for MM and we have shown before that it causes inflammasome priming and activation in mesothelial cells. MM tumor cells/tissues showed decreased levels of inflammasome components like NLRP3 and caspase-1 as compared to human mesothelial cells or normal tissue counterpart of tumor. Based on our preliminary findings we hypothesized that treatment of MMs with chemotherapeutic drugs may elevate the levels of NLRP3 and caspase-1 resulting in increased cell death by pyroptosis while increasing the levels of IL-1β and other pro-inflammatory molecules. Therefore, a combined strategy of chemotherapeutic drug and IL-1R antagonist may play a beneficial role in MM therapy. To test our hypothesis we used two human MM tumor cell lines (Hmeso, H2373) and two chemotherapeutic drugs (doxorubicin, cisplatin). Through a series of experiments we showed that both chemotherapeutic drugs caused increases in NLRP3 levels, caspase-1 activation, pyroptosis and pro-inflammatory molecules released from MM cells. In vivo studies using SCID mice and Hmeso cells showed that tumors were smaller in combined treatment group of cisplatin and IL-1R antagonist (Anakinra) as compared to cisplatin alone or untreated control groups. Taken together our study suggests that chemotherapeutic drugs in combination with IL-1R antagonist may have a beneficial role in MM treatment.
Published: 2015
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20. Molecular characterization of the peripheral airway field of cancerization in lung adenocarcinoma.

Author: Jun-Chieh J Tsay, Zhiguo Li, Ting-An Yie, Feng Wu, Leopoldo Segal, Alissa K Greenberg, Eric Leibert, Michael D Weiden, Harvey Pass, John Munger, Alexander Statnikov, Kam-Meng Tchou-Wong, and William N Rom
Subjects: Medicine, Science
Abstract: Field of cancerization in the airway epithelium has been increasingly examined to understand early pathogenesis of non-small cell lung cancer. However, the extent of field of cancerization throughout the lung airways is unclear. Here we sought to determine the differential gene and microRNA expressions associated with field of cancerization in the peripheral airway epithelial cells of patients with lung adenocarcinoma. We obtained peripheral airway brushings from smoker controls (n=13) and from the lung contralateral to the tumor in cancer patients (n=17). We performed gene and microRNA expression profiling on these peripheral airway epithelial cells using Affymetrix GeneChip and TaqMan Array. Integrated gene and microRNA analysis was performed to identify significant molecular pathways. We identified 26 mRNAs and 5 miRNAs that were significantly (FDR
Published: 2015
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21. Development of a biosensor for detection of pleural mesothelioma cancer biomarker using surface imprinting.

Author: Aabhas Mathur, Steven Blais, Chandra M V Goparaju, Thomas Neubert, Harvey Pass, and Kalle Levon
Subjects: Medicine, Science
Abstract: Hyaluronan-linked protein 1 (HAPLN1) which has been shown to be highly expressed in malignant pleural mesotheliomas (MPM), was detected in serum using an electrochemical surface-imprinting method. First, the detection method was optimized using Bovine serum albumin (BSA) as a model protein to mimic the optimal conditions required to imprint the similar molecular weight protein HAPLN1. BSA was imprinted on the gold electrode with hydroxyl terminated alkane thiols, which formed a self-assembled monolayer (SAM) around BSA. The analyte (BSA) was then washed away and its imprint (empty cavity with shape-memory) was used for detection of BSA in a solution, using electrochemical open-circuit potential method, namely potentiometry. Factors considered to optimize the conditions include incubation time, protein concentration, limit of detection and size of electrode. Matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) was used to confirm selectivity of imprints. With the obtained imprinting control parameters, HAPLN1 was imprinted in duplicate and the detection of spiked HAPLN1 was successfully conducted in serum.
Published: 2013
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22. Peroxiredoxin 3 is a redox-dependent target of thiostrepton in malignant mesothelioma cells.

Author: Kheng Newick, Brian Cunniff, Kelsey Preston, Paul Held, Jack Arbiser, Harvey Pass, Brooke Mossman, Arti Shukla, and Nicholas Heintz
Subjects: Medicine, Science
Abstract: Thiostrepton (TS) is a thiazole antibiotic that inhibits expression of FOXM1, an oncogenic transcription factor required for cell cycle progression and resistance to oncogene-induced oxidative stress. The mechanism of action of TS is unclear and strategies that enhance TS activity will improve its therapeutic potential. Analysis of human tumor specimens showed FOXM1 is broadly expressed in malignant mesothelioma (MM), an intractable tumor associated with asbestos exposure. The mechanism of action of TS was investigated in a cell culture model of human MM. As for other tumor cell types, TS inhibited expression of FOXM1 in MM cells in a dose-dependent manner. Suppression of FOXM1 expression and coincidental activation of ERK1/2 by TS were abrogated by pre-incubation of cells with the antioxidant N-acetyl-L-cysteine (NAC), indicating its mechanism of action in MM cells is redox-dependent. Examination of the mitochondrial thioredoxin reductase 2 (TR2)-thioredoxin 2 (TRX2)-peroxiredoxin 3 (PRX3) antioxidant network revealed that TS modifies the electrophoretic mobility of PRX3. Incubation of recombinant human PRX3 with TS in vitro also resulted in PRX3 with altered electrophoretic mobility. The cellular and recombinant species of modified PRX3 were resistant to dithiothreitol and SDS and suppressed by NAC, indicating that TS covalently adducts cysteine residues in PRX3. Reduction of endogenous mitochondrial TRX2 levels by the cationic triphenylmethane gentian violet (GV) promoted modification of PRX3 by TS and significantly enhanced its cytotoxic activity. Our results indicate TS covalently adducts PRX3, thereby disabling a major mitochondrial antioxidant network that counters chronic mitochondrial oxidative stress. Redox-active compounds like GV that modify the TR2/TRX2 network may significantly enhance the efficacy of TS, thereby providing a combinatorial approach for exploiting redox-dependent perturbations in mitochondrial function as a therapeutic approach in mesothelioma.
Published: 2012
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23. CT scan screening for lung cancer: risk factors for nodules and malignancy in a high-risk urban cohort.

Author: Alissa K Greenberg, Feng Lu, Judith D Goldberg, Ellen Eylers, Jun-Chieh Tsay, Ting-An Yie, David Naidich, Georgeann McGuinness, Harvey Pass, Kam-Meng Tchou-Wong, Doreen Addrizzo-Harris, Abraham Chachoua, Bernard Crawford, and William N Rom
Subjects: Medicine, Science
Abstract: Low-dose computed tomography (CT) for lung cancer screening can reduce lung cancer mortality. The National Lung Screening Trial reported a 20% reduction in lung cancer mortality in high-risk smokers. However, CT scanning is extremely sensitive and detects non-calcified nodules (NCNs) in 24-50% of subjects, suggesting an unacceptably high false-positive rate. We hypothesized that by reviewing demographic, clinical and nodule characteristics, we could identify risk factors associated with the presence of nodules on screening CT, and with the probability that a NCN was malignant.We performed a longitudinal lung cancer biomarker discovery trial (NYU LCBC) that included low-dose CT-screening of high-risk individuals over 50 years of age, with more than 20 pack-year smoking histories, living in an urban setting, and with a potential for asbestos exposure. We used case-control studies to identify risk factors associated with the presence of nodules (n=625) versus no nodules (n=557), and lung cancer patients (n=30) versus benign nodules (n=128).The NYU LCBC followed 1182 study subjects prospectively over a 10-year period. We found 52% to have NCNs >4 mm on their baseline screen. Most of the nodules were stable, and 9.7% of solid and 26.2% of sub-solid nodules resolved. We diagnosed 30 lung cancers, 26 stage I. Three patients had synchronous primary lung cancers or multifocal disease. Thus, there were 33 lung cancers: 10 incident, and 23 prevalent. A sub-group of the prevalent group were stable for a prolonged period prior to diagnosis. These were all stage I at diagnosis and 12/13 were adenocarcinomas.NCNs are common among CT-screened high-risk subjects and can often be managed conservatively. Risk factors for malignancy included increasing age, size and number of nodules, reduced FEV1 and FVC, and increased pack-years smoking. A sub-group of screen-detected cancers are slow-growing and may contribute to over-diagnosis and lead-time biases.
Published: 2012
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24. New insight into the molecular mechanisms of the biological effects of DNA minor groove binders.

Author: Xinbo Zhang, Siyu Crystal Zhang, Dejun Sun, Jiang Hu, Anil Wali, Harvey Pass, Felix Fernandez-Madrid, Michael R Harbut, and Naimei Tang
Subjects: Medicine, Science
Abstract: Bisbenzimides, or Hoechst 33258 (H258), and its derivative Hoechst 33342 (H342) are archetypal molecules for designing minor groove binders, and widely used as tools for staining DNA and analyzing side population cells. They are supravital DNA minor groove binders with AT selectivity. H342 and H258 share similar biological effects based on the similarity of their chemical structures, but also have their unique biological effects. For example, H342, but not H258, is a potent apoptotic inducer and both H342 and H258 can induce transgene overexpression in in vitro studies. However, the molecular mechanisms by which Hoechst dyes induce apoptosis and enhance transgene overexpression are unclear.To determine the molecular mechanisms underlying different biological effects between H342 and H258, microarray technique coupled with bioinformatics analyses and multiple other techniques has been utilized to detect differential global gene expression profiles, Hoechst dye-specific gene expression signatures, and changes in cell morphology and levels of apoptosis-associated proteins in malignant mesothelioma cells. H342-induced apoptosis occurs in a dose-dependent fashion and is associated with morphological changes, caspase-3 activation, cytochrome c mitochondrial translocation, and cleavage of apoptosis-associated proteins. The antagonistic effect of H258 on H342-induced apoptosis indicates a pharmacokinetic basis for the two dyes' different biological effects. Differential global gene expression profiles induced by H258 and H342 are accompanied by unique gene expression signatures determined by DNA microarray and bioinformatics software, indicating a genetic basis for their different biological effects.A unique gene expression signature associated with H342-induced apoptosis provides a new avenue to predict and classify the therapeutic class of minor groove binders in the drug development process. Further analysis of H258-upregulated genes of transcription regulation may identify the genes that enhance transgene overexpression in gene therapy and promote recombinant protein products in biopharmaceutical companies.The microarray data reported in this article have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession no.GSE28616).
Published: 2011
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25. IASLC Lung Cancer Staging Project: The New Database to Inform Revisions in the Ninth Edition of the TNM Classification of Lung Cancer

Author: Hisao Asamura, Katherine K. Nishimura, Dorothy J. Giroux, Kari Chansky, Antje Hoering, Valerie Rusch, Ramón Rami-Porta, Luiz Henrique Araujo, David Beer, Pietro Bertoglio, Ricardo Beyruti, Andrea Billè, Souheil Boubia, Elisabeth Brambilla, A.K. Cangir, David Carbone, Vanessa Cilento, Casey Connolly, Gail Darling, Frank Detterbeck, Daniel Dibaba, Xavier Benoit D’Journo, Jessica Donington, Wilfried Eberhardt, John Edwards, Jeremy Erasmus, Wentao Fang, Dean Fennell, Kwun Fong, Françoise Galateau-Sallé, Oliver Gautschi, Ritu R. Gill, Dorothy Giroux, Meredith Giuliani, Jin Mo Goo, Seiki Hasegawa, Fred Hirsch, Hans Hoffman, Wayne Hofstetter, James Huang, Philippe Joubert, Kemp Kernstine, Keith Kerr, Young Tae Kim, Dong Kwan Kim, Hedy Kindler, Yolande Lievens, Hui Liu, Donald E. Low, Gustavo Lyons, Heber MacMahon, Alyson Mahar, Mirella Marino, Edith M. Marom, José-María Matilla, Jan van Meerbeeck, Luis M. Montuenga, Andrew Nicholson, Katie Nishimura, Anna Nowak, Isabelle Opitz, Meinoshin Okumura, Raymond U. Osarogiagbon, Harvey Pass, Marc de Perrot, Helmut Prosch, David Rice, Andreas Rimner, Adam Rosenthal, Enrico Rufﬁni, Shuji Sakai, Paul Van Schil, Navneet Singh, Francisco Suárez, Ricardo M. Terra, William D. Travis, Ming S. Tsao, Paula Ugalde, Shun-ichi Watanabe, Ignacio Wistuba, Murry Wynes, and Yasushi Yatabe
Subjects: Pulmonary and Respiratory Medicine, Oncology
Published: 2023

26. DNA Methylation Profiling Identifies Subgroups of Lung Adenocarcinoma with Distinct Immune Cell Composition, DNA Methylation Age, and Clinical Outcome

Author: Kayla Guidry, Varshini Vasudevaraja, Kristen Labbe, Hussein Mohamed, Jonathan Serrano, Brett W. Guidry, Michael DeLorenzo, Hua Zhang, Jiehui Deng, Soumyadip Sahu, Christina Almonte, Andre L. Moreira, Aristotelis Tsirigos, Thales Papagiannakopoulos, Harvey Pass, Matija Snuderl, and Kwok-Kin Wong
Subjects: Cancer Research, Lung Neoplasms, Oncology, Mutation, Tumor Microenvironment, Humans, Adenocarcinoma of Lung, Adenocarcinoma, DNA Methylation
Abstract: Purpose: Lung adenocarcinoma (LUAD) is a clinically heterogeneous disease, which is highlighted by the unpredictable recurrence in low-stage tumors and highly variable responses observed in patients treated with immunotherapies, which cannot be explained by mutational profiles. DNA methylation–based classification and understanding of microenviromental heterogeneity may allow stratification into clinically relevant molecular subtypes of LUADs. Experimental Design: We characterize the genome-wide DNA methylation landscape of 88 resected LUAD tumors. Exome sequencing focusing on a panel of cancer-related genes was used to genotype these adenocarcinoma samples. Bioinformatic and statistical tools, the immune cell composition, DNA methylation age (DNAm age), and DNA methylation clustering were used to identify clinically relevant subgroups. Results: Deconvolution of DNA methylation data identified immunologically hot and cold subsets of LUADs. In addition, concurrent factors were analyzed that could affect the immune microenvironment, such as smoking history, ethnicity, or presence of KRAS or TP53 mutations. When the DNAm age was calculated, a lower DNAm age was correlated with the presence of a set of oncogenic drivers, poor overall survival, and specific immune cell populations. Unsupervised DNA methylation clustering identified six molecular subgroups of LUAD tumors with distinct clinical and microenvironmental characteristics. Conclusions: Our results demonstrate that DNA methylation signatures can stratify LUAD into clinically relevant subtypes, and thus such classification of LUAD at the time of resection may lead to better methods in predicting tumor recurrence and therapy responses.
Published: 2022

27. The International Association for the Study of Lung Cancer Thymic Epithelial Tumor Staging Project: Unresolved Issues to be Addressed for the Next Ninth Edition of the TNM Classification of Malignant Tumors

