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1. Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation

Author

Friedman, J.M., Baross, Agnes, Delaney, Allen D., Ally, Adrian, Arbour, Laura, Asano, Jennifer, Bailey, Dione K., Barber, Sarah, Birch, Patricia, Brown-John, Mabel, Cao, Manqiu, Chan, Susanna, Charest, David L., Farnoud, Noushin, Fernandes, Nicole, Flibotte, Stephane, Go, Anne, Gibson, William T., Holt, Robert A., Jones, Steven J.M., Kennedy, Giulia C., Krzywinski, Martin, Langlois, Sylvie, Haiyan I. Li, McGillivray, Barbara C., Nayar, Tarun, Pugh, Trevor J., Rajcan-Separovic, Evica, Schein, Jacqueline E., Schnerch, Angelique, Siddiqui, Asim, Allen, Margot I. Van, Wilson, Gary, Siu-Li Yong, Zahir, Farah, Eydoux, Patrice, and Marra, Marco A.

Subjects
DNA microarrays -- Research, Chromosome mapping -- Research, Cytogenetics -- Research, Mental retardation -- Research, Biological sciences
Abstract

Whole-genome sampling analysis with Affymetrix GeneChip Human Mapping 100K arrays is used to study 100 children with idiopathic mental retardation and normal results of standard chromosomal analysis. It is found that this technology can detect at least twice as many potentially pathogenic de novo copy-number variants, as conventional cytogenetic analysis can in people with mental retardation.

Published
2006

2. Spatial heterogeneity in medulloblastoma

Author

David T.W. Jones, Yusanne Ma, Xin Wang, Betty Luu, Cynthia Hawkins, Adrian Ally, Marc Remke, John S. Myseros, Nada Jabado, Adam M. Fontebasso, Volker Hovestadt, Michael D. Taylor, Craig Daniels, Borja L. Holgado, Steffen Albrecht, Uri Tabori, David Malkin, Andrey Korshunov, Diana M. Merino, Stuart Horswell, Rebecca Carlsen, James T. Rutka, Daniel Picard, Marco A. Marra, David Shih, Angela Tam, Patrick Plettner, Roger J. Packer, Gary D. Bader, Erin N. Kiehna, Hamza Farooq, Eloi Mercier, John Peacock, Stephen C. Mack, A. Sorana Morrissy, Sameer Agnihotri, Jonathon Torchia, Vijay Ramaswamy, Young Cheng, Kane Tse, Steven J.M. Jones, Laura K. Donovan, Richard A. Moore, Sunit Das, Annie Huang, Nina Thiessen, James Loukides, Darlene Lee, Yisu Li, Marcel Kool, Charles Swanton, Eric Chuah, Tenzin Gayden, Xiaochong Wu, Michael Mayo, Eric Bouffet, Chelsea Mayoh, Peter Lichter, Noreen Dhalla, Brian R. Rood, Jacek Majewski, Ulrich Schüller, Haiyan I. Li, Richard Corbett, Tina Wong, Paul A. Northcott, Pawel Buczkowicz, Florence M.G. Cavalli, Yuan Yao Thompson, William Long, Maria C. Vladoiu, Peter B. Dirks, Hamid Nikbakht, Livia Garzia, Stefan M. Pfister, Jacqueline E. Schein, Simon Papillon-Cavanagh, Andrew J. Mungall, and Jüri Reimand

Subjects
Adult, Male, 0301 basic medicine, renal cell carcinoma, DNA Copy Number Variations, Genome-wide association study, Biology, medulloblastoma, Bioinformatics, Polymorphism, Single Nucleotide, Article, whole exome sequencing, Genetic Heterogeneity, glioblastoma multiforme, 03 medical and health sciences, INDEL Mutation, Renal cell carcinoma, Glioma, Biopsy, gene expression profiling, Genetics, medicine, Cluster Analysis, Humans, Cerebellar Neoplasms, Child, Aged, Aged, 80 and over, Medulloblastoma, Principal Component Analysis, medicine.diagnostic_test, Reverse Transcriptase Polymerase Chain Reaction, business.industry, Genetic heterogeneity, Middle Aged, medicine.disease, 3. Good health, Gene Expression Regulation, Neoplastic, Gene expression profiling, 030104 developmental biology, Child, Preschool, Mutation, Cancer research, Female, Spatial heterogeneity, Personalized medicine, Transcriptome, business, Genome-Wide Association Study
Abstract

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

Published
2017

3. Comprehensive Pan-Genomic Characterization of Adrenocortical Carcinoma

Author

Siyuan Zheng, Andrew D. Cherniack, Ninad Dewal, Richard A. Moffitt, Ludmila Danilova, Bradley A. Murray, Antonio M. Lerario, Tobias Else, Theo A. Knijnenburg, Giovanni Ciriello, Seungchan Kim, Guillaume Assie, Olena Morozova, Rehan Akbani, Juliann Shih, Katherine A. Hoadley, Toni K. Choueiri, Jens Waldmann, Ozgur Mete, A. Gordon Robertson, Hsin-Ta Wu, Benjamin J. Raphael, Lina Shao, Matthew Meyerson, Michael J. Demeure, Felix Beuschlein, Anthony J. Gill, Stan B. Sidhu, Madson Q. Almeida, Maria C.B.V. Fragoso, Leslie M. Cope, Electron Kebebew, Mouhammed A. Habra, Timothy G. Whitsett, Kimberly J. Bussey, William E. Rainey, Sylvia L. Asa, Jérôme Bertherat, Martin Fassnacht, David A. Wheeler, Gary D. Hammer, Thomas J. Giordano, Roel G.W. Verhaak, Guillaume Assié, Hsin-Tu Wu, Madson Almeida, Maria Candida Barisson Fragoso, Mouhammed Amir Habra, Christopher Benz, Adrian Ally, Miruna Balasundaram, Reanne Bowlby, Denise Brooks, Yaron S.N. Butterfield, Rebecca Carlsen, Noreen Dhalla, Ranabir Guin, Robert A. Holt, Steven J.M. Jones, Katayoon Kasaian, Darlene Lee, Haiyan I. Li, Lynette Lim, 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, Peter J. Park, Matthias Kroiss, Jianjiong Gao, Chris Sander, Nikolaus Schultz, Corbin D. Jones, Raju Kucherlapati, Piotr A. Mieczkowski, Joel S. Parker, Charles M. Perou, Donghui Tan, Umadevi Veluvolu, Matthew D. Wilkerson, D. Neil Hayes, Marc Ladanyi, Marcus Quinkler, J. Todd Auman, Ana Claudia Latronico, Berenice B. Mendonca, Mathilde Sibony, Zack Sanborn, Michelle Bellair, Christian Buhay, Kyle Covington, Mahmoud Dahdouli, Huyen Dinh, Harsha Doddapaneni, Brittany Downs, Jennifer Drummond, Richard Gibbs, Walker Hale, Yi Han, Alicia Hawes, Jianhong Hu, Nipun Kakkar, Divya Kalra, Ziad Khan, Christine Kovar, Sandy Lee, Lora Lewis, Margaret Morgan, Donna Morton, Donna Muzny, Jireh Santibanez, Liu Xi, Bertrand Dousset, Lionel Groussin, Rossella Libé, Lynda Chin, Sheila Reynolds, Ilya Shmulevich, Sudha Chudamani, Jia Liu, Laxmi Lolla, Ye Wu, Jen Jen Yeh, Saianand Balu, Tom Bodenheimer, Alan P. Hoyle, Stuart R. Jefferys, Shaowu Meng, Lisle E. Mose, Yan Shi, Janae V. Simons, Matthew G. Soloway, Junyuan Wu, Wei Zhang, Kenna R. Mills Shaw, John A. Demchok, Ina Felau, Margi Sheth, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean C. Zenklusen, Jiashan (Julia) Zhang, Tanja Davidsen, Catherine Crawford, Carolyn M. Hutter, Heidi J. Sofia, Jeffrey Roach, Wiam Bshara, Carmelo Gaudioso, Carl Morrison, Patsy Soon, Shelley Alonso, Julien Baboud, Todd Pihl, Rohini Raman, Qiang Sun, Yunhu Wan, Rashi Naresh, Harindra Arachchi, Rameen Beroukhim, Scott L. Carter, Juok Cho, Scott Frazer, Stacey B. Gabriel, Gad Getz, David I. Heiman, Jaegil Kim, Michael S. Lawrence, Pei Lin, Michael S. Noble, Gordon Saksena, Steven E. Schumacher, Carrie Sougnez, Doug Voet, Hailei Zhang, Jay Bowen, Sara Coppens, Julie M. Gastier-Foster, Mark Gerken, Carmen Helsel, Kristen M. Leraas, Tara M. Lichtenberg, Nilsa C. Ramirez, Lisa Wise, Erik Zmuda, Stephen Baylin, James G. Herman, Janine LoBello, Aprill Watanabe, David Haussler, Amie Radenbaugh, Arjun Rao, Jingchun Zhu, Detlef K. Bartsch, Silviu Sbiera, Bruno Allolio, Timo Deutschbein, Cristina Ronchi, Victoria M. Raymond, Michelle Vinco, Linda Amble, Moiz S. Bootwalla, Phillip H. Lai, David J. Van Den Berg, Daniel J. Weisenberger, Bruce Robinson, Zhenlin Ju, Hoon Kim, Shiyun Ling, Wenbin Liu, Yiling Lu, Gordon B. Mills, Kanishka Sircar, Qianghu Wang, Kosuke Yoshihara, Peter W. Laird, Yu Fan, Wenyi Wang, Eve Shinbrot, Martin Reincke, John N. Weinstein, Sam Meier, and Timothy Defreitas