Author: Enrico Ruffini, Ramon Rami-Porta, James Huang, Usman Ahmad, Sarit Appel, Andrea Bille, Souheil Boubia, Cecilia Brambilla, Ayten Kayi Cangir, Vanessa Cilento, Frank Detterbeck, Conrad Falkson, Wentao Fang, Pier Luigi Filosso, Giuseppe Giaccone, Nicolas Girard, Francesco Guerrera, Maurizio Infante, Dong Kwan Kim, Marco Lucchi, Mirella Marino, Edith M. Marom, Andrew G. Nicholson, Meinoshin Okumura, Andreas Rimner, Charles B. Simone, Hisao Asamura, Valerie Rusch, Luiz Henrique Araujo, David Beer, Pietro Bertoglio, Ricardo Beyruti, Elisabeth Brambilla, A.K. Cangir, Casey Connolly, Gail Darling, Daniel Dibaba, Xavier Benoit D’ Journo, Wilfried Eberhardt, Jeremy Erasmus, Dean Fennell, Kwun Fong, Françoise Galateau-Salle, Ritu R. Gill, Dorothy Giroux, Meredith Giuliani, Jin Mo Goo, Fred Hirsch, Hans Hoffman, Wayne Hofstetter, Philippe Joubert, Kemp Kernstine, Keith Kerr, Young Tae Kim, Yolande Lievens, Hui Liu, Donald E. Low, Gustavo Lyons, Heber MacMahon, José-María Matilla, Jan van Meerbeeck, Luis M. Montuenga, Andrew Nicholson, Katie Nishimura, Anna Nowak, Isabelle Opitz, Raymond U. Osarogiagbon, Harvey Pass, Marc de Perrot, David Rice, Adam Rosenthal, Shuji Sakai, Paul Van Schil, Navneet Singh, Francisco Suárez, Ricardo M. Terra, William D. Travis, Ming S. Tsao, Paula Ugalde, Shun-Ichi Watanabe, Ignacio Wistuba, Murry Wynes, Yasushi Yatabe, Samuel Armato, Lawek Berzenji, Alex Brunelli, Giuseppe Cardillo, Keneng Chen, Wendy Cooper, Liyan Jiang, Mark Krasnik, Kauro Kubota, Catherine Labbe, Ho Yun Lee, Eric Lim, Geoffrey Liu, Hongxu Liu, Philip Mack, David Naidich, Mizuki Nishino, Marcin Ostrowski, Charles Powell, Carolyn Presley, Paul Martin Putora, Harry Ren, M. Patricia Rivera, Gaetano Rocco, Maria Teresa Ruiz Tzukazan, Robert Samstein, Yu Yang Soon, Kenichi Suda, Martin Tammemägi, Akif Turna, Benny Weksler, Terence Williams, Dawei Yang, Jeff Yang, Masaya Yotsukura, Conrad B. Falkson, Mark Ferguson, Jennifer Sauter, Andrea Wolf, Pier Liugi Filosso, Hong Kwan Kim, and Hong Kwuan Kim
Subjects: Pulmonary and Respiratory Medicine, Lung Neoplasms, Oncology, Humans, Neoplasms, Glandular and Epithelial, Thymus Neoplasms, Prognosis, Neoplasm Staging
Abstract: Thymic epithelial tumors are presently staged using a consistent TNM classification developed by the International Association for the Study of Lung Cancer (IASLC) and approved by the Union for International Cancer Control and the American Joint Committee on Cancer. The stage classification is incorporated in the eight edition of the TNM classification of thoracic malignancies. The IASLC Staging and Prognostic Factors Committee (SPFC)-Thymic Domain (TD) is in charge for the next (ninth) edition expected in 2024. The present article represents the midterm report of the SPFC-TD: in particular, it describes the unresolved issues identified by the group in the current stage classification which are worth being addressed and discussed for the ninth edition of the TNM classification on the basis of the available data collected in the central thymic database which will be managed and analyzed by Cancer Research And Biostatistics. These issues are grouped into issues of general importance and those specifically related to T, N, and M categories. Each issue is described in reference to the most recent reports on the subject, and the priority assigned by the IASLC SPFC-TD for the discussion of the ninth edition is provided.
Published: 2022

28. Table S6 from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author: Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak
Abstract: Table S6 contains results from the analysis of DNA methylation in SETD2 mutated and BAP1 inactivated samples.
Published: 2023

29. Data from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author: Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak
Abstract: Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options.Significance:Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM.See related commentary by Aggarwal and Albelda, p. 1508.This article is highlighted in the In This Issue feature, p. 1494
Published: 2023

30. Supplementary Data from Integrative Molecular Characterization of Malignant Pleural Mesothelioma

Author: Erik Zmuda, Hongxin Zhang, Hailei Zhang, Jiashan Zhang, Jean C. Zenklusen, Marjorie G. Zauderer, Liming Yang, Shogo Yamamoto, Ye Wu, Tina Wong, Ignacio Wistuba, Lisa Wise, Matthew D. Wilkerson, Daniel J. Weisenberger, John N. Weinstein, Joellen Weaver, Jing Wang, Zhining Wang, Yunhu Wan, Douglas Voet, Luciano S. Viana, Umadevi Veluvolu, Nico van Zandwijk, David J. Van Den Berg, Federico Valdivieso, Tohru Tsujimura, Kane Tse, Anne Tsao, Eric Thompson, Nina Thiessen, Barry S Taylor, Kenji Tatsuno, Roy Tarnuzzer, Donghui Tan, Angela Tam, Qiang Sun, Josh Stuart, Chip Stewart, Paul Spellman, Matthew G. Soloway, Heidi J. Sofia, Tara Skelly, Payal Sipahimalani, Janae V. Simons, Henrique C. S. Silveira, Ilya Shmulevich, Yuichi Shiraishi, Yan Shi, Robert Sheridan, Troy Shelton, Candace Shelton, David T Severson, Tanguy Seiwert, Steven E. Schumacher, Nikolaus Schultz, Jacqueline E. Schein, Cristovam Scapulatempo-Neto, Ayuko Sato, Chris Sander, Gordon Saksena, Sara Sadeghi, Valerie Rusch, Jeffrey Roach, Robert C. Rintoul, William G Richards, David Rice, Sheila M. Reynolds, Rui M. Reis, Glen Reid, Gloria Ravegnini, Doris M. Rassl, Nilsa C. Ramirez, Todd Pihl, Charles M. Perou, Robert Penny, Nathan A. Pennell, Arjun Pennathur, Joseph Paulauskis, Harvey I. Pass, Joel S. Parker, Hatice Osmanbeyoglu, Angelica Ochoa, Yulia Newton, Rashi Naresh, Takashi Nakano, Karen Mungall, Andrew J. Mungall, Lisle E. Mose, Scott Morris, Cesar Moran, Richard A. Moore, Gordon B. Mills, Piotr A. Mieczkowski, Matthew Meyerson, Shaowu Meng, Jonathan Melamed, Sam Meier, Michael Mayo, Marco A. Marra, David Mallory, Dennis T. Maglinte, Yussanne Ma, James Luketich, Yiling Lu, Adhemar Longatto-Filho, Laxmi Lolla, Eric Minwei Liu, Wenbin Liu, Jia Liu, Pei Lin, Tara M. Lichtenberg, Kristen M. Leraas, Darlene Lee, Michael S. Lawrence, Peter W. Laird, Phillip H. Lai, David J. Kwiatkowski, Kozo Kuribayashi, Ritika Kundra, Thomas Krausz, Nobuyuki Kondo, Jaegil Kim, Katayoon Kasaian, Rupa S. Kanchi, Corbin D. Jones, Steven J.M. Jones, Stuart R. Jefferys, Carolyn M. Hutter, Aliya Husain, Alan P. Hoyle, Robert A. Holt, Katherine A. Hoadley, Zachary Heins, David I. Heiman, D. Neil Hayes, David Haussler, Seiki Hasegawa, Guangwu Guo, Benjamin Gross, Chandra Goparaju, Gad Getz, Mark Gerken, Nils Gehlenborg, Julie M. Gastier-Foster, Johanna Gardner, Jianjiong Gao, Françoise Galateau Sallé, Stacey B. Gabriel, Shiro Fukuda, Martin L. Ferguson, Michael Feldman, Rajiv Dhir, Noreen Dhalla, John A. Demchok, Timothy DeFreitas, Assunta De Rienzo, Ludmila Danilova, Erin Curley, Daniel Crain, Leslie Cope, Carrie Cibulskis, Sudha Chudamani, Eric Chuah, Juok Cho, Lucian Chirieac, Dorothy Cheung, Andrew D. Cherniack, Andre L. Carvalho, Rebecca Carlsen, Flávio M. Cárcano, Lauren Averett Byers, Denise Brooks, Moiz S. Bootwalla, Tom Bodenheimer, Craig Bielski, Rameen Beroukhim, Carmen Behrens, Michael Becich, Stephen B. Baylin, Saianand Balu, Miruna Balasundaram, J. Todd Auman, Joshua Armenia, Pavana Anur, Adrian Ally, Marc Ladanyi, Peter Campbell, Bruce W. Robinson, Hiroyuki Aburatani, Ronglai Shen, A. Gordon Robertson, Jonathan A. Fletcher, Michael S. Noble, Lauren A. Byers, Rehan Akbani, Jean Claude Zenklusen, Ina Felau, Jay Bowen, Kristen Leraas, Tara Lichtenberg, Jenette Creaney, Anne S. Tsao, Raphael Bueno, Hedy Kindler, Harvey Pass, Valerie W. Rusch, Henrique C. Silveira, Aliya N. Husain, Junya Fujimoto, Françoise Galateau-Sallé, Lucian R. Chirieac, Sanja Dacic, William D. Travis, Achim A. Jungbluth, Patrice Desmeules, David T. Severson, Havish Kantheti, Lisa Iype, Vesteinn Thorsson, David L. Gibbs, Lixia Diao, Carl M. Gay, Manaswi Gupta, Kiley Graim, Jumpei Takeshita, Yoshitaka Sekido, Hatice U. Osmanbeyoglu, Rupa Kanchi, Reanne Bowlby, Ewan A. Gibb, Esther Drill, Patrick Tarpey, David Heiman, Juliann Shih, Francisco Sanchez-Vega, and Julija Hmeljak
Abstract: Supplementary materials and methods, as well as supplementary figures S1-S7.
Published: 2023

31. Table S2 from A Gene Expression Classifier from Whole Blood Distinguishes Benign from Malignant Lung Nodules Detected by Low-Dose CT

Author: Louise C. Showe, Michael K. Showe, William N. Rom, Brian Nam, Thomas Bauer, Anil Vachani, Sai Yendamuri, Harvey Pass, Jun-Chieh J. Tsay, Gerard Criner, Eric Konnisto, Wen-Hwai Horng, Trisha Kumar, Sandy Widura, Celia Chang, R. Sonali Majumdar, Qin Liu, Jayamanna Wickramasinghe, Noor B. Dawany, Rehman Qureshi, and Andrew V. Kossenkov
Abstract: Number of samples used on different platforms for training and validation sets
Published: 2023

32. Supplementary File S1 from A Gene Expression Classifier from Whole Blood Distinguishes Benign from Malignant Lung Nodules Detected by Low-Dose CT

Author: Louise C. Showe, Michael K. Showe, William N. Rom, Brian Nam, Thomas Bauer, Anil Vachani, Sai Yendamuri, Harvey Pass, Jun-Chieh J. Tsay, Gerard Criner, Eric Konnisto, Wen-Hwai Horng, Trisha Kumar, Sandy Widura, Celia Chang, R. Sonali Majumdar, Qin Liu, Jayamanna Wickramasinghe, Noor B. Dawany, Rehman Qureshi, and Andrew V. Kossenkov
Abstract: Ranking of Nanostring Custom panel probes in nPNC classifier
Published: 2023

33. Figure S2 from A Gene Expression Classifier from Whole Blood Distinguishes Benign from Malignant Lung Nodules Detected by Low-Dose CT

Author: Louise C. Showe, Michael K. Showe, William N. Rom, Brian Nam, Thomas Bauer, Anil Vachani, Sai Yendamuri, Harvey Pass, Jun-Chieh J. Tsay, Gerard Criner, Eric Konnisto, Wen-Hwai Horng, Trisha Kumar, Sandy Widura, Celia Chang, R. Sonali Majumdar, Qin Liu, Jayamanna Wickramasinghe, Noor B. Dawany, Rehman Qureshi, and Andrew V. Kossenkov
Abstract: Performance of the Pulmonary Nodule Classifier
Published: 2023

34. Supplementary Data from DNA Methylation Profiling Identifies Subgroups of Lung Adenocarcinoma with Distinct Immune Cell Composition, DNA Methylation Age, and Clinical Outcome

Author: Kwok-Kin Wong, Matija Snuderl, Harvey Pass, Thales Papagiannakopoulos, Aristotelis Tsirigos, Andre L. Moreira, Christina Almonte, Soumyadip Sahu, Jiehui Deng, Hua Zhang, Michael DeLorenzo, Brett W. Guidry, Jonathan Serrano, Hussein Mohamed, Kristen Labbe, Varshini Vasudevaraja, and Kayla Guidry
Abstract: Supplementary Data from DNA Methylation Profiling Identifies Subgroups of Lung Adenocarcinoma with Distinct Immune Cell Composition, DNA Methylation Age, and Clinical Outcome
Published: 2023

35. Data from DNA Methylation Profiling Identifies Subgroups of Lung Adenocarcinoma with Distinct Immune Cell Composition, DNA Methylation Age, and Clinical Outcome

Author: Kwok-Kin Wong, Matija Snuderl, Harvey Pass, Thales Papagiannakopoulos, Aristotelis Tsirigos, Andre L. Moreira, Christina Almonte, Soumyadip Sahu, Jiehui Deng, Hua Zhang, Michael DeLorenzo, Brett W. Guidry, Jonathan Serrano, Hussein Mohamed, Kristen Labbe, Varshini Vasudevaraja, and Kayla Guidry
Abstract: Purpose:Lung adenocarcinoma (LUAD) is a clinically heterogeneous disease, which is highlighted by the unpredictable recurrence in low-stage tumors and highly variable responses observed in patients treated with immunotherapies, which cannot be explained by mutational profiles. DNA methylation–based classification and understanding of microenviromental heterogeneity may allow stratification into clinically relevant molecular subtypes of LUADs.Experimental Design:We characterize the genome-wide DNA methylation landscape of 88 resected LUAD tumors. Exome sequencing focusing on a panel of cancer-related genes was used to genotype these adenocarcinoma samples. Bioinformatic and statistical tools, the immune cell composition, DNA methylation age (DNAm age), and DNA methylation clustering were used to identify clinically relevant subgroups.Results:Deconvolution of DNA methylation data identified immunologically hot and cold subsets of LUADs. In addition, concurrent factors were analyzed that could affect the immune microenvironment, such as smoking history, ethnicity, or presence of KRAS or TP53 mutations. When the DNAm age was calculated, a lower DNAm age was correlated with the presence of a set of oncogenic drivers, poor overall survival, and specific immune cell populations. Unsupervised DNA methylation clustering identified six molecular subgroups of LUAD tumors with distinct clinical and microenvironmental characteristics.Conclusions:Our results demonstrate that DNA methylation signatures can stratify LUAD into clinically relevant subtypes, and thus such classification of LUAD at the time of resection may lead to better methods in predicting tumor recurrence and therapy responses.
Published: 2023

36. Supplementary Figure from DNA Methylation Profiling Identifies Subgroups of Lung Adenocarcinoma with Distinct Immune Cell Composition, DNA Methylation Age, and Clinical Outcome

Author: Kwok-Kin Wong, Matija Snuderl, Harvey Pass, Thales Papagiannakopoulos, Aristotelis Tsirigos, Andre L. Moreira, Christina Almonte, Soumyadip Sahu, Jiehui Deng, Hua Zhang, Michael DeLorenzo, Brett W. Guidry, Jonathan Serrano, Hussein Mohamed, Kristen Labbe, Varshini Vasudevaraja, and Kayla Guidry
Abstract: Supplementary Figure from DNA Methylation Profiling Identifies Subgroups of Lung Adenocarcinoma with Distinct Immune Cell Composition, DNA Methylation Age, and Clinical Outcome
Published: 2023

37. Data from A Gene Expression Classifier from Whole Blood Distinguishes Benign from Malignant Lung Nodules Detected by Low-Dose CT

Author: Louise C. Showe, Michael K. Showe, William N. Rom, Brian Nam, Thomas Bauer, Anil Vachani, Sai Yendamuri, Harvey Pass, Jun-Chieh J. Tsay, Gerard Criner, Eric Konnisto, Wen-Hwai Horng, Trisha Kumar, Sandy Widura, Celia Chang, R. Sonali Majumdar, Qin Liu, Jayamanna Wickramasinghe, Noor B. Dawany, Rehman Qureshi, and Andrew V. Kossenkov
Abstract: Low-dose CT (LDCT) is widely accepted as the preferred method for detecting pulmonary nodules. However, the determination of whether a nodule is benign or malignant involves either repeated scans or invasive procedures that sample the lung tissue. Noninvasive methods to assess these nodules are needed to reduce unnecessary invasive tests. In this study, we have developed a pulmonary nodule classifier (PNC) using RNA from whole blood collected in RNA-stabilizing PAXgene tubes that addresses this need. Samples were prospectively collected from high-risk and incidental subjects with a positive lung CT scan. A total of 821 samples from 5 clinical sites were analyzed. Malignant samples were predominantly stage 1 by pathologic diagnosis and 97% of the benign samples were confirmed by 4 years of follow-up. A panel of diagnostic biomarkers was selected from a subset of the samples assayed on Illumina microarrays that achieved a ROC-AUC of 0.847 on independent validation. The microarray data were then used to design a biomarker panel of 559 gene probes to be validated on the clinically tested NanoString nCounter platform. RNA from 583 patients was used to assess and refine the NanoString PNC (nPNC), which was then validated on 158 independent samples (ROC-AUC = 0.825). The nPNC outperformed three clinical algorithms in discriminating malignant from benign pulmonary nodules ranging from 6–20 mm using just 41 diagnostic biomarkers. Overall, this platform provides an accurate, noninvasive method for the diagnosis of pulmonary nodules in patients with non–small cell lung cancer.Significance:These findings describe a minimally invasive and clinically practical pulmonary nodule classifier that has good diagnostic ability at distinguishing benign from malignant pulmonary nodules.
Published: 2023

38. Results of Two Cases of Pig-to-Human Kidney Xenotransplantation

Author: Robert A. Montgomery, Jeffrey M. Stern, Bonnie E. Lonze, Vasishta S. Tatapudi, Massimo Mangiola, Ming Wu, Elaina Weldon, Nikki Lawson, Cecilia Deterville, Rebecca A. Dieter, Brigitte Sullivan, Gabriella Boulton, Brendan Parent, Greta Piper, Philip Sommer, Samantha Cawthon, Erin Duggan, David Ayares, Amy Dandro, Ana Fazio-Kroll, Maria Kokkinaki, Lars Burdorf, Marc Lorber, Jef D. Boeke, Harvey Pass, Brendan Keating, Adam Griesemer, Nicole M. Ali, Sapna A. Mehta, and Zoe A. Stewart
Subjects: Animals, Genetically Modified, Graft Rejection, Brain Death, Swine, Transplantation, Heterologous, Animals, Heterografts, Humans, General Medicine, Kidney, Kidney Transplantation
Abstract: Xenografts from genetically modified pigs have become one of the most promising solutions to the dearth of human organs available for transplantation. The challenge in this model has been hyperacute rejection. To avoid this, pigs have been bred with a knockout of the alpha-1,3-galactosyltransferase gene and with subcapsular autologous thymic tissue.We transplanted kidneys from these genetically modified pigs into two brain-dead human recipients whose circulatory and respiratory activity was maintained on ventilators for the duration of the study. We performed serial biopsies and monitored the urine output and kinetic estimated glomerular filtration rate (eGFR) to assess renal function and xenograft rejection.The xenograft in both recipients began to make urine within moments after reperfusion. Over the 54-hour study, the kinetic eGFR increased from 23 ml per minute per 1.73 mGenetically modified kidney xenografts from pigs remained viable and functioning in brain-dead human recipients for 54 hours, without signs of hyperacute rejection. (Funded by Lung Biotechnology.).
Published: 2022

39. The IASLC Lung Cancer Staging Project: Analysis of Resection Margin Status and Proposals for Residual Tumor Descriptors for Non–Small Cell Lung Cancer

Author: John G. Edwards, Kari Chansky, Paul Van Schil, Andrew G. Nicholson, Souheil Boubia, Elisabeth Brambilla, Jessica Donington, Françoise Galateau-Sallé, Hans Hoffmann, Maurizio Infante, Mirella Marino, Edith M. Marom, Jun Nakajima, Marcin Ostrowski, William D. Travis, Ming-Sound Tsao, Yasushi Yatabe, Dorothy J. Giroux, Lynn Shemanski, John Crowley, Marc Krasnik, Hisao Asamura, Ramón Rami-Porta, Valerie Rusch, Luiz Henrique Araujo, David Beer, Pietro Bertoglio, Ricardo Beyruti, Andrea Bille, Vanessa Bolejack, James D. Brierley, A.K. Cangir, David Carbone, Gail Darling, Frank Detterbeck, Xavier Benoit D’Journo, Jessica Donnington, Wilfried Eberhardt, John Edwards, Jeremy Erasmus, Conrad Falkson, Wentao Fang, Dean Fennell, Kwun Fong, Françoise Galateau-Salle, Oliver Gautschi, Ritu Gill, Dorothy Giroux, Meredith Giuliani, Jin Mo Goo, Seiki Hasegawa, Fred Hirsch, Hans Hoffman, Wayne Hofstetter, James Huang, Philippe Joubert, Kemp Kernstine, Keith Kerr, Young Tae Kim, Hong Kwan Kim, Hedy Kindler, Yolande Lievens, Hui Liu, Donald E. Low, Gustavo Lyons, Heber MacMahon, Edith Marom, José-María Matilla, Jan van Meerbeeck, Luis M. Montuenga, Andrew Nicholson, Katie Nishimura, Anna Nowak, Isabelle Opitz, Meinoshin Okumura, Raymond U. Osarogiagbon, Harvey Pass, Marc de Perrot, Helmut Prosch, David Rice, Andreas Rimner, Enrico Ruffini, Shuji Sakai, Navneet Singh, Amy Stoll-D’Astice, Francisco Su´rez, Ricardo M. Terra, Ming S. Tsao, Paula Ugalde, David Waller, Shun-ichi Watanabe, Jacinta Wiens, Ignacio Wistuba, Liyan Jiang, Kaoru Kubota, Akif Turna, Benny Weksler, Maria Teresa Tzukazan, Martin Tammemägi, Charles Powell, David Naidich, Hongxu Liu, Samuel Armato, Alex Brunelli, Giuseppe Cardillo, Elizabeth David, Brigitte Fournier, Mark Krasnik, Kauro Kubota, Catherine Labbe, Eric Lim, Paul Martin Putora, Gaetano Rocco, Pier Luigi Filosso, Kazuya Kondo, Dong Kwan Kim, Giuseppe Giaccone, Marco Lucchi, Thomas Rice, Mark Ferguson, Prasad Adsusmilli, William Travis, Francisco Suárez, Kaura Kubota, Hisao Asamura Shun-ichi, Watanabe, Edith Marom Ramón, Rami-Porta, Ming Tsao, Ming Tsao Shun-ichi, Watanabe, Meredith Guiliani, James Brierley, Ricardo Terra, Ray Osarogiagbon, Luis Montuenga, Hongwei Wang, Françoise Galateau, Jim Mo Goo, Bill Travis, Jose Maria Matilla, Carolle St. Pierre, Ma Teresa Tzukazan, Nicholas Girard, Andreas Rimmer, Francoise Galateau, Prasad Adusumilli, Xavier D’Journo, Donald Low, Adam Rosenthal, and Int Assoc Study Lung Canc Staging
Subjects: 0301 basic medicine, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Lung Neoplasms, Neoplasm, Residual, 03 medical and health sciences, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Cytology, medicine, Humans, Lung cancer, Biology, Lymph node, Neoplasm Staging, Retrospective Studies, Computer. Automation, business.industry, Carcinoma in situ, Margins of Excision, Prognosis, medicine.disease, Clinical trial, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Resection margin, Human medicine, Radiology, Non small cell, Lung cancer staging, business, Mathematics
Abstract: Objective: Our aim was to validate the prognostic relevance in NSCLC of potential residual tumor (R) descriptors, including the proposed International Association for the Study of Lung Cancer definition for uncertain resection, referred to as R(un). Methods: A total of 14,712 patients undergoing resection with full R status and survival were analyzed. The following were also evaluated: whether fewer than three N2 stations were explored, lobe-specific nodal dissection, extracapsular extension, highest lymph node station status, carcinoma in situ at the bronchial resection margin, and pleural lavage cytologic examination result. Revised categories of R0, R(un), R1, and R2 were tested for survival impact. Results: In all, 14,293 cases were R0, 263 were R1, and 156 were R2 (median survivals not reached, 33 months, and 29 months, respectively). R status correlated with T and N categories. A total of 9290 cases (63%) had three or more N2 stations explored and 6641 cases (45%) had lobespecific nodal dissection, correlated with increasing pN2. Extracapsular extension was present in 62 of 364 cases with available data (17%). The highest station was positive in 942 cases (6.4%). The pleural lavage cytologic examination result was positive in 59 of 1705 cases (3.5%): 13 had carcinoma in situ at the bronchial resection margin. After reassignment because of inadequate nodal staging in 56% of cases, 6070 cases were R0, 8185 were R(un), 301 were R1, and 156 were R2. In node-positive cases, the median survival times were 70, 50, and 30 months for RO, R(un) (p < 0.0001), and R1 (p < 0.001), respectively, with no significant difference between RO and R(un) in pN0 cases. Conclusions: R descriptors have prognostic relevance, with R(un) survival stratifying between R0 and R1. Therefore, a detailed evaluation of R factor is of particular importance in the design and analyses of clinical trials of adjuvant therapies. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
Published: 2020

40. Surgical Workup and Management of Early-Stage Lung Cancer

Author: Stephanie H. Chang, Joshua Scheinerman, Jeffrey Jiang, Darian Paone, and Harvey Pass
Published: 2022

41. Effects of Smoking, Obesity, and Pulmonary Function on Home Oxygen Use after Curative Lung Cancer Surgery

Author: Daniel G. Nicastri, Huiwen Chan, Nan You, Rowena Yip, Keval Ray, Emanuela Taioli, David F. Yankelevitz, Claudia I. Henschke, Raja M. Flores, Andrew Kaufman, Dong-Seok Lee, Andrea Wolf, Kenneth Rosenzweig, Jorge Gomez, Mary Beth Beasley, Maureen Zakowski, Michael Chung, Rebecca Schwartz, Jeffrey Zhu, Sydney Kantor, Shana Adler, Wissam Raad, Zrzu Buyuk, Adie Friedman, Ronald Dreifuss, Stacey Verzosa, Mariya Yakubox, Karina Aloferdova, Patricia Stacey, Simone De Nobrega, Ardeshir Hakami, Harvey Pass, Berne Crawford, Jessica Donnington, Benjamin Cooper, Andre Moreirea, Audrey Sorensen, Leslie Kohman, Robert Dunton, Jason Wallen, Christopher Curtiss, Ernest Scalzetti, Linda Ellinwood, Clifford P. Connery, Emilo Torres, Dan Cruzer, Bruce Gendron, Sonya Alyea, Daniel Lackaye, Lauren Studer, Betsy Becker, and Artit Jirapatnakul
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Lung Neoplasms, Pulmonary function testing, Internal medicine, Carcinoma, Non-Small-Cell Lung, medicine, Humans, Obesity, Lung cancer, Pneumonectomy, Lung, Retrospective Studies, Lung cancer surgery, business.industry, Home oxygen, Smoking, Sequela, respiratory system, medicine.disease, respiratory tract diseases, Surgical morbidity, Oxygen, Pulmonary Diffusing Capacity, business
Abstract: Rationale: Lung cancer surgical morbidity has been decreasing, increasing attention to quality-of-life measures. A chronic sequela of lung cancer surgery is use of postoperative oxygen at home afte...
Published: 2021

42. 414.10: Cytokine Analysis of First Gal-KO Renal Xenotransplantation From a Pig-To-Human Recipient

Author: Jeffrey Stern, Bonnie E Lonze, Zoe A Stewart, Massimo Mangiola, Vasishta Tatapudi, Weimin Zhang, Brendan Camellato, Bo Xia, Jef Boeke, Harvey Pass, Elaina Weldon, Nikki Lawson, Adam Griesemer, Brendan Keating, and Robert A Montgomery
Subjects: Transplantation
Published: 2022