Subjects
Adult, Male, 0301 basic medicine, Cancer Research, Adolescent, Genomics, Biology, Genome, TERF2, Article, Disease-Free Survival, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Outcome Assessment, Health Care, Adrenocortical Carcinoma, medicine, Humans, Adrenocortical carcinoma, Genetic Predisposition to Disease, Child, Aged, Aged, 80 and over, Genetics, Genome, Human, business.industry, Gene Expression Profiling, Cell Biology, DNA Methylation, Middle Aged, Prognosis, medicine.disease, Adrenal Cortex Neoplasms, Human genetics, 3. Good health, Gene Expression Regulation, Neoplastic, Gene expression profiling, 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Mutation, Cancer cell, DNA methylation, Cancer research, Female, Human genome, business
Abstract

We describe a comprehensive genomic characterization of adrenocortical carcinoma (ACC). Using this dataset, we expand the catalogue of known ACC driver genes to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1. Genome wide DNA copy-number analysis revealed frequent occurrence of massive DNA loss followed by whole-genome doubling (WGD), which was associated with aggressive clinical course, suggesting WGD is a hallmark of disease progression. Corroborating this hypothesis were increased TERT expression, decreased telomere length, and activation of cell-cycle programs. Integrated subtype analysis identified three ACC subtypes with distinct clinical outcome and molecular alterations which could be captured by a 68-CpG probe DNA-methylation signature, proposing a strategy for clinical stratification of patients based on molecular markers.

Published
2016

4. Comprehensive genomic characterization of head and neck squamous cell carcinomas

Author

Ni Zhao, Carter Van Waes, Lori Boice, Ashley H. Salazar, Petar Stojanov, Michael B. Prystowsky, Akinyemi I. Ojesina, Tara M. Lichtenberg, Nikolaus Schultz, Joshua M. Stuart, Mitchell J. Frederick, Julie M. Gastier-Foster, Jeffrey N. Myers, Bradley A. Ozenberger, Margaret L. Gulley, Jean C. Zenklusen, Inanc Birol, Christina Yau, Mark E. Sherman, Saianand Balu, Angela Hadjipanayis, Barry S. Taylor, Piotr A. Mieczkowski, Anthony Saleh, Carol G. Shores, Ezra E.W. Cohen, Joonil Jung, Ari B. Kahn, Lisa Wise, Peter S. Hammerman, Pei Lin, Marc Ladanyi, Mark C. Weissler, Scott L. Carter, Michele C. Hayward, Rehan Akbani, Todd Pihl, J. Jack Lee, Sophie C. Egea, Harshad S. Mahadeshwar, Leigh B. Thorne, Matthew G. Soloway, Troy Shelton, Andrea Haddad, William N. William, Wiktoria Maria Suchorska, Johanna Gardner, Marco A. Marra, Julie Ahn, Travis I. Zack, Lihua Zou, Bayardo Perez-Ordonez, David A. Wheeler, Daniel Crain, Adrian Ally, Deepak Srinivasan, Jay Bowen, Aaron D. Black, Jing Wang, Ludmila Danilova, Roy Tarnuzzer, Brenda Diergaarde, Tod D. Casasent, Dean Cheng, Giovanni Ciriello, Ken Burnett, Jeff Bruce, Wojciech Golusiński, Jonathan G. Seidman, Corbin D. Jones, Daniel J. Weisenberger, Lisa A. Peterson, Thomas M. Harris, Angeliki Pantazi, Nina Thiessen, Curtis R. Pickering, Chandra Sekhar Pedamallu, Yingchun Liu, William Lee, Andrzej Mackiewicz, Hailei Zhang, Ronglai Shen, B. Arman Aksoy, Lixing Yang, Jeffrey Roach, Simion I. Chiosea, John Waldron, David Van Den Berg, James Stephen Marron, Tanja Davidsen, Liming Yang, Maciej Wiznerowicz, Benjamin Gross, Paul M. Weinberger, Yufeng Liu, Reanne Bowlby, Zhixiang Zuo, Bartosz Szybiak, Roni J. Bollag, Samuel S. Freeman, Heather M. Walline, Gad Getz, Scott Morris, Michael S. Noble, Charles Saller, Sahil Seth, Richard A. Gibbs, Jonathan C. Irish, Hollie A. Harper, George E. Sandusky, S. Onur Sumer, Trevor Hackman, Gordon B. Mills, Carol R. Bradford, Payal Sipahimalani, Nipun Kakkar, Robert Penny, Jennifer Drummond, Adam M. Zanation, Rebecca Carlsen, Andrew J. Mungall, Harshavardhan Doddapaneni, James G. Herman, Sylvia Wrenn, Andy Chu, Nilsa C. Ramirez, Patrick Kwok Shing Ng, Patrick K. Kimes, Tina Wong, Mark E. Prince, Han Si, Kristian Cibulskis, Katherine Tarvin, Peter W. Laird, Jiabin Tang, Raja R. Seethala, Michael Parfenov, Jan F. Prins, Erin Curley, Hui Cheng, Donna M. Muzny, Lynda Chin, D. Neil Hayes, Margi Sheth, Carmen Gomez-Fernandez, Jessica Walton, Paul C. Boutros, Ariane Nguyen, Kristen M. Leraas, Robert L. Ferris, Greg Eley, Christopher C. Benz, Jaegil Kim, Thomas E. Carey, Douglas B. Chepeha, Janae V. Simons, Jiexin Zhang, Laura S. Rozek, Maureen A. Sartor, Christopher A. Bristow, Justin A. Bishop, Adel K. El-Naggar, Nishant Agrawal, Yiling Lu, Carrie Sougnez, Evan G. Taylor, Raju Kucherlapati, Scott M. Lippman, Colleen Mitchell, Wendell G. Yarbrough, Chu Chen, Donghui Tan, Bhishamjit S. Chera, Michael Mayo, Wenbin Liu, Ranabir Guin, W. Kimryn Rathmell, Mayya Malakh, Jessica Frick, John N. Weinstein, Kevin Lau, Michelle Q. Pham, Gideon Dresdner, Luc G. T. Morris, David Mallery, Zhining Wang, Yichao Sun, Lynn M. Herbert, Christine M. Komarck, Lauren Averett Byers, Angela Tam, Thomas Bodenheimer, Doug Voet, Christie Kovar, Junyuan Wu, Walker Hale, Charles M. Perou, Angela B.Y. Hui, Kenna R. Mills Shaw, Timothy J. Triche, Dong Zeng, Steven J.M. Jones, Matthew D. Wilkerson, Jinze Liu, Yan Guo, Hsu Chao, Tamara R. Jones, Katherine A. Hoadley, Stuart R. Jefferys, Thomas C. Motter, Matthew Meyerson, Konstanty Korski, Timothy A. Chan, Mark A. Jensen, Julien Baboud, Alexei Protopopov, David I. Heiman, Nils Gehlenborg, Heidi J. Sofia, Aaron D. Tward, Eric S. Lander, Yunhu Wan, Scot Waring, Peggy Yena, Robert I. Haddad, Daniel DiCara, Gordon Saksena, Juok Cho, Richard A. Moore, Darshan Singh, Peter J. Park, Matthew Ibbs, Robert A. Holt, Andrew D. Cherniack, Tanguy Y. Seiwert, Lee Lichtenstein, Anders Jacobsen, Rameen Beroukhim, Brandee T. Brown, Stephen C. Benz, Paweł Golusiński, Vonn Walter, Lixia Diao, Erik Zmuda, Scott Frazer, Michael S. Lawrence, Nils Weinhold, Jacqueline E. Schein, Xiaojia Ren, Denise Brooks, Elizabeth Buda, Jianjiong Gao, Jianhua Zhang, William W. Shockley, J. Todd Auman, Xingzhi Song, Jennifer R. Grandis, Jonathan B. McHugh, Stacey Gabriel, Martin L. Ferguson, Jeffrey S. Reid, Joseph Paulauskis, Umadevi Veluvolu, John A. Demchok, Moiz S. Bootwalla, Fei-Fei Liu, Alan P. Hoyle, Shaowu Meng, Mei Huang, Ann Marie Egloff, Christina Beard, Liu Xi, Ricardo Ramirez, Donna Morton, Lisle E. Mose, Leslie Cope, Marjorie Romkes, Zubair Khan, Noreen Dhalla, Candace Shelton, Boris Reva, Stephen B. Baylin, Miruna Balasundaram, Psalm Haseley, Andrew Wei Xu, Yan Shi, A. Gordon Robertson, Gregory T. Wolf, Darlene Lee, Steven E. Schumacher, Semin Lee, Rileen Sinha, Dennis T. Maglinte, Haiyan I. Li, William K. Funkhouser, Yi Han, Sam Ng, Joel S. Parker, Kai Wang, Zhong Chen, You Hong Fan, Yaron S.N. Butterfield, Jeffrey S. Moyer, Robert A. Burton, David Pot, Chris Sander, Daryl Waggott, Joseph A. Califano, Netty Santoso, and Kyle Chang