43. New or enlarging hiatal hernias after thoracic surgery for early lung cancer

Author: Kimberly J. Song, Rowena Yip, Michael Chung, Qiang Cai, Yeqing Zhu, Ayushi Singh, Erik E. Lewis, David Yankelevitz, Emanuela Taioli, Claudia Henschke, Raja Flores, Andrew Kaufman, Dong-Seok Lee, Daniel Nicastri, Andrea Wolf, Kimberly Song, Kenneth Rosenzweig, Jorge Gomez, Mary Beth Beasley, Maureen Zakowski, David F. Yankelevitz, Claudia I. Henschke, Rebecca Schwartz, Huiwen Chan, Jeffrey Zhu, Sydney Kantor, Shana Adler, Wissam Raad, Zrzu Buyuk, Adie Friedman, Ronald Dreifuss, Stacey Verzosa, Mariya Yakubox, Karina Aloferdova, Patricia Stacey, Simone De Nobrega, Ardeshir Hakami, Harvey Pass, Berne Crawford, Jessica Donnington, Benjamin Cooper, Andre Moreirea, Audrey Sorensen, Leslie Kohman, Robert Dunton, Jason Wallen, Christopher Curtiss, Ernest Scalzetti, Linda Ellinwood, Clifford P. Connery, Emilo Torres, Dan Cruzer, Bruce Gendron, Sonya Alyea, Daniel Lackaye, Lauren Studer, Betsy Becker, Artit Jirapatnakul, Nan You, Daniel M. Libby, James P. Smith, Mark Pasmantier, A.P. Reeves, Steven Markowitz, Albert Miller, Jose Cervera Deval, Heidi Roberts, Demetris Patsios, Shusuke Sone, Takaomi Hanaoka, Javier Zulueta, Juan P. de-Torres, Maria D. Lozano, Ralph Aye, Kristin Manning, Christiana Care, Thomas Bauer, Stefano Canitano, Salvatore Giunta, Enser Cole, Karl Klingler, John H.M. Austin, Gregory D.N. Pearson, Dorith Shaham, Cheryl Aylesworth, Patrick Meyers, Shahriyour Andaz, Davood Vafai, David Naidich, Georgeann McGuinness, Barry Sheppard, Matthew Rifkin, M. Kristin Thorsen, Richard Hansen, Samuel Kopel, William Mayfield, Dan Luedke, Donald Klippenstein, Alan Litwin, Peter A. Loud, Leslie J. Kohman, Ernest M. Scalzetti, Richard Thurer, Nestor Villamizar, Arfa Khan, Rakesh Shah, Xueguo Liu, Gary Herzog, Diana Yeh, Ning Wu, Joseph Lowry, Mary Salvatore, Carmine Frumiento, David S. Mendelson, Michael V. Smith, Robert Korst, Jana Taylor, Michelle S. Ginsberg, Michaela Straznicka, Mark Widmann, Gary Cecchi, Terence A.S. Matalon, Paul Scheinberg, Shari-Lynn Odzer, David Olsen, Fred Grannis, Arnold Rotter, Daniel Ray, David Mullen, Peter H. Wiernik, Edson H. Cheung, Melissa Lim, Louis DeCunzo, Robert Glassberg, Carmen Endress, Mark Yoder, Palmi Shah, Laura Welch, Michael Kalafer, Jeremy Green, James Walsh, David Bertsch, Elmer Camacho, Cynthia Chin, James O'Brien, and James C. Willey
Subjects: Pulmonary and Respiratory Medicine, Surgery, Cardiology and Cardiovascular Medicine
Abstract: The study objective was to determine the relationship between lung resection and the development of postoperative hiatal hernia.Preoperative and postoperative computed tomography imaging from 373 patients from the International Early Lung Cancer Action Program and the Initiative for Early Lung Cancer Research on Treatment were compared at a median of 31.1 months of follow-up after resection of clinical early-stage non-small cell lung cancer. Incidence of new hiatal hernia or changes to preexisting hernias were recorded and evaluated by patient demographics, surgical approach, extent of resection, and resection site.New hiatal hernias were seen in 9.6% of patients after lung resection (5.6% after wedge or segmentectomy and 12.4% after lobectomy;Both open and minimally invasive lung resection for clinical early-stage lung cancer are associated with new or enlarging postoperative hiatal hernia, especially after resections involving the left lower lobe.
Published: 2021

44. Asbestos : Risk Assessment, Epidemiology, and Health Effects

Author: Michele Carbone, Ronald Dodson, Harvey Pass, Haining Yang, Michele Carbone, Ronald Dodson, Harvey Pass, and Haining Yang
Subjects: Risk assessment, Asbestosis, Asbestos--Toxicology
Abstract: Asbestos: Risk Assessment, Epidemiology, and Health Effects offers a key text on the evolving information regarding asbestos and human health. Now in its third edition, this bestseller explores the pathological complexities of asbestos-related disease and examines how asbestos induces diseases in biological systems. The book also discusses the types of instruments and methods available for evaluation of the content of asbestiform minerals in products, air, water, surface areas, and tissue. It explains the relevance of each of these applications and gives readers the tools to evaluate data in the future.Edited by leading authorities on the subject and with contributions from a team of international experts, this book takes a cross-disciplinary approach and an authoritative review of the history, pathology, epidemiology, sampling, and analysis of asbestos. Backed up with photos and numerous diagrams, tables, and photographs, it features case studies, methodologies, and sampling/analytical schemes that put learning into context. Fully up-to-date and featuring four brand new chapters covering asbestosis and immunity, asbestos litigation and surgical and non-surgical management of mesothelioma, this book remains the most comprehensive source of information on asbestos and the only guide the reader will ever need to own.This essential text will appeal to any professional at any level who requires the latest expertise in dealing with asbestos. It suits researchers and practitioners alike, as well as those in the fields of law, health, education, hospitality, emergency response, building management and maintenance, construction, safety, insurance, and industrial hygiene.
Published: 2024

45. The importance of low-dose CT screening to identify emphysema in asymptomatic participants with and without a prior diagnosis of COPD

Author: David Steiger, M. Faisal Siddiqi, Rowena Yip, David F. Yankelevitz, Claudia I. Henschke, Artit Jirapatnakul, Raja Flores, Andrea Wolf, Daniel M. Libby, James P. Smith, Mark Pasmantier, A.P. Reeves, Steven Markowitz, Albert Miller, Jose Cervera Deval, Heidi Roberts, Demetris Patsios, Shusuke Sone, Takaomi Hanaoka, Javier Zulueta, Juan P. de-Torres, Maria D. Lozano, Ralph Aye, Kristin Manning, Thomas Bauer, Stefano Canitano, Salvatore Giunta, Enser Cole, Karl Klingler, John H.M. Austin, Gregory D.N. Pearson, Dorith Shaham, Cheryl Aylesworth, Patrick Meyers, Shahriyour Andaz, Davood Vafai, David Naidich, Georgeann McGuinness, Barry Sheppard, Matthew Rifkin, M. Kristin Thorsen, Richard Hansen, Samuel Kopel, William Mayfield, Dan Luedke, Donald Klippenstein, Alan Litwin, Peter A. Loud, Leslie J. Kohman, Ernest M. Scalzetti, Richard Thurer, Nestor Villamizar, Arfa Khan, Rakesh Shah, Xueguo Liu, Gary Herzog, Diana Yeh, Ning Wu, Joseph Lowry, Mary Salvatore, Carmine Frumiento, David S. Mendelson, Michael V. Smith, Robert Korst, Jana Taylor, Michelle S. Ginsberg, Michaela Straznicka, Mark Widmann, Gary Cecchi, Terence A.S. Matalon, Paul Scheinberg, Shari-Lynn Odzer, David Olsen, Fred Grannis, Arnold Rotter, Daniel Ray, David Mullen, Peter H. Wiernik, Edson H. Cheung, Melissa Lim, Louis DeCunzo, Robert Glassberg, Harvey Pass, Carmen Endress, Mark Yoder, Palmi Shah, Laura Welch, Michael Kalafer, Jeremy Green, James Walsh, David Bertsch, Elmer Camacho, Cynthia Chin, James O'Brien, and James C. Willey
Subjects: Male, Chronic bronchitis, medicine.medical_specialty, medicine.medical_treatment, Prior diagnosis, Asymptomatic, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, Pulmonary Disease, Chronic Obstructive, 0302 clinical medicine, Internal medicine, medicine, Low dose ct, Humans, Radiology, Nuclear Medicine and imaging, Prospective Studies, Lung cancer, Prospective cohort study, Emphysema, COPD, business.industry, Infant, Newborn, respiratory system, medicine.disease, respiratory tract diseases, Pulmonary Emphysema, 030220 oncology & carcinogenesis, Smoking cessation, medicine.symptom, business, Tomography, X-Ray Computed
Abstract: Purpose Chronic Obstructive Pulmonary Disease (COPD) includes chronic bronchitis, small airways disease, and emphysema. Diagnosis of COPD requires spirometric evidence and may be normal even when small airways disease or emphysema is present. Emphysema increases the risk of exacerbations, and is associated with all-cause mortality and increased risk of lung cancer. We evaluated the prevalence of emphysema in participants with and without a prior history of COPD. Methods We reviewed a prospective cohort of 52,726 subjects who underwent baseline low dose CT screening for lung cancer from 2003 to 2016 in the International Early Lung Cancer Action Program. Results Of 52,726 participants, 23.8%(12,542) had CT evidence of emphysema. Of these 12,542 participants with emphysema, 76.5%(9595/12,542) had no prior COPD diagnosis even though 23.6% (2258/9595) had moderate or severe emphysema. Among 12,542 participants, significant predictors of no prior COPD diagnosis were: male (OR = 1.47, p Conclusion Emphysema was identified in 23.8% participants undergoing LDCT and was unsuspected in 76.5%. LDCT provides an opportunity to identify emphysema, and recommend smoking cessation.
Published: 2020

46. Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features

Author: Hitoshi Dejima, Xin Hu, Runzhe Chen, Jiexin Zhang, Junya Fujimoto, Edwin R. Parra, Cara Haymaker, Shawna Hubert, Dzifa Duose, Luisa M. Solis, Dan Su, Junya Fukuoka, Kazuhiro Tabata, Hoa Pharm, Nicholas Mcgranahan, Baili Zhang, Jie Ye, Lisha Ying, Latasha Little, Curtis Gumbs, Chi-Wan Chow, Marcos Roberto Estecio, Myrna C.B. Godoy, Mara B. Antonoff, Boris Sepesi, Harvey Pass, Carmen Behrens, Jianhua Zhang, Ara A. Vaporciyan, John V. Heymach, Paul Scheet, J. Jack Lee, P. Andrew Futreal, Alexandre Reuben, Humam Kadara, Ignacio Wistuba, and Jianjun Zhang
Subjects: medicine.medical_treatment, T cell, Immunotherapy, Human leukocyte antigen, Biology, respiratory system, medicine.disease, body regions, medicine.anatomical_structure, Immune system, DNA methylation, medicine, Cancer research, Adenocarcinoma, Atypical adenomatous hyperplasia, CD8
Abstract: SUMMARYHow anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. We characterized immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence. Our results demonstrated that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensely regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, higher infiltration of CD4+ T cells, lower infiltration of CD8+ T cells, decreased T cell clonality, and lower frequencies of top T cell clones in later stages. Driver mutations, HLA loss, chromosomal copy number aberrations and DNA methylation changes may collectively impinge host immune responses and facilitate immune evasion as a potential mechanism underlying outgrowth of the most fit subclones in preneoplasia into dominant clones in invasive ADC.SIGNIFICANCEThere has been a drastic increase in the detection of lung nodules, many of which are lung ADC precursors. The management of these lung nodules is controversial. We discovered that immune activation and evasion have started at preneoplastic stage and lung ADC precursors may exhibit an overall better-preserved anti-tumor immune contexture suggesting therapeutic strategies reprograming the immune microenvironment in patients with lung ADC precursors prior to further immunosuppression in invasive lung cancers may be beneficial. These findings have served as the critical scientific rationale for our immunoprevention clinical trial IMPRINT-Lung (NCT03634241) recruiting individuals diagnosed with lung nodules at high risk developing invasive lung cancers.
Published: 2020
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47. Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Author: Bailey, Matthew H, Meyerson, William U, Dursi, Lewis Jonathan, Wang, Liang-Bo, Dong, Guanlan, Liang, Wen-Wei, Weerasinghe, Amila, Shantao, Li, Kelso, Sean, Saksena, Gordon, Ellrott, Kyle, Wendl, Michael C, Wheeler, David A, Getz, Gad, Simpson, Jared T, Gerstein, Mark B, Ding, Lirehan, Akbani, Pavana, Anur, Matthew, H Bailey, Alex, Buchanan, Kami, Chiotti, Kyle, Covington, Allison, Creason, Ding, Li, Kyle, Ellrott, Fan, Yu, Steven, Foltz, Gad, Getz, Walker, Hale, David, Haussler, Julian, M Hess, Carolyn, M Hutter, Cyriac, Kandoth, Katayoon, Kasaian, Melpomeni, Kasapi, Dave, Larson, Ignaty, Leshchiner, John, Letaw, Singer, Ma, Michael, D McLellan, Yifei, Men, Gordon, B Mills, Beifang, Niu, Myron, Peto, Amie, Radenbaugh, Sheila, M Reynolds, Gordon, Saksena, Heidi, Sofia, Chip, Stewart, Adam, J Struck, Joshua, M Stuart, Wenyi, Wang, John, N Weinstein, David, A Wheeler, Christopher, K Wong, Liu, Xi, Kai, Ye, Matthias, Bieg, Paul, C Boutros, Ivo, Buchhalter, Adam, P Butler, Ken, Chen, Zechen, Chong, Oliver, Drechsel, Lewis Jonathan Dursi, Roland, Eils, Shadrielle M, G Espiritu, Robert, S Fulton, Shengjie, Gao, Josep L, L Gelpi, Mark, B Gerstein, Santiago, Gonzalez, Ivo, G Gut, Faraz, Hach, Michael, C Heinold, Jonathan, Hinton, Taobo, Hu, Vincent, Huang, Huang, Yi, Barbara, Hutter, David, R Jones, Jongsun, Jung, Natalie, Jäger, Hyung-Lae, Kim, Kortine, Kleinheinz, Sushant, Kumar, Yogesh, Kumar, Christopher, M Lalansingh, Ivica, Letunic, Dimitri, Livitz, Eric, Z Ma, Yosef, E Maruvka, R Jay Mashl, Andrew, Menzies, Ana, Milovanovic, Morten Muhlig Nielsen, Stephan, Ossowski, Nagarajan, Paramasivam, Jakob Skou Pedersen, Marc, D Perry, Montserrat, Puiggròs, Keiran, M Raine, Esther, Rheinbay, Romina, Royo, S Cenk Sahinalp, Iman, Sarrafi, Matthias, Schlesner, Jared, T Simpson, Lucy, Stebbings, Miranda, D Stobbe, Jon, W Teague, Grace, Tiao, David, Torrents, Jeremiah, A Wala, Jiayin, Wang, Sebastian, M Waszak, Joachim, Weischenfeldt, Michael, C Wendl, Johannes, Werner, 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T, Nakano, K, Nandi, T, Nangalia, J, Nastic, M, Navarro, A, Navarro, F, Neal, D, Nettekoven, G, Newell, F, Newhouse, S, Newton, Y, Ng, A, Nicholson, J, Nicol, D, Nie, Y, Nielsen, G, Nik-Zainal, S, Noble, M, Nones, K, Northcott, P, Notta, F, O'Connor, B, O'Donnell, P, O'Donovan, M, O'Meara, S, O'Neill, B, O'Neill, J, Ocana, D, Ochoa, A, Oesper, L, Ogden, C, Ohdan, H, Ohi, K, Ohno-Machado, L, Oien, K, Ojesina, A, Ojima, H, Okusaka, T, Omberg, L, Ong, C, Ott, G, Ouellette, B, P'Ng, C, Paczkowska, M, Paiella, S, Pairojkul, C, Pajic, M, Pan-Hammarstrom, Q, Papaemmanuil, E, Papatheodorou, I, Park, J, Park, K, Park, P, Parker, J, Parsons, S, Pass, H, Pasternack, D, Pastore, A, Patch, A, Pauporte, I, Pea, A, Pearson, J, Pedamallu, C, Pederzoli, P, Peifer, M, Pennell, N, Perou, C, Petersen, G, Petrelli, N, Petryszak, R, Pfister, S, Phillips, M, Pich, O, Pickett, H, Pihl, T, Pillay, N, Pinder, S, Pinese, M, Pinho, A, Pitkanen, E, Pivot, X, Pineiro-Yanez, E, Planko, L, Plass, C, Polak, P, Pons, T, Popescu, I, Potapova, O, Prasad, A, Preston, S, Prinz, M, Pritchard, A, Prokopec, S, Provenzano, E, Puente, X, Puig, S, Pulido-Tamayo, S, Pupo, G, Purdie, C, Quinn, M, Rabionet, R, Rader, J, Radlwimmer, B, Radovic, P, Raeder, B, Ramakrishna, M, Ramakrishnan, K, Ramalingam, S, Raphael, B, Rathmell, W, Rausch, T, Reifenberger, G, Reimand, J, Reis-Filho, J, Reuter, V, Reyes-Salazar, I, Reyna, M, Riazalhosseini, Y, Richardson, A, Richter, J, Ringel, M, Ringner, M, Rino, Y, Rippe, K, Roach, J, Roberts, L, Roberts, N, Roberts, S, Robertson, A, Rodriguez, J, Rodriguez-Martin, B, Rodriguez-Gonzalez, F, Roehrl, M, Rohde, M, Rokutan, H, Romieu, G, Rooman, I, Roques, T, Rosebrock, D, Rosenberg, M, Rosenstiel, P, Rosenwald, A, Rowe, E, Rozen, S, Rubanova, Y, Rubin, M, Rubio-Perez, C, Rudneva, V, Rusev, B, Ruzzenente, A, Ratsch, G, Sabarinathan, R, Sabelnykova, V, Sadeghi, S, Saini, N, Saito-Adachi, M, Salcedo, A, Salgado, R, Salichos, L, Sallari, R, Saller, C, Salvia, R, Sam, M, Samra, J, Sanchez-Vega, F, Sander, C, Sanders, G, Sarin, R, Sasaki-Oku, A, Sauer, T, Sauter, G, Saw, R, Scardoni, M, Scarlett, C, Scarpa, A, Scelo, G, Schadendorf, D, Schein, J, Schilhabel, M, Schlomm, T, Schmidt, H, Schramm, S, Schreiber, S, Schultz, N, Schumacher, S, Schwarz, R, Scolyer, R, Scott, D, Scully, R, Seethala, R, Segre, A, Selander, I, Semple, C, Senbabaoglu, Y, Sengupta, S, Sereni, E, Serra, S, Sgroi, D, Shackleton, M, Shah, N, Shahabi, S, Shang, C, Shang, P, Shapira, O, Shelton, T, Shen, C, Shen, H, Shepherd, R, Shi, R, Shi, Y, Shiah, Y, Shibata, T, Shih, J, Shimizu, E, Shimizu, K, Shin, S, Shiraishi, Y, Shmaya, T, Shmulevich, I, Shorser, S, Short, C, Shrestha, R, Shringarpure, S, Shriver, C, Shuai, S, Sidiropoulos, N, Siebert, R, Sieuwerts, A, Sieverling, L, Signoretti, S, Sikora, K, Simbolo, M, Simon, R, Simons, J, Simpson, P, Singer, S, Sinnott-Armstrong, N, Sipahimalani, P, Skelly, T, Smid, M, Smith, J, Smith-McCune, K, Socci, N, Soloway, M, Song, L, Sood, A, Sothi, S, Sotiriou, C, Soulette, C, Span, P, Spellman, P, Sperandio, N, Spillane, A, Spiro, O, Spring, J, Staaf, J, Stadler, P, Staib, P, Stark, S, Stefansson, O, Stegle, O, Stein, L, Stenhouse, A, Stilgenbauer, S, Stratton, M, Stretch, J, Stunnenberg, H, Su, H, Su, X, Sun, R, Sungalee, S, Susak, H, Suzuki, A, Sweep, F, Szczepanowski, M, Sultmann, H, Yugawa, T, Tam, A, Tamborero, D, Tan, B, Tan, D, Tan, P, Tanaka, H, Taniguchi, H, Tanskanen, T, Tarabichi, M, Tarnuzzer, R, Tarpey, P, Taschuk, M, Tatsuno, K, Tavare, S, Taylor, D, Taylor-Weiner, A, Teh, B, Tembe, V, Temes, J, Thai, K, Thayer, S, Thiessen, N, Thomas, G, Thomas, S, Thompson, A, Thompson, J, Thompson, R, Thorne, H, Thorne, L, Thorogood, A, Tijanic, N, Timms, L, Tirabosco, R, Tojo, M, Tommasi, S, Toon, C, Toprak, U, Tortora, G, Tost, J, Totoki, Y, Townend, D, Traficante, N, Treilleux, I, Trotta, J, Trumper, L, Tsao, M, Tsunoda, T, Tubio, J, Tucker, O, Turkington, R, Turner, D, Tutt, A, Ueno, M, Ueno, N, Umbricht, C, Umer, H, Underwood, 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Yamamoto, S, Yamaue, H, Yang, F, Yang, H, Yang, J, Yang, L, Yang, S, Yang, T, Yang, Y, Yao, X, Yaspo, M, Yates, L, Yau, C, Ye, C, Yoon, C, Yoon, S, Yousif, F, Yu, J, Yu, K, Yu, W, Yu, Y, Yuan, K, Yuan, Y, Yuen, D, Zaikova, O, Zamora, J, Zapatka, M, Zenklusen, J, Zenz, T, Zeps, N, Zhang, C, Zhang, F, Zhang, H, Zhang, X, Zhang, Y, Zhang, Z, Zhao, Z, Zheng, L, Zheng, X, Zhou, W, Zhou, Y, Bin, Z, Zhu, H, Zhu, J, Zhu, S, Zou, L, Zou, X, Defazio, A, van As, N, van Deurzen, C, van de Vijver, M, van't Veer, L, von Mering, C, Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Tampere University, BioMediTech, TAYS Cancer Centre, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, University of St Andrews. Cellular Medicine Division, University of St Andrews. Statistics, University of St Andrews. School of Medicine, University of Zurich, Gerstein, Mark B, Ding, Li, Bailey, Matthew H [0000-0003-4526-9727], Wheeler, David A [0000-0002-9056-6299], Gerstein, Mark B [0000-0002-9746-3719], Faculty of Economic and Social Sciences and Solvay Business School, Lauri Antti Aaltonen / Principal Investigator, Genome-Scale Biology (GSB) Research Program, Department of Medical and Clinical Genetics, Organismal and Evolutionary Biology Research Programme, Helsinki Institute for Information Technology, Institute of Biotechnology, Bioinformatics, Department of Computer Science, Faculty of Medicine, and HUS Helsinki and Uusimaa Hospital District
Subjects: VARIANTS, 0302 clinical medicine, 706/648/697/129/2043, Databases, Genetic, Cancer genomics, SOMATIC POINT MUTATIONS, Càncer, lcsh:Science, Exome, Exome sequencing, Cancer, Base Composition, Neoplasms -- genetics, 1184 Genetics, developmental biology, physiology, 3100 General Physics and Astronomy, 3. Good health, 030220 oncology & carcinogenesis, Science & Technology - Other Topics, Transformació genètica, Genetic databases, Erfðarannsóknir, Human, GENES, Science, 1600 General Chemistry, General Biochemistry, Genetics and Molecular Biology, RC0254, 03 medical and health sciences, Genetic, SDG 3 - Good Health and Well-being, 1300 General Biochemistry, Genetics and Molecular Biology, Exome Sequencing, Genetics, Humans, Author Correction, Retrospective Studies, Whole genome sequencing, Comparative genomics, Science & Technology, RC0254 Neoplasms. Tumors. Oncology (including Cancer), INSERTIONS, DNA, PERFORMANCE, Human genetics, Communication and replication, Cancérologie, 692/4028/67/69, Genòmica, 030104 developmental biology, Mutation, Genome mutation, Human genome, lcsh:Q, COMPREHENSIVE CHARACTERIZATION, Genètica, 0301 basic medicine, Medizin, General Physics and Astronomy, Genome, Whole Exome Sequencing, Genetic transformation, International Cancer Genome Consortium, Neoplasms, 631/114/2399, Genamengi, Medicine and Health Sciences, Medicine(all), Women's cancers Radboud Institute for Molecular Life Sciences [Radboudumc 17], Multidisciplinary, 318 Medical biotechnology, Exome -- genetics, article, Exons, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], Multidisciplinary Sciences, CAPTURE, 1181 Ecology, evolutionary biology, oncology, DNA, Intergenic, 139, Medical Genetics, Biotechnology, ICGC/TCGA Pan-Cancer Analysis, 3122 Cancers, 610 Medicine & health, 45/23, QH426 Genetics, Biology, MC3 Working Group, Databases, Germline mutation, PCAWG novel somatic mutation calling methods working group, Krabbameinsrannsóknir, Cancer Genome Atlas, Genome, Human -- genetics, ddc:610, QH426, Medicinsk genetik, Krabbamein, Intergenic, Whole Genome Sequencing, Genome, Human, Human Genome, PCAWG Consortium, DAS, General Chemistry, DELETIONS, Good Health and Well Being, 10032 Clinic for Oncology and Hematology, 3111 Biomedicine, 631/1647/2217/748
Abstract: MC3 Working Group: Rehan Akbani21, Pavana Anur22, Matthew H. Bailey1,2,3, Alex Buchanan9, Kami Chiotti9, Kyle Covington12,23, Allison Creason9, Li Ding1,2,3,20, Kyle Ellrott9, Yu Fan21, Steven Foltz1,2, Gad Getz8,14,15,16, Walker Hale12, David Haussler24,25, Julian M. Hess8,26, Carolyn M. Hutter27, Cyriac Kandoth28, Katayoon Kasaian29,30, Melpomeni Kasapi27, Dave Larson1 , Ignaty Leshchiner8, John Letaw31, Singer Ma32, Michael D. McLellan1,3,20, Yifei Men32, Gordon B. Mills33,34, Beifang Niu35, Myron Peto22, Amie Radenbaugh24, Sheila M. Reynolds36, Gordon Saksena8, Heidi Sofia27, Chip Stewart8, Adam J. Struck31, Joshua M. Stuart24,37, Wenyi Wang21, John N. Weinstein38, David A. Wheeler12,13, Christopher K. Wong24,39, Liu Xi12 & Kai Ye40,41 21Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. 22Molecular and Medical Genetics, OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA. 23Castle Biosciences Inc, Friendswood, TX 77546, USA. 24UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 25Howard Hughes Medical Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 26Massachusetts General Hospital Center for Cancer Research, Charlestown, MA 02114, USA. 27National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20894, USA. 28Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. 29Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada. 30Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V5Z 4S6, Canada. 31Computational Biology Program, School of Medicine, Oregon Health and Science University, Portland, OR 97239, USA. 32DNAnexus Inc, Mountain View, CA 94040, USA. 33Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX 77030, USA. 34Precision Oncology, OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA. 35Computer Network Information Center, Chinese Academy of Sciences, Beijing, China. 36Institute for Systems Biology, Seattle, WA 98109, USA. 37Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 38Department of Bioinformatics and Computational Biology and Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. 