Subjects
Male, DNA Copy Number Variations, Somatic cell, Biology, Article, 03 medical and health sciences, 0302 clinical medicine, CDKN2A, Humans, HRAS, Molecular Targeted Therapy, RNA, Neoplasm, Gene, neoplasms, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Oncogene, Genome, Human, Squamous Cell Carcinoma of Head and Neck, Wnt signaling pathway, DNA, Neoplasm, Genomics, Oncogenes, Cell cycle, 3. Good health, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms, 030220 oncology & carcinogenesis, Mutation, Cancer research, Carcinoma, Squamous Cell, Female, FAT1, Signal Transduction, Transcription Factors
Abstract

The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs.

Published
2015

5. COMPREHENSIVE MOLECULAR CHARACTERIZATION OF CLEAR CELL RENAL CELL CARCINOMA

Author

Kelinda Tucker, Raju Kucherlapati, Ng Sam, John N. Weinstein, Lori Boice, Satish K. Tickoo, Saianand Balu, John C. Cheville, B. Arman Aksoy, Chip Stewart, Preethi H. Gunaratne, Martin L. Ferguson, Bogdan Czerniak, Christie Kovar, Theodore C. Goldstein, Mark E. Sherman, Juan M. Mosquera, Chris Sander, Yaron S.N. Butterfield, Leigh Anne Zach, Yiling Lu, Chandra Lebovitz, Gary Witkin, David Pot, Gordon Robertson, Richard A. Gibbs, James J. Hsieh, Benjamin P. Berman, Doug Voet, Kyle Chang, W. Marston Linehan, Margaret Morgan, Joan Pontius, Jodi Harr, Lihua Zhou, Joel S. Parker, David Van Den Berg, Michael B. Atkins, Sheila Reynolds, Petar Stojanov, Joel B. Nelson, Gordon B. Mills, Toni K. Choueiri, Weimin Xiao, Hye Jung E. Chun, Ronglai Shen, Rebecca Carlsen, Jennifer Brown, Tod D. Casasent, Sabina Signoretti, Jo Ellen Weaver, Phillip H. Lai, Dominique L. Berton, Patrick Plettner, Irina Ostrovnaya, Lisle E. Mose, Leslie Cope, Nils Gehlenborg, Heidi J. Sofia, Peter J. Park, Scott Morris, Hsin-Ta Wu, Fabio Vandin, Ranabir Guin, Daniel E. Carlin, Jacqueline E. Schein, Xi Liu, Nils Weinhold, Wandaliz Torres-Garcia, Cureline Olga Potapova, Daniel DiCara, Juok Cho, Steve Schumacher, Chris Wakefield, A. Rose Brannon, Susan M. Benton, Tom Bodenheimer, J. Todd Auman, Brenda Rabeno, Sharon M. Gorski, Eric E. Snyder, Divya Kalra, Brenda Ayala, Jiashan Zhang, Zhang Wei, Kyle Ellrott, Zhining Wang, Stacey Gabriel, Dominik Stoll, Daniel L. Rubin, W. Kimryn Rathmell, Eric Chuah, David Mallery, Tanja Davidsen, David Cogdell, Anders Jacobsen, John A. Demchok, Robert C. Onofrio, Anna Chu, Piotr A. Mieczkowski, Zhiyong Ding, Erin Curley, Johanna Gardner, Robert Worrell, Hailei Zhang, Jennifer C. Fisher, Donna M. Muzny, Rajiv Dhir, Walker Hale, Ari B. Kahn, Sheila Fisher, Giovanni Ciriello, Ken Burnett, Marco A. Marra, Wiam Bshara, Anil V. Parwani, Joshua M. Stuart, Richard Varhol, Kristin G. Ardlie, Han Yi, Lisa R. Trevino, Roy Tarnuzzer, Michael S. Noble, Erin Pleasance, Jesse Walsh, Leigh B. Thorne, Andy Chu, Peter W. Laird, Andrew J. Mungall, Rashmi N. Sanbhadti, Mark Backus, David A. Wheeler, Bradley A. Ozenberger, Jodi K. Maranchie, William Mallard, Jared R. Slobodan, Christine Czerwinski, Jireh Santibanez, Andrew J. Stout, Donghui Tan, Laura S. Schmidt, Junyuan Wu, Jianjiong Gao, Daniel J. Weisenberger, D. Neil Hayes, Scott Frazer, Alan P. Hoyle, Konstantin V. Fedosenko, Rehan Akbani, Todd Pihl, Rahul Vegesna, Lynda Chin, Shelley Alonso, Jeffrey G. Reid, Donna Morton, Cathy D. Vocke, R. Houston Thompson, Christopher C. Benz, Kenna R. Mills Shaw, Liming Yang, Carmelo Gaudioso, Nianxiang Zhang, Caleb F. Davis, Carrie Hirst, Shi Yan, Michael L. Blute, Barry S. Taylor, Mathew G. Soloway, Nina Thiessen, Paul T. Spellman, Deepak Srinivasan, Yongjun Zhao, Boris Reva, Wang Min, Stuart R. Jefferys, Benjamin J. Raphael, Nicholas J. Petrelli, Arash Shafiei, Lora Lewis, Eric Jonasch, David I. Heiman, Scot Waring, Richard A. Moore, Eric S. Lander, Evan O. Paull, Hoon Kim, Janae V. Simons, Stephen B. Baylin, Gad Getz, Stanley Girshik, Victor E. Reuter, Benjamin Gross, Ethan Cerami, Andrew D. Cherniack, Christine I. Smith, Christina Yau, Michael D. Topal, Peter Waltman, Jeff Boyd, Rameen Beroukhim, Angela Tam, Yingchun Liu, Peter A. Kigonya, Miruna Balasundaram, Maria J. Merino, David Haussler, Dinh Huyen, Elizabeth Buda, Michael S. Lawrence, Lin Pei, Charles M. Perou, Timothy J. Triche, Jessica Walton, Greg Eley, Tiffany Ting Liu, Joseph Paulauskis, Matthew Meyerson, Marc Ladanyi, Jaegil Kim, Katherine A. Hoadley, Huang Mei, Ilya Shmulevich, Robin J.N. Coope, Mary Iacocca, Natasja Wye, Adrian Ally, Mark A. Rubin, A. Ari Hakimi, Lori Huelsenbeck-Dill, Steven J.M. Jones, James Peterson, Mark A. Jensen, Barbara Tabak, Andrey Sivachenko, Julie Bergsten, John Eckman, Inanc Birol, Rohini Raman, Nipun Kakkar, Christina Liquori, Rileen Sinha, Dennis T. Maglinte, Lichtenstein Lee, Haiyan I. Li, William G. Kaelin, Anna K. Unruh, Noreen Dhalla, Candace Shelton, Roel G.W. Verhaak, Christopher J. Ricketts, Carrie Sougnez, Harsha Doddapaneni, Mark S. Guyer, Robert Penny, Michael F. Berger, Margi Sheth, Darlene Lee, Dimitra Tsavachidou, Chad J. Creighton, Prachi Kothiyal, Scott L. Carter, Michael Mayo, Zhu Jing, Kenneth Aldape, Corbin D. Jones, Moiz S. Bootwalla, Payal Sipahimalani, Martin Hirst, Sean P. Barletta, Kristian Cibulskis, Jerome Myers, Matthew C. Nicholls, Yidi J. Turman, Julien Baboud, Jeff Gentry, Carl Morrison, Gordon Saksena, Troy Shelton, Swapna Mahurkar, Robert A. Holt, Robert Sfeir, Shen Hui, Suzanne S. Fei, Christopher G. Wood, Candace Carter, S. Onur Sumer, Pheroze Tamboli, Yiming Zhu, Broad Institute of MIT and Harvard, Massachusetts Institute of Technology. Department of Biology, Getz, Gad Asher, Voet, Douglas, Lin, Pei, Chin, Lynda, and Lander, Eric Steven

Subjects
DNA Mutational Analysis, GRB10 Adaptor Protein, AMP-Activated Protein Kinases, Epigenesis, Genetic, PBRM1, Pentose Phosphate Pathway, Phosphatidylinositol 3-Kinases, RNA, Neoplasm, BAP1, Genome, Multidisciplinary, Genomics, Chromatin, Gene Expression Regulation, Neoplastic, DNA methylation, Signal transduction, Acetyl-CoA Carboxylase, Carcinoma, Renal Cell, Chromatin Assembly and Disassembly, Citric Acid Cycle, DNA Methylation, Gene Expression Profiling, Genome, Human, Histone-Lysine N-Methyltransferase, Humans, Metabolic Networks and Pathways, MicroRNAs, Mutation, PTEN Phosphohydrolase, Proto-Oncogene Proteins c-akt, Signal Transduction, Survival Analysis, Human, Biology, Article, Genetic, SETD2, microRNA, medicine, Neoplastic, Carcinoma, Renal Cell, medicine.disease, Clear cell renal cell carcinoma, Gene Expression Regulation, Cancer research, RNA, Neoplasm, Epigenesis
Abstract

Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3)K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment.