39Biomolecular Engineering Department, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 40School of Elect, PCAWG novel somatic mutation calling methods working group: Matthew H. Bailey1,2,3, Beifang Niu35, Matthias Bieg42,43, Paul C. Boutros6,44,45,46, Ivo Buchhalter43,47,48, Adam P. Butler49, Ken Chen50, Zechen Chong51, Li Ding1,2,3,20, Oliver Drechsel52,53, Lewis Jonathan Dursi6,7, Roland Eils47,48,54,55, Kyle Ellrott9, Shadrielle M. G. Espiritu6, Yu Fan21, Robert S. Fulton1,3,20, Shengjie Gao56, Josep L. l. Gelpi57,58, Mark B. Gerstein5,18,19, Gad Getz8,14,15,16, Santiago Gonzalez59,60, Ivo G. Gut52,61, Faraz Hach62,63, Michael C. Heinold47,48, Julian M. Hess8,26, Jonathan Hinton49, Taobo Hu64, Vincent Huang6, Yi Huang65,66, Barbara Hutter43,67,68, David R. Jones49, Jongsun Jung69, Natalie Jäger47, Hyung-Lae Kim70, Kortine Kleinheinz47,48, Sushant Kumar5,19, Yogesh Kumar64, Christopher M. Lalansingh6, Ignaty Leshchiner8, Ivica Letunic71, Dimitri Livitz8, Eric Z. Ma64, Yosef E. Maruvka8,26,72, R. Jay Mashl1,2, Michael D. McLellan1,3,20, Andrew Menzies49, Ana Milovanovic57, Morten Muhlig Nielsen73, Stephan Ossowski52,53,74, Nagarajan Paramasivam43,47, Jakob Skou Pedersen73,75, Marc D. Perry76,77, Montserrat Puiggròs57, Keiran M. Raine49, Esther Rheinbay8,14,72, Romina Royo57, S. Cenk Sahinalp62,78,79, Gordon Saksena8, Iman Sarrafi62,78, Matthias Schlesner47,80, Jared T. Simpson6,17, Lucy Stebbings49, Chip Stewart8, Miranda D. Stobbe52,61, Jon W. Teague49, Grace Tiao8, David Torrents57,81, Jeremiah A. Wala8,14,82, Jiayin Wang1,40,66, Wenyi Wang21, Sebastian M. Waszak60, Joachim Weischenfeldt60,83,84, Michael C. Wendl1,10,11, Johannes Werner47,85, Zhenggang Wu64, Hong Xue64, Sergei Yakneen60, Takafumi N. Yamaguchi6, Kai Ye40,41, Venkata D. Yellapantula20,86, Christina K. Yung76 & Junjun Zhang76, PCAWG Consortium: Lauri A. Aaltonen87, Federico Abascal49, Adam Abeshouse88, Hiroyuki Aburatani89, David J. Adams49, Nishant Agrawal90, Keun Soo Ahn91, Sung-Min Ahn92, Hiroshi Aikata93, Rehan Akbani21, Kadir C. Akdemir50, Hikmat Al-Ahmadie88, Sultan T. Al-Sedairy94, Fatima Al-Shahrour95, Malik Alawi96,97, Monique Albert98, Kenneth Aldape99,100, Ludmil B. Alexandrov49,101,102, Adrian Ally30, Kathryn Alsop103, Eva G. Alvarez104,105,106, Fernanda Amary107, Samirkumar B. Amin108,109,110, Brice Aminou76, Ole Ammerpohl111,112, Matthew J. Anderson113, Yeng Ang114, Davide Antonello115, Pavana Anur22, Samuel Aparicio116, Elizabeth L. Appelbaum1,117, Yasuhito Arai118, Axel Aretz119, Koji Arihiro93, Shun-ichi Ariizumi120, Joshua Armenia121, Laurent Arnould122, Sylvia Asa123,124, Yassen Assenov125, Gurnit Atwal6,126,127, Sietse Aukema112,128, J. Todd Auman129, Miriam R. Aure130, Philip Awadalla6,126, Marta Aymerich131, Gary D. Bader126, Adrian Baez-Ortega132, Matthew H. Bailey1,2,3, Peter J. Bailey133, Miruna Balasundaram30, Saianand Balu134, Pratiti Bandopadhayay8,135,136, Rosamonde E. Banks137, Stefano Barbi138, Andrew P. Barbour139,140, Jonathan Barenboim6, Jill Barnholtz-Sloan141,142, Hugh Barr143, Elisabet Barrera59, John Bartlett98,144, Javier Bartolome57, Claudio Bassi115, Oliver F. Bathe145,146, Daniel Baumhoer147, Prashant Bavi148, Stephen B. Baylin149,150, Wojciech Bazant59, Duncan Beardsmore151, Timothy A. Beck152,153, Sam Behjati49, Andreas Behren154, Beifang Niu35, Cindy Bell155, Sergi Beltran52,61, Christopher Benz156, Andrew Berchuck157, Anke K. Bergmann158, Erik N. Bergstrom101,102, Benjamin P. Berman159,160,161, Daniel M. Berney162, Stephan H. Bernhart163,164,165, Rameen Beroukhim8,14,82, Mario Berrios166, Samantha Bersani167, Johanna Bertl73,168, Miguel Betancourt169, Vinayak Bhandari6,44, Shriram G. Bhosle49, Andrew V. Biankin133,170,171,172, Matthias Bieg42,43, Darell Bigner173, Hans Binder163,164, Ewan Birney59, Michael Birrer72, Nidhan K. Biswas174, Bodil Bjerkehagen147,175, Tom Bodenheimer134, Lori Boice176, Giada Bonizzato177, Johann S. De Bono178, Arnoud Boot179,180, Moiz S. Bootwalla166, Ake Borg181, Arndt Borkhardt182, Keith A. Boroevich183,184, Ivan Borozan6, Christoph Borst185, Marcus Bosenberg186, Mattia Bosio52,53,57, Jacqueline Boultwood187, Guillaume Bourque188,189, Paul C. Boutros6,44,45,46, G. Steven Bova190, David T. Bowen49,191, Reanne Bowlby30, David D. L. Bowtell103, Sandrine Boyault192, Rich Boyce59, Jeffrey Boyd193, Alvis Brazma59, Paul Brennan194, Daniel S. Brewer195,196, Arie B. Brinkman197, Robert G. Bristow44,198,199,200,201, Russell R. Broaddus99, Jane E. Brock202, Malcolm Brock203, Annegien Broeks204, Angela N. Brooks8,24,37,82, Denise Brooks30, Benedikt Brors67,205,206, Søren Brunak207,208, Timothy J. C. Bruxner113,209, Alicia L. Bruzos104,105,106, Alex Buchanan9, Ivo Buchhalter43,47,48, Christiane Buchholz210, Susan Bullman8,82, Hazel Burke211, Birgit Burkhardt212, Kathleen H. Burns213,214, John Busanovich8,215, Carlos D. Bustamante216,217, Adam P. Butler49, Atul J. Butte218, Niall J. Byrne76, Anne-Lise Børresen-Dale130,219, Samantha J. Caesar-Johnson220, Andy Cafferkey59, Declan Cahill221, Claudia Calabrese59,60, Carlos Caldas222,223, Fabien Calvo224, Niedzica Camacho178, Peter J. Campbell49,225, Elias Campo226,227, Cinzia Cantù177, Shaolong Cao21, Thomas E. Carey228, Joana Carlevaro-Fita229,230,231, Rebecca Carlsen30, Ivana Cataldo167,177, Mario Cazzola232, Jonathan Cebon154, Robert Cerfolio233, Dianne E. Chadwick234, Dimple Chakravarty235, Don Chalmers236, Calvin Wing Yiu Chan47,237, Kin Chan238, Michelle Chan-Seng-Yue148, Vishal S. Chandan239, David K. Chang133,170, Stephen J. Chanock240, Lorraine A. Chantrill170,241, Aurélien Chateigner76,242, Nilanjan Chatterjee149,243, Kazuaki Chayama93, Hsiao-Wei Chen114,121, Jieming Chen218, Ken Chen50, Yiwen Chen21, Zhaohong Chen244, Andrew D. Cherniack8,82, Jeremy Chien245, Yoke-Eng Chiew246,247, Suet-Feung Chin222,223, Juok Cho8, Sunghoon Cho248, Jung Kyoon Choi249, Wan Choi250, Christine Chomienne251, Zechen Chong51, Su Pin Choo252, Angela Chou170,246, Angelika N. Christ113, Elizabeth L. Christie103, Eric Chuah30, Carrie Cibulskis8, Kristian Cibulskis8, Sara Cingarlini253, Peter Clapham49, Alexander Claviez254, Sean Cleary148,255, Nicole Cloonan256, Marek Cmero257,258,259, Colin C. Collins62, Ashton A. Connor255,260, Susanna L. Cooke133, Colin S. Cooper178,196,261, Leslie Cope149, Vincenzo Corbo138,177, Matthew G. Cordes1,262, Stephen M. Cordner263, Isidro Cortés-Ciriano264,265,266, Kyle Covington12,23, Prue A. Cowin267, Brian Craft24, David Craft8,268, Chad J. Creighton269, Yupeng Cun270, Erin Curley271, Ioana Cutcutache179,180, Karolina Czajka272, Bogdan Czerniak99,273, Rebecca A. Dagg274, Ludmila Danilova149, Maria Vittoria Davi275, Natalie R. Davidson276,277,278,279,280, Helen Davies49,281,282, Ian J. Davis283, Brandi N. Davis-Dusenbery284, Kevin J. Dawson49, Francisco M. De La Vega216,217,285, Ricardo De Paoli-Iseppi211, Timothy Defreitas8, Angelo P. Dei Tos286, Olivier Delaneau287,288,289, John A. Demchok220, Jonas Demeulemeester290,291, German M. Demidov52,53,74, Deniz Demircioğlu292,293, Nening M. Dennis221, Robert E. Denroche148, Stefan C. Dentro49,290,294, Nikita Desai76, Vikram Deshpande72, Amit G. Deshwar295, Christine Desmedt296,297, Jordi Deu-Pons298,299, Noreen Dhalla30, Neesha C. Dhani300, Priyanka Dhingra301,302, Rajiv Dhir303, Anthony DiBiase304, Klev Diamanti305, Li Ding1,2,3,20, Shuai Ding306, Huy Q. Dinh159, Luc Dirix307, HarshaVardhan Doddapaneni12, Nilgun Donmez62,78, Michelle T. Dow244, Ronny Drapkin308, Oliver Drechsel52,53, Ruben M. Drews223, Serge Serge49, Tim Dudderidge150,221, Ana Dueso-Barroso57, Andrew J. Dunford8, Michael Dunn309, Lewis Jonathan Dursi6,7, Fraser R. Duthie133,310, Ken Dutton-Regester311, Jenna Eagles272, Douglas F. Easton312,313, Stuart Edmonds314, Paul A. Edwards223,315, Sandra E. Edwards178, Rosalind A. Eeles178,221, Anna Ehinger316, Juergen Eils54,55, Roland Eils47,48,54,55, Adel El-Naggar99,273, Matthew Eldridge223, Kyle Ellrott9, Serap Erkek60, Georgia Escaramis53,317,318, Shadrielle M. G. Espiritu6, Xavier Estivill53,319, Dariush Etemadmoghadam103, Jorunn E. Eyfjord320, Bishoy M. Faltas280, Daiming Fan321, Yu Fan21, William C. Faquin72, Claudiu Farcas244, Matteo Fassan322, Aquila Fatima323, Francesco Favero324, Nodirjon Fayzullaev76, Ina Felau220, Sian Fereday103, Martin L. Ferguson325, Vincent Ferretti76,326, Lars Feuerbach205, Matthew A. Field327, J. Lynn Fink57,113, Gaetano Finocchiaro328, Cyril Fisher221, Matthew W. Fittall290, Anna Fitzgerald329, Rebecca C. Fitzgerald282, Adrienne M. Flanagan330, Neil E. Fleshner331, Paul Flicek59, John A. Foekens332, Kwun M. Fong333, Nuno A. Fonseca59,334, Christopher S. Foster335,336, Natalie S. Fox6, Michael Fraser6, Scott Frazer8, Milana Frenkel-Morgenstern337, William Friedman338, Joan Frigola298, Catrina C. Fronick1,262, Akihiro Fujimoto184, Masashi Fujita184, Masashi Fukayama339, Lucinda A. Fulton1 , Robert S. Fulton1,3,20, Mayuko Furuta184, P. Andrew Futreal340, Anja Füllgrabe59, Stacey B. Gabriel8, Steven Gallinger148,255,260, Carlo Gambacorti-Passerini341, Jianjiong Gao121, Shengjie Gao56, Levi Garraway82, Øystein Garred342, Erik Garrison49, Dale W. Garsed103, Nils Gehlenborg8,343, Josep L. l. Gelpi57,58, Joshy George110, Daniela S. Gerhard344, Clarissa Gerhauser345, Jeffrey E. Gershenwald346,347, Mark B. Gerstein5,18,19, Moritz Gerstung59,60, Gad Getz8,14,15,16, Mohammed Ghori49, Ronald Ghossein348, Nasra H. Giama349, Richard A. Gibbs12, Anthony J. Gill170,350, Pelvender Gill351, Dilip D. Giri348, Dominik Glodzik49, Vincent J. Gnanapragasam352,353, Maria Elisabeth Goebler354, Mary J. Goldman24, Carmen Gomez355, Santiago Gonzalez59,60, Abel Gonzalez-Perez298,299,356, Dmitry A. Gordenin357, James Gossage358, Kunihito Gotoh359, Ramaswamy Govindan3, Dorthe Grabau360, Janet S. Graham133,361, Robert C. Grant148,260, Anthony R. Green315, Eric Green27, Liliana Greger59, Nicola Grehan282, Sonia Grimaldi177, Sean M. Grimmond362, Robert L. Grossman363, Adam Grundhoff97,364, Gunes Gundem88, Qianyun Guo75, Manaswi Gupta8, Shailja Gupta365, Ivo G. Gut52,61, Marta Gut52,61, Jonathan Göke292,366, Gavin Ha8, Andrea Haake111, David Haan37, Siegfried Haas185, Kerstin Haase290, James E. Haber367, Nina Habermann60, Faraz Hach62,63, Syed Haider6, Natsuko Hama118, Freddie C. Hamdy351, Anne Hamilton267, Mark P. Hamilton368, Leng Han369, George B. Hanna370, Martin Hansmann371, Nicholas J. Haradhvala8,72, Olivier Harismendy102,372, Ivon Harliwong113, Arif O. Harmanci5,373, Eoghan Harrington374, Takanori Hasegawa375, David Haussler24,25, Steve Hawkins223, Shinya Hayami376, Shuto Hayashi375, D. Neil Hayes134,377,378, Stephen J. Hayes379,380, Nicholas K. Hayward211,311, Steven Hazell221, Yao He381, Allison P. Heath382, Simon C. Heath52,61, David Hedley300, Apurva M. Hegde38, David I. Heiman8, Michael C. Heinold47,48, Zachary Heins88, Lawrence E. Heisler152, Eva Hellstrom-Lindberg383, Mohamed Helmy384, Seong Gu Heo385, Austin J. Hepperla134, José María Heredia-Genestar386, Carl Herrmann47,48,387, Peter Hersey211, Julian M. Hess8,26, Holmfridur Hilmarsdottir320, Jonathan Hinton49, Satoshi Hirano388, Nobuyoshi Hiraoka389, Katherine A. Hoadley134,390, Asger Hobolth75,168, Ermin Hodzic78, Jessica I. Hoell182, Steve Hoffmann163,164,165,391, Oliver Hofmann392, Andrea Holbrook166, Aliaksei Z. Holik53, Michael A. Hollingsworth393, Oliver Holmes209,311, Robert A. Holt30, Chen Hong205,237, Eun Pyo Hong385, Jongwhi H. Hong394, Gerrit K. Hooijer395, Henrik Hornshøj73, Fumie Hosoda118, Yong Hou56,396, Volker Hovestadt397, William Howat352, Alan P. Hoyle134, Ralph H. Hruban149, Jianhong Hu12, Taobo Hu64, Xing Hua240, Kuan-lin Huang1,398, Mei Huang176, Mi Ni Huang179,180, Vincent Huang6, Yi Huang65,66, Wolfgang Huber60, Thomas J. Hudson272,399, Michael Hummel400, Jillian A. Hung246,247, David Huntsman401, Ted R. Hupp402, Jason Huse88, Matthew R. Huska403, Barbara Hutter43,67,68, Carolyn M. Hutter27, Daniel Hübschmann48,54,404,405,406, Christine A. Iacobuzio-Donahue348, Charles David Imbusch205, Marcin Imielinski407,408, Seiya Imoto375, William B. Isaacs409, Keren Isaev6,44, Shumpei Ishikawa410, Murat Iskar397, S. M. Ashiqul Islam244, Michael Ittmann411,412,413, Sinisa Ivkovic284, Jose M. G. Izarzugaza414, Jocelyne Jacquemier415, Valerie Jakrot211, Nigel B. Jamieson133,172,416, Gun Ho Jang148, Se Jin Jang417, Joy C. Jayaseelan12, Reyka Jayasinghe1 , Stuart R. Jefferys134, Karine Jegalian418, Jennifer L. Jennings419, Seung-Hyup Jeon250, Lara Jerman60,420, Yuan Ji421,422, Wei Jiao6, Peter A. Johansson311, Amber L. Johns170, Jeremy Johns272, Rory Johnson230,423, Todd A. Johnson183, Clemency Jolly290, Yann Joly424, Jon G. Jonasson320, Corbin D. Jones425, David R. Jones49, David T. W. Jones426,427, Nic Jones428, Steven J. M. Jones30, Jos Jonkers204, Young Seok Ju49,249, Hartmut Juhl429, Jongsun Jung69, Malene Juul73, Randi Istrup Juul73, Sissel Juul374, Natalie Jäger47, Rolf Kabbe47, Andre Kahles276,277,278,279,430, Abdullah Kahraman431,432,433, Vera B. Kaiser434, Hojabr Kakavand211, Sangeetha Kalimuthu148, Christof von Kalle405, Koo Jeong Kang91, Katalin Karaszi351, Beth Karlan435, Rosa Karlić436, Dennis Karsch437, Katayoon Kasaian29,30, Karin S. Kassahn113,438, Hitoshi Katai439, Mamoru Kato440, Hiroto Katoh410, Yoshiiku Kawakami93, Jonathan D. Kay117, Stephen H. Kazakoff209,311, Marat D. Kazanov441,442,443, Maria Keays59, Electron Kebebew444,445, Richard F. Kefford446, Manolis Kellis8,447, James G. Kench170,350,448, Catherine J. Kennedy246,247, Jules N. A. Kerssemakers47, David Khoo273, Vincent Khoo221, Narong Khuntikeo115,449, Ekta Khurana301,302,450,451, Helena Kilpinen117, Hark Kyun Kim452, Hyung-Lae Kim70, Hyung-Yong Kim415, Hyunghwan Kim250, Jaegil Kim8, Jihoon Kim453, Jong K. Kim454, Youngwook Kim455,456, Tari A. King457,458,459, Wolfram Klapper128, Kortine Kleinheinz47,48, Leszek J. Klimczak460, Stian Knappskog49,461, Michael Kneba437, Bartha M. Knoppers424, Youngil Koh462,463, Jan Komorowski305,464, Daisuke Komura410, Mitsuhiro Komura375, Gu Kong415, Marcel Kool426,465, Jan O. Korbel59,60, Viktoriya Korchina12, Andrey Korshunov465, Michael Koscher465, Roelof Koster466, Zsofia Kote-Jarai178, Antonios Koures244, Milena Kovacevic284, Barbara Kremeyer49, Helene Kretzmer164,165, Markus Kreuz467, Savitri Krishnamurthy99,468, Dieter Kube469, Kiran Kumar8, Pardeep Kumar221, Sushant Kumar5,19, Yogesh Kumar64, Ritika Kundra114,121, Kirsten Kübler8,14,72, Ralf Küppers470, Jesper Lagergren383,471, Phillip H. Lai166, Peter W. Laird472, Sunil R. Lakhani473, Christopher M. Lalansingh6, Emilie Lalonde6, Fabien C. Lamaze6, Adam Lambert351, Eric Lander8, Pablo Landgraf474,475, Luca Landoni115, Anita Langerød130, Andrés Lanzós230,231,423, Denis Larsimont476, Erik Larsson477, Mark Lathrop189, Loretta M. S. Lau478, Chris Lawerenz55, Rita T. Lawlor177, Michael S. Lawrence8,72,183, Alexander J. Lazar99,108, Xuan Le479, Darlene Lee30, Donghoon Lee5, Eunjung Alice Lee480, Hee Jin Lee417, Jake June-Koo Lee264,266, Jeong-Yeon Lee481, Juhee Lee482, Ming Ta Michael Lee340, Henry Lee-Six49, Kjong-Van Lehmann276,277,278,279,430, Hans Lehrach483, Dido Lenze400, Conrad R. Leonard209,311, Daniel A. Leongamornlert49,178, Ignaty Leshchiner8, Louis Letourneau484, Ivica Letunic71, Douglas A. Levine88,485, Lora Lewis12, Tim Ley486, Chang Li56,396, Constance H. Li6,44, Haiyan Irene Li30, Jun Li21, Lin Li56, Shantao Li5, Siliang Li56,396, Xiaobo Li56,396, Xiaotong Li5, Xinyue Li56, Yilong Li49, Han Liang21, Sheng-Ben Liang234, Peter Lichter68,397, Pei Lin8, Ziao Lin8,487, W. M. Linehan488, Ole Christian Lingjærde489, Dongbing Liu56,396, Eric Minwei Liu88,301,302, Fei-Fei Liu201,490, Fenglin Liu381,491, Jia Liu492, Xingmin Liu56,396, Julie Livingstone6, Dimitri Livitz8, Naomi Livni221, Lucas Lochovsky5,19,110, Markus Loeffler467, Georgina V. Long211, Armando Lopez-Guillermo493, Shaoke Lou5,19, David N. Louis72, Laurence B. Lovat117, Yiling Lu38, Yong-Jie Lu162,494, Youyong Lu495,496,497, Claudio Luchini167, Ilinca Lungu144,148, Xuemei Luo152, Hayley J. Luxton117, Andy G. Lynch223,315,498, Lisa Lype36, Cristina López111,112, Carlos López-Otín499, Eric Z. Ma64, Yussanne Ma30, Gaetan MacGrogan500, Shona MacRae501, Geoff Macintyre223, Tobias Madsen73, Kazuhiro Maejima184, Andrea Mafficini177, Dennis T. Maglinte166,502, Arindam Maitra174, Partha P. Majumder174, Luca Malcovati232, Salem Malikic62,78, Giuseppe Malleo115, Graham J. Mann211,246,503, Luisa Mantovani-Löffler504, Kathleen Marchal505,506, Giovanni Marchegiani115, Elaine R. Mardis1,193,507, Adam A. Margolin31, Maximillian G. Marin37, Florian Markowetz223,315, Julia Markowski403, Jeffrey Marks508, Tomas Marques-Bonet61,81,386,509, Marco A. Marra30, Luke Marsden351, John W. M. Martens332, Sancha Martin49,510, Jose I. Martin-Subero81,511, Iñigo Martincorena49, Alexander Martinez-Fundichely301,302,451 Yosef E. Maruvka8,26,72, R. Jay Mashl1,2, Charlie E. Massie223, Thomas J. Matthew37, Lucy Matthews178, Erik Mayer221,512, Simon Mayes513, Michael Mayo30, Faridah Mbabaali272, Karen McCune514, Ultan McDermott49, Patrick D. McGillivray19, Michael D. McLellan1,3,20, John D. McPherson148,272,515, John R. McPherson179,180, Treasa A. McPherson260, Samuel R. Meier8, Alice Meng516, Shaowu Meng134, Andrew Menzies49, Neil D. Merrett115,517, Sue Merson178, Matthew Meyerson8,14,82, William U. Meyerson4,5, Piotr A. Mieczkowski518, George L. Mihaiescu76, Sanja Mijalkovic284, Ana Mijalkovic Mijalkovic-Lazic284, Tom Mikkelsen519, Michele Milella253, Linda Mileshkin103, Christopher A. Miller1 , David K. Miller113,170, Jessica K. Miller272, Gordon B. Mills33,34, Ana Milovanovic57, Sarah Minner520, Marco Miotto115, Gisela Mir Arnau267, Lisa Mirabello240, Chris Mitchell103, Thomas J. Mitchell49,315,352, Satoru Miyano375, Naoki Miyoshi375, Shinichi Mizuno521, Fruzsina Molnár-Gábor522, Malcolm J. Moore300, Richard A. Moore30, Sandro Morganella49, Quaid D. Morris127,490, Carl Morrison523,524, Lisle E. Mose134, Catherine D. Moser349, Ferran Muiños298,299, Loris Mularoni298,299, Andrew J. Mungall30, Karen Mungall30, Elizabeth A. Musgrove133, Ville Mustonen525,526,527, David Mutch528, Francesc Muyas52,53,74, Donna M. Muzny12, Alfonso Muñoz59, Jerome Myers529, Ola Myklebost461, Peter Möller530, Genta Nagae89, Adnan M. Nagrial170, Hardeep K. Nahal-Bose76, Hitoshi Nakagama531, Hidewaki Nakagawa184, Hiromi Nakamura118, Toru Nakamura388, Kaoru Nakano184, Tannistha Nandi532, Jyoti Nangalia49, Mia Nastic284, Arcadi Navarro61,81,386, Fabio C. P. Navarro19, David E. Neal223,352, Gerd Nettekoven533, Felicity Newell209,311, Steven J. Newhouse59, Yulia Newton37, Alvin Wei Tian Ng534, Anthony Ng535, Jonathan Nicholson49, David Nicol221, Yongzhan Nie321,536, G. Petur Nielsen72, Morten Muhlig Nielsen73, Serena Nik-Zainal49,281,282,537, Michael S. Noble8, Katia Nones209,311, Paul A. Northcott538, Faiyaz Notta148,539, Brian D. O’Connor76,540, Peter O’Donnell541, Maria O’Donovan282, Sarah O’Meara49, Brian Patrick O’Neill542, J. Robert O’Neill543, David Ocana59, Angelica Ochoa88, Layla Oesper544, Christopher Ogden221, Hideki Ohdan93, Kazuhiro Ohi375, Lucila Ohno-Machado244, Karin A. Oien523,545, Akinyemi I. Ojesina546,547,548, Hidenori Ojima549, Takuji Okusaka550, Larsson Omberg551, Choon Kiat Ong552, Stephan Ossowski52,53,74, German Ott553, B. F. Francis Ouellette76,554, Christine P’ng6, Marta Paczkowska6, Salvatore Paiella115, Chawalit Pairojkul523, Marina Pajic170, Qiang Pan-Hammarström56,555, Elli Papaemmanuil49, Irene Papatheodorou59, Nagarajan Paramasivam43,47, Ji Wan Park385, Joong-Won Park556, Keunchil Park557,558, Kiejung Park559, Peter J. Park264,266, Joel S. Parker518, Simon L. Parsons124, Harvey Pass560, Danielle Pasternack272, Alessandro Pastore276, Ann-Marie Patch209,311, Iris Pauporté251, Antonio Pea115, John V. Pearson209,311, Chandra Sekhar Pedamallu8,14,82, Jakob Skou Pedersen73,75, Paolo Pederzoli115, Martin Peifer270, Nathan A. Pennell561, Charles M. Perou129,518, Marc D. Perry76,77, Gloria M. Petersen562, Myron Peto22, Nicholas Petrelli563, Robert Petryszak59, Stefan M. Pfister426,465,564, Mark Phillips424, Oriol Pich298,299, Hilda A. Pickett478, Todd D. Pihl565, Nischalan Pillay566, Sarah Pinder567, Mark Pinese170, Andreia V. Pinho568, Esa Pitkänen60, Xavier Pivot569, Elena Piñeiro-Yáñez95, Laura Planko533, Christoph Plass345, Paz Polak8,14,15, Tirso Pons570, Irinel Popescu571, Olga Potapova572, Aparna Prasad52, Shaun R. Preston573, Manuel Prinz47, Antonia L. Pritchard311, Stephenie D. Prokopec6, Elena Provenzano574, Xose S. Puente499, Sonia Puig176, Montserrat Puiggròs57, Sergio Pulido-Tamayo505,506, Gulietta M. Pupo246, Colin A. Purdie575, Michael C. Quinn209,311, Raquel Rabionet52,53,576, Janet S. Rader577, Bernhard Radlwimmer397, Petar Radovic284, Benjamin Raeder60, Keiran M. Raine49, Manasa Ramakrishna49, Kamna Ramakrishnan49, Suresh Ramalingam578, Benjamin J. Raphael579, W. Kimryn Rathmell580, Tobias Rausch60, Guido Reifenberger475, Jüri Reimand6,44, Jorge Reis-Filho348, Victor Reuter348, Iker Reyes-Salazar298, Matthew A. Reyna579, Sheila M. Reynolds36, Esther Rheinbay8,14,72, Yasser Riazalhosseini189, Andrea L. Richardson323, Julia Richter111,128, Matthew Ringel581, Markus Ringnér181, Yasushi Rino582, Karsten Rippe405, Jeffrey Roach583, Lewis R. Roberts349, Nicola D. Roberts49, Steven A. Roberts584, A. Gordon Robertson30, Alan J. Robertson113, Javier Bartolomé Rodriguez57, Bernardo Rodriguez-Martin104,105,106, F. Germán Rodríguez-González83,332, Michael H. A. Roehrl44,123,148,234,585,586, Marius Rohde587, Hirofumi Rokutan440, Gilles Romieu588, Ilse Rooman170, Tom Roques262, Daniel Rosebrock8, Mara Rosenberg8,72, Philip C. Rosenstiel589, Andreas Rosenwald590, Edward W. Rowe221,591, Romina Royo57, Steven G. Rozen179,180,592, Yulia Rubanova17,127, Mark A. Rubin423,593,594,595,596, Carlota Rubio-Perez298,299,597, Vasilisa A. Rudneva60, Borislav C. Rusev177, Andrea Ruzzenente598, Gunnar Rätsch276,277,278,279,280,430, Radhakrishnan Sabarinathan298,299,599, Veronica Y. Sabelnykova6, Sara Sadeghi30, S. Cenk Sahinalp62,78,79, Natalie Saini357, Mihoko Saito-Adachi440, Gordon Saksena8, Adriana Salcedo6, Roberto Salgado600, Leonidas Salichos5,19, Richard Sallari8, Charles Saller601, Roberto Salvia115, Michelle Sam272, Jaswinder S. Samra115,602, Francisco Sanchez-Vega114,121, Chris Sander276,603,604, Grant Sanders134, Rajiv Sarin605, Iman Sarrafi62,78, Aya Sasaki-Oku184, Torill Sauer489, Guido Sauter520, Robyn P. M. Saw211, Maria Scardoni167, Christopher J. Scarlett170,606, Aldo Scarpa177, Ghislaine Scelo194, Dirk Schadendorf68,607, Jacqueline E. Schein30, Markus B. Schilhabel589, Matthias Schlesner47,80, Thorsten Schlomm84,608, Heather K. Schmidt1 , Sarah-Jane Schramm246, Stefan Schreiber609, Nikolaus Schultz121, Steven E. Schumacher8,323, Roland F. Schwarz59,403,405,610, Richard A. Scolyer211,448,602, David Scott428, Ralph Scully611, Raja Seethala612, Ayellet V. Segre8,613, Iris Selander260, Colin A. Semple434, Yasin Senbabaoglu276, Subhajit Sengupta614, Elisabetta Sereni115, Stefano Serra585, Dennis C. Sgroi72, Mark Shackleton103, Nimish C. Shah352, Sagedeh Shahabi234, Catherine A. Shang329, Ping Shang211, Ofer Shapira8,323, Troy Shelton271, Ciyue Shen603,604, Hui Shen615, Rebecca Shepherd49, Ruian Shi490, Yan Shi134, Yu-Jia Shiah6, Tatsuhiro Shibata118,616, Juliann Shih8,82, Eigo Shimizu375, Kiyo Shimizu617, Seung Jun Shin618, Yuichi Shiraishi375, Tal Shmaya285, Ilya Shmulevich36, Solomon I. Shorser6, Charles Short59, Raunak Shrestha62, Suyash S. Shringarpure217, Craig Shriver619, Shimin Shuai6,126, Nikos Sidiropoulos83, Reiner Siebert112,620, Anieta M. Sieuwerts332, Lina Sieverling205,237, Sabina Signoretti202,621, Katarzyna O. Sikora177, Michele Simbolo138, Ronald Simon520, Janae V. Simons134, Jared T. Simpson6,17, Peter T. Simpson473, Samuel Singer115,458, Nasa Sinnott-Armstrong8,217, Payal Sipahimalani30, Tara J. Skelly390, Marcel Smid332, Jaclyn Smith622, Karen Smith-McCune514, Nicholas D. Socci276, Heidi J. Sofia27, Matthew G. Soloway134, Lei Song240, Anil K. Sood623,624,625, Sharmila Sothi626, Christos Sotiriou244, Cameron M. Soulette37, Paul N. Span627, Paul T. Spellman22, Nicola Sperandio177, Andrew J. Spillane211, Oliver Spiro8, Jonathan Spring628, Johan Staaf181, Peter F. Stadler163,164,165, Peter Staib629, Stefan G. Stark277,279,618,630, Lucy Stebbings49, Ólafur Andri Stefánsson631, Oliver Stegle59,60,632, Lincoln D. Stein6,126, Alasdair Stenhouse633, Chip Stewart8, Stephan Stilgenbauer634, Miranda D. Stobbe52,61, Michael R. Stratton49, Jonathan R. Stretch211, Adam J. Struck31, Joshua M. Stuart24,37, Henk G. Stunnenberg396,635, Hong Su56,396, Xiaoping Su99, Ren X. Sun6, Stephanie Sungalee60, Hana Susak52,53, Akihiro Suzuki89,636, Fred Sweep637, Monika Szczepanowski128, Holger Sültmann67,638, Takashi Yugawa617, Angela Tam30, David Tamborero298,299, Benita Kiat Tee Tan639, Donghui Tan518, Patrick Tan180,532,592,640, Hiroko Tanaka375, Hirokazu Taniguchi616, Tomas J. Tanskanen641, Maxime Tarabichi49,290, Roy Tarnuzzer220, Patrick Tarpey642, Morgan L. Taschuk152, Kenji Tatsuno89, Simon Tavaré223,643, Darrin F. Taylor113, Amaro Taylor-Weiner8, Jon W. Teague49, Bin Tean Teh180,592,640,644,645, Varsha Tembe246, Javier Temes104,105, Kevin Thai76, Sarah P. Thayer393, Nina Thiessen30, Gilles Thomas646, Sarah Thomas221, Alan Thompson221, Alastair M. Thompson633, John F. Thompson211, R. Houston Thompson647, Heather Thorne103, Leigh B. Thorne176, Adrian Thorogood424, Grace Tiao8, Nebojsa Tijanic284, Lee E. Timms272, Roberto Tirabosco648, Marta Tojo106, Stefania Tommasi649, Christopher W. Toon170, Umut H. Toprak48,650, David Torrents57,81, Giampaolo Tortora651,652, Jörg Tost653, Yasushi Totoki118, David Townend654, Nadia Traficante103, Isabelle Treilleux655,656, Jean-Rémi Trotta61, Lorenz H. P. Trümper469, Ming Tsao124,539, Tatsuhiko Tsunoda183,657,658,659, Jose M. C. Tubio104,105,106, Olga Tucker660, Richard Turkington661, Daniel J. Turner513, Andrew Tutt323, Masaki Ueno376, Naoto T. Ueno662, Christopher Umbricht151,213,663, Husen M. Umer305,664, Timothy J. Underwood665, Lara Urban59,60, Tomoko Urushidate616, Tetsuo Ushiku339, Liis Uusküla-Reimand666,667, Alfonso Valencia57,81, David J. Van Den Berg166, Steven Van Laere307, Peter Van Loo290,291, Erwin G. Van Meir668, Gert G. Van den Eynden307, Theodorus Van der Kwast123, Naveen Vasudev137, Miguel Vazquez57,669, Ravikiran Vedururu267, Umadevi Veluvolu518, Shankar Vembu490,670, Lieven P. C. Verbeke506,671, Peter Vermeulen307, Clare Verrill351,672, Alain Viari177, David Vicente57, Caterina Vicentini177, K. Vijay Raghavan365, Juris Viksna673, Ricardo E. Vilain674, Izar Villasante57, Anne Vincent-Salomon635, Tapio Visakorpi190, Douglas Voet8, Paresh Vyas311,351, Ignacio Vázquez-García49,86,675,676, Nick M. Waddell209, Nicola Waddell209,311, Claes Wadelius677, Lina Wadi6, Rabea Wagener111,112, Jeremiah A. Wala8,14,82, Jian Wang56, Jiayin Wang1,40,66, Linghua Wang12, Qi Wang465, Wenyi Wang21, Yumeng Wang21, Zhining Wang220, Paul M. Waring523, Hans-Jörg Warnatz483, Jonathan Warrell5,19, Anne Y. Warren352,678, Sebastian M. Waszak60, David C. Wedge49,294,679, Dieter Weichenhan345, Paul Weinberger680, John N. Weinstein38, Joachim Weischenfeldt60,83,84, Daniel J. Weisenberger166, Ian Welch681, Michael C. Wendl1,10,11, Johannes Werner47,85, Justin P. Whalley61,682, David A. Wheeler12,13, Hayley C. Whitaker117, Dennis Wigle683, Matthew D. Wilkerson518, Ashley Williams244, James S. Wilmott211, Gavin W. Wilson6,148, Julie M. Wilson148, Richard K. Wilson1,684, Boris Winterhoff685, Jeffrey A. Wintersinger17,127,384, Maciej Wiznerowicz686,687, Stephan Wolf688, Bernice H. Wong689, Tina Wong1,30, Winghing Wong690, Youngchoon Woo250, Scott Wood209,311, Bradly G. Wouters44, Adam J. Wright6, Derek W. Wright133,691, Mark H. Wright217, Chin-Lee Wu72, Dai-Ying Wu285, Guanming Wu692, Jianmin Wu170, Kui Wu56,396, Yang Wu179,180, Zhenggang Wu64, Liu Xi12, Tian Xia693, Qian Xiang76, Xiao Xiao66, Rui Xing497, Heng Xiong56,396, Qinying Xu209,311, Yanxun Xu694, Hong Xue64, Shinichi Yachida118,695, Sergei Yakneen60, Rui Yamaguchi375, Takafumi N. Yamaguchi6, Masakazu Yamamoto120, Shogo Yamamoto89, Hiroki Yamaue376, Fan Yang490, Huanming Yang56, Jean Y. Yang696, Liming Yang220, Lixing Yang697, Shanlin Yang306, Tsun-Po Yang270, Yang Yang369, Xiaotong Yao408,698, Marie-Laure Yaspo483, Lucy Yates49, Christina Yau156, Chen Ye56,396, Kai Ye40,41, Venkata D. Yellapantula20,86, Christopher J. Yoon249, Sung-Soo Yoon463, Fouad Yousif6, Jun Yu699, Kaixian Yu700, Willie Yu701, Yingyan Yu702, Ke Yuan223,510,703, Yuan Yuan21, Denis Yuen6, Takashi Yugawa617, Christina K. Yung76, Olga Zaikova704, Jorge Zamora49,104,105,106, Marc Zapatka397, Jean C. Zenklusen220, Thorsten Zenz67, Nikolajs Zeps705,706, Cheng-Zhong Zhang8,707, Fan Zhang381, Hailei Zhang8, Hongwei Zhang494, Hongxin Zhang121, Jiashan Zhang220, Jing Zhang5, Junjun Zhang76, Xiuqing Zhang56, Xuanping Zhang66,369, Yan Zhang5,708,709, Zemin Zhang381,710, Zhongming Zhao711, Liangtao Zheng381, Xiuqing Zheng381, Wanding Zhou615, Yong Zhou56, Bin Zhu240, Hongtu Zhu700,712, Jingchun Zhu24, Shida Zhu56,396, Lihua Zou713, Xueqing Zou49, Anna deFazio246,247,714, Nicholas van As221, Carolien H. M. van Deurzen715, Marc J. van de Vijver523, L. van’t Veer716 & Christian von Mering433,717, The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.
Published: 2020