Published
2013

6. Integrated genomic characterization of endometrial carcinoma

Author

Ding Li, Esther Elishaev, Linda Dao, Juok Cho, Alexei Protopopov, Heather Schmidt, Tod D. Casasent, Bobbie S. Gostout, P.J. DiSaia, Jacqueline E. Schein, J. Todd Auman, Jay Bowen, S. Onur Sumer, Beth Y. Karlan, Gordon Saksena, Prachi Kothiyal, Robert E. Pyatt, Theodore C. Goldstein, Lisle E. Mose, Paul J. Goodfellow, Brenda Ayala, Nilsa C. Ramirez, Thomas Barr, Payal Sipahimalani, Gordon B. Mills, Rebecca Carlsen, Linda Van Le, Andy Chu, Peter W. Laird, Russell Broaddus, Helga B. Salvesen, Sam Ng, Cyriac Kandoth, Christopher Adams, Yiling Lu, Donghui Tan, Peter White, Lori Boice, Saianand Balu, Daniel DiCara, Robert A. Holt, Christopher C. Benz, Shi Yan, Joel S. Parker, Jessica Frick, Adrian Ally, Boris Winterhoff, Pamela M. Pollock, Patrick Plettner, Ethan Cerami, Angela Tam, Katherine A. Hoadley, Melissa Hart-Kothari, Robert C. Onofrio, John N. Weinstein, Sheila Reynolds, David Haussler, Kristian Cibulskis, Charles M. Perou, Timothy J. Triche, Rehan Akbani, Jeff Roach, Michael Mayo, Ranabir Guin, W. Kimryn Rathmell, Carmen Helsel, Junyuan Wu, Will Mallard, Nandita Barnabas, Todd Pihl, Ruibin Xi, Nianxiang Zhang, David Mallery, Douglas A. Levine, Aaron D. Black, David I. Heiman, Sugy Kodeeswaran, Lynda Chin, Guoyan Liu, Mark E. Borowsky, Daniel J. Weisenberger, Yuexin Liu, Hailei Zhang, Kenna R. Mills Shaw, Anna K. Unruh, Andrew Berchuck, Michael Button, Noreen Dhalla, Bryan Hernandez, Rayna K. Matsuno, David G. Mutch, Chen Wang, Teresa R. Tabler, Yaron S.N. Butterfield, Jeff Gentry, Stuart R. Jefferys, Thomas Grossman, Kelley Kneile, Fanny Dao, Scot Waring, Barbara Tabak, Eric E. Snyder, Eric S. Lander, Richard A. Moore, David J. Dooling, David Van Den Berg, Jiabin Tang, Piotr A. Mieczkowski, Victoria Blanc, Wei Zhang, Inanc Birol, Harkness Kuck, Mathew G. Soloway, Johanna Gardner, Gary Witkin, Sahil Seth, Heidi J. Sofia, B. Arman Aksoy, Nikolaus Schultz, Marco A. Marra, Andrew D. Cherniack, D L Rotin, Anders Jacobsen, Erik Zmuda, Candace Carter, Christina Yau, Stephen C. Benz, Alexander A. Green, Michael D. Topal, Jean MacKenzie, Elena Nemirovich-Danchenko, Nicholas J. Petrelli, Dana Nicholson, Eve Shinbrot, Han Liang, Rameen Beroukhim, Charlenia Berry-Green, Kristin G. Ardlie, Joan Pontius, David Pot, Ari B. Kahn, Marc T. Goodman, Yevgeniy Antipin, Christopher Szeto, Jianhua Zhang, Ilya Shmulevich, Lori Huelsenbeck-Dill, Steven J.M. Jones, Carrie Sougnez, Kristen M. Leraas, Pei Lin, Robert A. Soslow, Erin Curley, Leigh B. Thorne, Hye Jung E. Chun, Michael S. Lawrence, Michelle O'Laughlin, Moiz S. Bootwalla, Lixing Yang, Mark A. Jensen, Rajiv Dhir, David A. Wheeler, C. Blake Gilks, Jianjiong Gao, Lisa Wise, Giovanni Ciriello, Joelle Kalicki-Veizer, Shaowu Meng, Mei Huang, Elaine R. Mardis, Faina Bogomolniy, Kai Ye, Jenny Lester, Lihua Zou, Hollie A. Harper, Robert Edwards, Ronglai Shen, Xiaojia Ren, Nils Weinhold, Harshad S. Mahadeshwar, Sandra Orsulic, Tom Bodenheimer, Zhenlin Ju, Chris Wakefield, Scott Frazer, John M. S. Bartlett, Gideon Dresdner, Hui Shen, Deepak Srinivasan, Aaron Hobensack, Cynthia McAllister, Marc Ladanyi, Tanja Davidsen, Lucinda Fulton, Michael D. McLellan, Richard K. Wilson, Zeng Dong, Olga Potapova, Sean C. Dowdy, Rui Jing, Kristin K. Zorn, Robert S. Fulton, Matti Annala, Chris Sander, Michael S. Noble, Benjamin Gross, Janae V. Simons, Phillip H. Lai, Laura Monovich, Andrew J. Mungall, Peter J. Park, Fedor Moiseenko, Liming Yang, Gad Getz, John Deardurff, Matthew Meyerson, Jeremy Parfitt, A. Gordon Robertson, Bradley M. Broom, Blaise A. Clarke, Greg Eley, Jennifer O. Fisher, Andrey Sivachenko, Narciso Olvera, Carrie Hirst, Adam M. Farkas, Karuna Garg, Wendy Winckler, Eric Chuah, Stacey Gabriel, Michael E. Carney, Stephen B. Baylin, Doug Voet, Miruna Balasundaram, Christine Czerwinski, Daphne W. Bell, Richard Varhol, Alexandra Meuter, Alan P. Hoyle, Darlene Lee, Elizabeth Buda, Li Ding, Xingzhi Song, Steven E. Schumacher, Anna L. Chu, Attila Teoman, Mary Iacocca, Semin Lee, Rileen Sinha, Itai Pashtan, Haiyan I. Li, Mikhail Abramov, Mark S. Guyer, Robert Penny, Margi Sheth, Scott L. Carter, Corbin D. Jones, Michael J. Birrer, Julie M. Gastier-Foster, D. Neil Hayes, Nathan Vanhoose, Brenda Rabeno, Raju Kucherlapati, Martin L. Ferguson, Joshua M. Stuart, Steve E. Kalloger, Mark G. Cadungog, Petar Stojanov, Tara M. Lichtenberg, Bradley A. Ozenberger, Angela Hadjipanayis, Barry S. Taylor, Boris Reva, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., and Park, Peter J.

Subjects
DNA Copy Number Variations, endocrine system diseases, ARID1A, DNA Mutational Analysis, Breast Neoplasms, Biology, medicine.disease_cause, Article, Uterine serous carcinoma, 03 medical and health sciences, 0302 clinical medicine, medicine, Humans, PTEN, Exome, Poly-ADP-Ribose Binding Proteins, neoplasms, 030304 developmental biology, Chromosome Aberrations, Ovarian Neoplasms, 0303 health sciences, Endometrial intraepithelial neoplasia, Multidisciplinary, Genome, Human, Microsatellite instability, DNA Polymerase II, Genomics, medicine.disease, Molecular biology, female genital diseases and pregnancy complications, Endometrial Neoplasms, 3. Good health, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Serous fluid, 030220 oncology & carcinogenesis, DNA methylation, Cancer research, biology.protein, Female, KRAS, Signal Transduction, Transcription Factors
Abstract

We performed an integrated genomic, transcriptomic and proteomic characterization of 373 endometrial carcinomas using array- and sequencing-based technologies. Uterine serous tumours and ~25% of high-grade endometrioid tumours had extensive copy number alterations, few DNA methylation changes, low oestrogen receptor/progesterone receptor levels, and frequent TP53 mutations. Most endometrioid tumours had few copy number alterations or TP53 mutations, but frequent mutations in PTEN, CTNNB1, PIK3CA, ARID1A and KRAS and novel mutations in the SWI/SNF chromatin remodelling complex gene ARID5B. A subset of endometrioid tumours that we identified had a markedly increased transversion mutation frequency and newly identified hotspot mutations in POLE. Our results classified endometrial cancers into four categories: POLE ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high. Uterine serous carcinomas share genomic features with ovarian serous and basal-like breast carcinomas. We demonstrated that the genomic features of endometrial carcinomas permit a reclassification that may affect post-surgical adjuvant treatment for women with aggressive tumours., National Institutes of Health (U.S.) (Grant 5U24CA143799-04), National Institutes of Health (U.S.) (Grant 5U24CA143835-04), National Institutes of Health (U.S.) (Grant 5U24CA143840-04), National Institutes of Health (U.S.) (Grant 5U24CA143843-04), National Institutes of Health (U.S.) (Grant 5U24CA143845-04), National Institutes of Health (U.S.) (Grant 5U24CA143848-04), National Institutes of Health (U.S.) (Grant 5U24CA143858-04), National Institutes of Health (U.S.) (Grant 5U24CA143866-04), National Institutes of Health (U.S.) (Grant 5U24CA143867-04), National Institutes of Health (U.S.) (Grant 5U24CA143882-04), National Institutes of Health (U.S.) (Grant 5U24CA143883-04), National Institutes of Health (U.S.) (Grant 5U24CA144025-04), National Institutes of Health (U.S.) (Grant U54HG003067-11), National Institutes of Health (U.S.) (Grant U54HG003079-10), National Institutes of Health (U.S.) (Grant U54HG003273-10)

Published
2013

7. Alternative expression analysis by RNA sequencing

Author

Gregg B. Morin, Allen Delaney, A. Sorana Morrissy, Yongjun Zhao, Haiyan I. Li, Richard Corbett, Isabella T. Tai, Rodrigo Goya, Michelle J. Tang, Adrian Ally, Helen McDonald, Ryan D. Morin, Gordon Robertson, Jennifer Asano, Suganthi Chittaranjan, Trevor J. Pugh, Jill Mwenifumbo, Thomas Zeng, Ying-Chen Hou, Kevin Teague, Obi L. Griffith, Malachi Griffith, Susanna Y. Chan, Marco A. Marra, Martin Hirst, and Steven J.M. Jones

Subjects
Gene isoform, Antimetabolites, Antineoplastic, genetic processes, Gene Expression, Biology, Biochemistry, Cell Line, Tumor, Databases, Genetic, Expression analysis, Humans, Protein Isoforms, natural sciences, RNA, Messenger, Molecular Biology, Oligonucleotide Array Sequence Analysis, Sequence (medicine), Expressed Sequence Tags, Genetics, Reverse Transcriptase Polymerase Chain Reaction, Sequence Analysis, RNA, Gene Expression Profiling, RNA, Cell Biology, Alternative Splicing, Drug Resistance, Neoplasm, Fluorouracil, Colorectal Neoplasms, Sequence Alignment, Biotechnology
Abstract

In alternative expression analysis by sequencing (ALEXA-seq), we developed a method to analyze massively parallel RNA sequence data to catalog transcripts and assess differential and alternative expression of known and predicted mRNA isoforms in cells and tissues. As proof of principle, we used the approach to compare fluorouracil-resistant and -nonresistant human colorectal cancer cell lines. We assessed the sensitivity and specificity of the approach by comparison to exon tiling and splicing microarrays and validated the results with reverse transcription-PCR, quantitative PCR and Sanger sequencing. We observed global disruption of splicing in fluorouracil-resistant cells characterized by expression of new mRNA isoforms resulting from exon skipping, alternative splice site usage and intron retention. Alternative expression annotation databases, source code, a data viewer and other resources to facilitate analysis are available at http://www.alexaplatform.org/alexa_seq/.

Published
2010

8. Genomic Classification of Cutaneous Melanoma

Author

W. Kimryn Rathmell, Lauren E. Haydu, Nils Gehlenborg, David Mallery, Lynn M. Herbert, Hailei Zhang, Darlene Lee, Payal Sipahimalani, Richard A. Scolyer, Jonathan R. Stretch, Amanda Clarke, Sudha Chudamani, Dirk Schadendorf, Jeffrey Roach, Troy Shelton, Kerwin F. Shannon, Kadir C. Akdemir, Alexander J. Lazar, Lixing Yang, D. Murawa, Jingchun Zhu, Michael Mayo, Steven E. Schumacher, Marc Ladanyi, Yiling Lu, Levi A. Garraway, Andrew J. Spillane, Giandomenico Russo, Ian R. Watson, Matthew D. Wilkerson, Mei Huang, Chang Jiun Wu, Pedamallu Chandra Sekhar, Laura Brockway-Lunardi, Wiktoria Maria Suchorska, Michael A. Davies, John M. S. Bartlett, Benjamin Gross, Mark Gerken, Georgy Manikhas, William R. Jeck, Michael Dinikin, Sam Ng, Antje Sucker, Sharon K. Huang, Donghui Tan, Semin Lee, Da Yang, Yardena Samuels, Boris C. Bastian, Katherine A. Hoadley, Kenna R. Mills Shaw, Shaowu Meng, Kunal Rai, Sheila Fisher, Tom Bodenheimer, Robyn P. M. Saw, Joel S. Parker, Victoria Fulidou, Scot Waring, Vesteinn Thorsson, Jacqueline E. Schein, Heidi J. Sofia, Jia Liu, Eric S. Lander, Martin L. Miller, Scott E. Woodman, Yunhu Wan, Olga Voronina, Brenda Ayala, Moiz S. Bootwalla, Rileen Sinha, Yonathan Lissanu Deribe, Yussanne Ma, Gabriel Sica, Matthew Ibbs, Pam Bartlett, Arkadiusz Spychała, Sheila Reynolds, Nikolaus Schultz, Jianhua Zhang, Stephen B. Baylin, Saianand Balu, Jay Bowen, Eran Hodis, Olga Potapova, Lori Boice, Julie M. Gastier-Foster, Singer Ma, Victor G. Prieto, Steven J.M. Jones, Konstantin V. Fedosenko, Rehan Akbani, Todd Pihl, Ruibin Xi, Stergios J. Moschos, Lisa Iype, Robert Penny, Vonn Walter, Peter Hersey, Umadevi Veluvolu, Jiabin Tang, Mark A. Jensen, Aaron Chevalier, Nils Weinhold, Yaron S.N. Butterfield, S. Onur Sumer, Lisle E. Mose, Leslie Cope, Angela Tam, Carmelo Gaudioso, Giovanni