48. Initiative for Early Lung Cancer Research on Treatment: Development of Study Design and Pilot Implementation

Author: Raja Flores, Emanuela Taioli, David F. Yankelevitz, Betsy J. Becker, Artit Jirapatnakul, Anthony Reeves, Rebecca Schwartz, Rowena Yip, Esther Fevrier, Kathleen Tam, Benjamin Steiger, Claudia I. Henschke, Andrew Kaufman, Dong-Seok Lee, Daniel Nicastri, Andrea Wolf, Kenneth Rosenzweig, Jorge Gomez, Mary Beth Beasley, Maureen Zakowski, Michael Chung, David Yankelevitz, Claudia Henschke, Rita Futamura, Sydney Kantor, Carly Wallace, Faiz Bhora, Wissam Raad, Andrew Evans, Walter Choi, Zrzu Buyuk, Adie Friedman, Ronald Dreifuss, Stacey Verzosa, Mariya Yakubox, Karina Aloferdova, Patricia Stacey, Simone De Nobrega, Ardeshir Hakami, Harvey Pass, Berne Crawford, Jessica Donnington, Benjamin Cooper, Andre Moreirea, Audrey Sorensen, Leslie Kohman, Robert Dunton, Jason Wallen, Christopher Curtiss, Ernest Scalzetti, Linda Ellinwood, Ralph Aye, Eric Vallieres, Brian Louie, Alex Frivar, Vivek Mehta, Kristin Manning, Maria Chona, Andrew Smith, Clifford P. Connery, Emilo Torres, Dan Cruzer, Bruce Gendron, Sonya Alyea, Daniel Lackaye, Lauren Studer, and Betsy Becker
Subjects: Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Lung Neoplasms, medicine.medical_treatment, 030204 cardiovascular system & hematology, Radiosurgery, Pulmonary function testing, 03 medical and health sciences, 0302 clinical medicine, Quality of life, Carcinoma, Non-Small-Cell Lung, medicine, Humans, Prospective Studies, Pneumonectomy, Lung cancer, Lymph node, Aged, Neoplasm Staging, business.industry, General surgery, Health Plan Implementation, medicine.disease, Institutional review board, Radiation therapy, Treatment Outcome, medicine.anatomical_structure, Oncology, Research Design, 030220 oncology & carcinogenesis, Mediastinal lymph node, Feasibility Studies, Lymph Node Excision, Female, business, Follow-Up Studies, Cohort study
Abstract: Introduction To maximize the benefits of computed tomographic screening for lung cancer, optimal treatment for small, early lung cancers is needed. Limiting the extent of surgery spares lung tissue, preserves pulmonary function, and decreases operative time, complications, and morbidities. It also increases the likelihood of resecting future new primary lung cancers. The goal is to assess alternative treatments in a timely manner. Methods The focus sessions with patients and physicians separately highlighted the need to consider their perceptions. Literature reviews and analyses of treatment results using large databases were performed to formulate critical questions about long-term treatment outcomes, recurrence, and quality of life of alternative treatments. Based on these analyses, the investigators developed a prospective multi-institutional cohort study, the Initiative for Early Lung Cancer Research for Treatment, to compare treatments for stage I NSCLC. HIPAA compliant institutional review board approval was obtained and we performed a feasibility study of the first 206 surgical patients. Results Lobectomy was performed in 89 (43.2%) patients, and sublobar resection was performed in 117 (56.7%) patients. Mediastinal lymph node resection was performed in 173 (84.0%) patients, 8 had N1 and 3 N2 lymph node metastases. Patients stated that both the surgeon's opinion (93%) and the patient's own opinion (93%) were extremely important, followed by the patients' view that the chosen procedure would provide the best quality of life (90%). Conclusions It was feasible to obtain pre- and postsurgical information from patients and surgeons. We anticipate statistically meaningful results about treatment alternatives in 3 to 5 years.
Published: 2018

49. Discussion

Author: Harvey Pass
Subjects: Pulmonary and Respiratory Medicine, Surgery, Cardiology and Cardiovascular Medicine
Published: 2020

50. Buffy Coat Immunotranscriptomics for Diagnosis of Malignant Pleural Mesothelioma

Author: Gerardo Velez, Harvey Pass, Michele Carbone, Haining Yang, and Chandra Goparaju
Subjects: 0301 basic medicine, business.industry, General Medicine, Buffy coat, Gene signature, medicine.disease, Transplantation, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Immunophenotyping, Immune system, 030220 oncology & carcinogenesis, Immunology, medicine, Biomarker (medicine), Mesothelioma, Liquid biopsy, business
Abstract: Malignant pleural mesothelioma is a highly aggressive tumor primarily caused by asbestos exposure and associated with poor clinical outcomes. The availability of a robust non-invasive test for the screening of asbestos-exposed subjects is therefore an important unmet clinical need. It is widely recognized that the immune system can play a fundamental role in the control of tumor growth within an organism. Simultaneously, the presence of cancer cells can activate different immune cells to undergo various phenotypic and functional changes. Buffy coat—a novel circulating microenvironment of leukocytes and platelets—may thus reflect critical immuno-oncologic activity, pathways, and molecular programs. We hypothesized the immunotranscriptome of circulating buffy coat could accurately distinguish malignant pleural mesothelioma from high-risk asbestos exposure. Buffy coat RNA was extracted from 84 patients having resection: 40 patients with malignant pleural mesothelioma and 44 patients with asbestos exposure. Gene expression profiling was performed using a Pan Cancer Immune Panel for 770 immune genes and cytokines, and significantly different genes between cohorts were selected to develop diagnostic models. Using 1000 loops of cross validation, a 37 gene signature separated malignant pleural mesothelioma from asbestos exposure with a mean validation AUCS of 0.925. Our buffy coat immunotranscriptomic signature is at least comparable to the most commonly used blood-based diagnostic biomarker for MPM, serum mesothelin-related peptide. In addition, immunophenotyping and pathway analysis of differentially expressed genes characterized MPM buffy coat as a relatively tumorigenic and immunosuppressive state. Several of the most differentially expressed genes encode proteins implicated in cancer development (e.g., CD63, CD44, ISG15, CD59, IL1R2, and TAPBP) and may hold clinical value as therapeutic targets. Larger studies on externally validated cohorts are needed to refine the signature for clinical relevance and develop a more robust diagnostic panel.
Published: 2021

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