Ciriello, Jaegil Kim, Noreen Dhalla, Candace Shelton, Andrzej Mackiewicz, Travis I. Zack, James G. Herman, Lisa Zimmer, Chia Chin Wu, Elena Pagani, Franklin W. Huang, Tanja Davidsen, Stuart R. Jefferys, Andy Chu, Harmanjatinder S. Sekhon, Richard A. Moore, Scott L. Carter, Ludmila Danilova, Peter W. Laird, Nicholas K. Hayward, Julien Baboud, A. Gordon Robertson, Scott Morris, Honorata Tatka, Gordon Saksena, Robert A. Holt, Angela Hadjipanayis, Jakub Brzezinski, Lihua Zou, Nilsa C. Ramirez, Witold Kycler, Yasin Senbabaoglu, Xingzhi Song, Barbara Tabak, Christopher C. Benz, Michael Dubina, Wei Zhang, Sophie Egea, Fedor Moiseenko, Marcus Bosenberg, Piotr A. Mieczkowski, Michael J. Quinn, Harindra Arachchi, Andrew J. Mungall, Lynn Cherney, Suresh Ramalingam, Christopher A. Bristow, Hojabr Kakavand, Chris Sander, Peiling Tsou, Anil Korkut, Alan P. Hoyle, Arshi Arora, Kenneth K. Lee, Netty Santoso, Raymond J. Cho, Ricardo Ramirez, Melissa Saul, Haiyan I. Li, Jeremy Parfitt, Valerie Jakrot, Tiffany L. Calderone, Jessica Frick, John N. Weinstein, Brady Bernard, John M. Kirkwood, Dave S.B. Hoon, Carolyn J. Shiau, Carmen Gomez-Fernandez, Michael Krauthammer, Carrie Sougnez, George E. Sandusky, Xiaojia Ren, Charles Schwallier, Carolyn M. Hutter, Radoslaw Łaźniak, Dmitry Belyaev, Richard F. Kefford, Jeffrey M. Trent, Ouida Liu, J. Stephen Ebrom, Yoon La Choi, Maciej Wiznerowicz, Ranabir Guin, Yan Shi, Ewa Leporowska, Zhenlin Ju, Charles Saller, Hyojin Kang, Jean C. Zenklusen, Tony Gutschner, Peter White, Luigi Nezi, Oxana Paklina, Harshad S. Mahadeshwar, Wiam Bshara, Roeland Verhaak, Kenneth Y. Tsai, Ilya Shmulevich, Kristian Cibulskis, Jonathan G. Seidman, Corbin D. Jones, Ayush T. Raman, D. Neil Hayes, Nandita Barnabas, Uma Rao, Jennifer Eschbacher, Timothy R. Fennell, Jeffrey E. Lee, Matthew Meyerson, Jeffrey E. Gershenwald, Elizabeth Buda, Xiaobei Zhao, Jason Roszik, M. Teresiak, Daniel DiCara, Pei Lin, Eliezer M. Van Allen, Scott Frazer, Genevieve M. Boland, Zhining Wang, Susan Hoppough, Konstanty Korski, Michael S. Noble, B. Arman Aksoy, Reanne Bowlby, Adeboye Osunkoya, Taofeek K. Owonikoko, Madhusmita Behera, Shiyun Ling, Erin Curley, Rajiv Dhir, Andrew Wei Xu, David I. Heiman, Samirkumar B. Amin, Andrew D. Cherniack, Brenna Matejka, Rameen Beroukhim, Michael S. Lawrence, Kelsey Zhu, Wen-Bin Liu, Stacey Gabriel, Martin L. Ferguson, Samantha Sharpe, Giannicola Genovese, Jay Engel, Johanna Gardner, Junyuan Wu, Marco A. Marra, Roy Tarnuzzer, John F. Thompson, Denise Brooks, Lawrence N. Kwong, Woong-Yang Park, Daniel J. Weisenberger, J. Todd Auman, Kristen M. Leraas, Margi Sheth, Riccardo Bono, John A. Demchok, Stefania D'Atri, Candace D. Carter, Miruna Balasundaram, Natalie Bir, Matthew G. Soloway, Angeliki Pantazi, Sahil Seth, Qixia A. Deng, Junehawk Lee, Dana Nicholson, Ye Wu, Keith T. Flaherty, Peter J. Park, Amie Radenbaugh, Benjamin Hanf, Katherine Tarvin, James S. Wilmott, Giancarlo Antonini Cappellini, Pawel Murawa, Maria Synott, Jonna Grimsby, Stephen Coons, Joachim Klode, Michael Button, Alyssa Janning, Alexei Protopopov, Florian L. Muller, Donald L. Morton, Joshua M. Stuart, Ina Felau, Cindy Sander, Ruth Halaban, John P. Miller, David Haussler, Monique Albert, Charles M. Perou, Timothy J. Triche, Yichao Sun, Aaron D. Black, Adrian Ally, Sousan Mehrabi, David Van Den Berg, Graham J. Mann, Erik Zmuda, Carl Morrison, Daniel Crain, Douglas Voet, Janae V. Simons, Norman E. Sharpless, Fadlo R. Khuri, Phillip H. Lai, Liming Yang, Anders Jacobsen, Keith A. Delman, Teresa R. Tabler, Gad Getz, Tara M. Lichtenberg, William Lee, Georgina V. Long, Nina Thiessen, Ronglai Shen, Francesca Passarelli, Bradley A. Ozenberger, Gordon B. Mills, Jessica Walton, Greg Eley, Leigh B. Thorne, Merrick I. Ross, Jared Malke, Barry S. Taylor, Juok Cho, William R. Burns, Michael Parfenov, Thomas Gribbin, Yuling Wang, Raju Kucherlapati, Lynda Chin, Bradley A. Murray, Lee Lichtenstein, Jianjiong Gao, and Lisa Wise

Subjects
Skin Neoplasms, Mutant, Medizin, Biology, General Biochemistry, Genetics and Molecular Biology, Subclass, Article, Transcriptome, chemistry.chemical_compound, Databases, Genetic, medicine, Humans, Gene, Melanoma, Genetics, Biochemistry, Genetics and Molecular Biology(all), Cancer, Binimetinib, medicine.disease, National Cancer Institute (U.S.), United States, 3. Good health, chemistry, Cutaneous melanoma, Mutation, Cancer research
Abstract

Summary We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF , mutant RAS , mutant NF1 , and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.

Published
2015

9. Divergent clonal selection dominates medulloblastoma at recurrence

Author

Yaron S.N. Butterfield, David Shih, Janet C. Lindsey, Olivier Ayrault, James T. Rutka, Carlos Gilberto Carlotti, Borja L. Holgado, Livia Garzia, Ji Yeoun Lee, Paul A. Northcott, Laura K. Donovan, K. A. Michealraj, Vijay Ramaswamy, Toshihiro Kumabe, Nada Jabado, Thomas Zeng, Michael A. Grotzer, Michael D. Taylor, Jessica Liu, Darlene Lee, Eric Chuah, Gudrun Fleischhack, Scott Zuyderduyn, Xi Huang, Andrey Korshunov, Jacqueline E. Schein, Steven C. Clifford, Ute Bartels, V. Peter Collins, Peter B. Dirks, Stuart Matan-Lithwick, Claudia C. Faria, Daniel W. Fults, Xiao-Nan Li, Tobey J. MacDonald, Yusanne Ma, Mikhail Bilenky, Inanc Birol, Gary D. Bader, Nina Thiessen, Anne Bendel, Marc Remke, Eloi Mercier, Alex Manno, Haiyan I. Li, William A. Weiss, Stéphanie Puget, Noreen Dhalla, Marco A. Marra, Wendy J. Ingram, Sohrab P. Shah, Stefan M. Pfister, Ulrich Schüller, José Pimentel, Jaroslav Sterba, Marcel Kool, Ronald L. Hamilton, Lei Qin, Seung-Ki Kim, An He, Trevor J. Pugh, Stephen C. Mack, Kory Zayne, Xin Wang, Yoon Jae Cho, Kyu-Chang Wang, Patryk Skowron, Betty Luu, Ian F. Pollack, Cynthia Hawkins, Erwin G. Van Meir, Salomeh Jelveh, Andrew J. Mungall, Caitlin Hoffman, Andrew W. Walter, Helen Wheeler, Adi Rolider, Young Cheng, Michael K. Cooper, A. Sorana Morrissy, Jüri Reimand, Uri Tabori, Michael Mayo, Hamza Farooq, Florence M.G. Cavalli, Maria Luisa Garrè, Eric Bouffet, Adrian Ally, Richard A. Moore, Yongjun Zhao, Duncan Stearns, William Long, Richard Corbett, Karel Zitterbart, Yisu Li, Jeffrey H. Wisoff, Tina Wong, Robert J. Wechsler-Reya, Simon Bailey, Yuan Yao Thompson, Lara S. Collier, Luca Massimi, Andrew R. Hallahan, Byung Kyu Cho, Torsten Pietsch, David Lyden, Teiji Tominaga, Angela Tam, James Garvin, Roger J. Packer, John Peacock, Jeffrey J. Olson, Karey Shumansky, Adam J. Dupuy, Kane Tse, David A. Largaespada, Sandra E. Dunn, David T.W. Jones, Young Shin Ra, Patricia Lindsay, Tarek Shalaby, Rebecca Carlsen, Patrick Plettner, Andrew Roth, Chelsea Mayoh, Karen Mungall, Charles G. Eberhart, Xiaochong Wu, Daniela Pretti da Cunha Tirapelli, Sofia Nunes, Jenny Q. Qian, David Malkin, Maura Massimino, John J.Y. Lee, Steven J.M. Jones, Stephan Tippelt, Carolina Nor, and Noriyuki Kijima

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, medicine.medical_treatment, DNA Mutational Analysis, Clone (cell biology), Medizin, Biology, Article, Targeted therapy, 03 medical and health sciences, Mice, Craniospinal Irradiation, Internal medicine, medicine, Animals, Humans, Molecular Targeted Therapy, Selection, Genetic, Cerebellar Neoplasms, Medulloblastoma, Multidisciplinary, Genome, Human, Cancer, medicine.disease, Xenograft Model Antitumor Assays, Human genetics, 3. Good health, Clone Cells, Radiation therapy, Clinical trial, Disease Models, Animal, 030104 developmental biology, Drosophila melanogaster, Immunology, Human genome, Female, Neoplasm Recurrence, Local, Radiotherapy, Image-Guided, Signal Transduction
Abstract

The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (

Published
2015

10. Characterization of HPV and host genome interactions in primary head and neck cancers

Author

J. Jack Lee, Carter Van Waes, Michael B. Prystowsky, Akinyemi I. Ojesina, Joshua M. Stuart, Mitchell J. Frederick, Angela By Hui, Saianand Balu, Scot Waring, Inanc Birol, Bayardo Perez-Ordonez, Aaron D. Black, Payal Sipahimalani, Wiktoria Maria Suchorska, Michele C. Hayward, Jeffrey Roach, Adrian Ally, Ranabir Guin, Samuel S. Freeman, J. Todd Auman, Hollie A. Harper, Mark E. Prince, David Van Den Berg, Nipun Kakkar, James G. Herman, Adam M. Zanation, Nilsa C. Ramirez, Daniel DiCara, Carol R. Bradford, Paul C. Boutros, Peter W. Laird, Evan G. Taylor, Yan Shi, Jonathan M. Irish, Kristian Cibulskis, Junyuan Wu, Darlene Lee, Katherine A. Hoadley, Jeff Bruce, Yingchun Liu, Heather M. Walline, Carol G. Shores, Raju Kucherlapati, Scott M. Lippman, Colleen Mitchell, Steven E. Schumacher, Wendell G. Yarbrough, Tanguy Y. Seiwert, Sophie C. Egea, Elena Ivanova, Troy Shelton, Jiexin Zhang, Patrick K. Kimes, Nikolaus Schultz, Noreen Dhalla, Maciej Wiznerowicz, Daniel J. Weisenberger, Martin L. Ferguson, Tamara R. Jones, Haiyan I. Li, Nishant Agrawal, Yiling Lu, Lixing Yang, Brandee T. Brown, Julie M. Gastier-Foster, Nils Weinhold, Harshad S. Mahadeshwar, Angela Tam, Lihua Zou, Tom Bodenheimer, Gordon B. Mills, W. Kimryn Rathmell, David Mallery, Semin Lee, Scott J. Morris, Lynn M. Herbert, Hailei Zhang, Thomas C. Motter, Walker Hale, Tina Wong, Yichao Sun, Heidi J. Sofia, Rileen Sinha, Dennis T. Maglinte, Robert I. Haddad, Matthew D. Wilkerson, Jinze Liu, Julien Baboud, Brenda Diergaarde, Michelle Q. Pham, Tanja M. Davidsen, Maureen A. Sartor, Robert A. Holt, Angela Hadjipanayis, Pei Lin, Anders Jacobsen, Stephen C. Benz, Dean Cheng, Matthew Meyerson, Andy Chu, Ezra E.W. Cohen, Joonil Jung, Ari B. Kahn, Scott Frazer, Leigh B. Thorne, Andrew J. Mungall, David A. Wheeler, Nina Thiessen, Jay Bowen, Hui Cheng, D. Neil Hayes, Jennifer Drummond, Patrick Kwok Shing Ng, Harshavardhan Doddapaneni, S. Onur Sumer, Katherine Tarvin, John W.F. Waldron, Nils Gehlenborg, Douglas B. Chepeha, Janae V. Simons, Robert L. Ferris, Paweł Golusiński, Christina Beard, Donna Morton, Boris Reva, Psalm Haseley, Andrew Wei Xu, Giovanni Ciriello, Gregory T. Wolf, Ken Burnett, Lisa A. Peterson, Sylvia Wrenn, Mark A. Jensen, Travis I. Zack, Deepak Srinivasan, Thomas E. Carey, Lisle E. Mose, Mark E. Sherman, Leslie Cope, Adel K. El-Naggar, Marjorie Romkes, D Wheeler, Christopher A. Bristow, Andrea Haddad, Mayya Malakh, Ludmila Danilova, Jean C. Zenklusen, Jiabin Tang, Laura S. Rozek, Jon G. Seidman, Steven J.M. Jones, Hsu Chao, Candance Shelton, Carmen Gomez-Fernandez, Carrie Sougnez, Piotr A. Mieczkowski, Lee Lichtenstein, Erik Zmuda, Johanna Gardner, Jianjiong Gao, Marco A. Marra, Juok Cho, Alexei Protopopov, Roy Tarnuzzer, Tod D. Casasent, Timothy M. Chan, Michael Parfenov, Jing Wang, Christine M. Komarck, Lauren Averett Byers, Rehan Akbani, Todd Pihl, Curtis R. Pickering, Aaron D. Tward, Chandra Sekhar Pedamallu, Han Si, Jan F. Prins, Vonn Walter, Simion I. Chiosea, Jacqueline E. Schein, James Stephen Marron, Ariane Nguyen, William W. Shockley, Jennifer R. Grandis, Zhining Wang, Jeffrey N. Myers, Konstanty Korski, Bradley A. Ozenberger, Margaret L. Gulley, Barry S. Taylor, B. Arman Aksoy, Ni Zhao, Ashley H. Salazar, Petar Stojanov, Tara M. Lichtenberg, Chu Chen, Donghui Tan, Bhishamjit S. Chera, Andrzej Mackiewicz, A. Gordon Robertson, Ronglai Shen, Lisa Wise, Charles M. Perou, Michael Mayo, Charles Saller, Timothy J. Triche, Dong Zeng, Yan Guo, Lixia Diao, Jonathan B. McHugh, Zhixiang Zuo, Gad Getz, John A. Demchok, Raja R. Seethala, Gordon Saksena, Liu Xi, Liming Yang, Justin A. Bishop, Jessica Walton, Greg Eley, Jessica Frick, John N. Weinstein, Kevin Lau, Jianhua Zhang, Kenna R. Mills Shaw, Miruna Balasundaram, Zubair Khan, Umadevi Veluvolu, Stuart R. Jefferys, Christie Kovar, Moiz S. Bootwalla, Rebecca Carlsen, Daniel Crain, Fei-Fei Liu, Matthiew Ibbs, Michael S. Noble, William K. Funkhouser, Shaowu Meng, Mei Huang, Ann Marie Egloff, George E. Sandusky, Yi Han, Eric S. Lander, Sam Ng, William Lee, Christina Yau, Reanne Bowlby, Erin Curley, Donna M. Muzny, Lynda Chin, Joel S. Parker, Stephen B. Baylin, Peter S. Hammerman, Julie Ahn, Christopher C. Benz, Benjamin Gross, Paul M. Weinberger, Gideon Dresdner, Luc G. T. Morris, Zhong Chen, You Hong Fan, Angeliki Pantazi, David I. Heiman, Bartosz Szybiak, Sahil Seth, Richard A. Gibbs, Trevor Hackman, Peggy Yena, Richard A. Moore, Darshan Singh, Yaron S.N. Butterfield, Andrew D. Cherniack, Jeffrey S. Moyer, Robert A. Burton, Peter J. Park, Rameen Beroukhim, Ricardo Ramirez, Natalia Issaeva, Michael S. Lawrence, Wen-Bin Liu, Xiaojia Ren, Chris Sander, Yunhu Wan, Daryl Waggott, Joseph A. Califano, David A. Pot, Mathew G. Soloway, Roni J. Bollag, Stacey Gabriel, Jeffrey S. Reid, Netty Santoso, Elizabeth Buda, Doug Voet, Xingzhi Song, Kyle Chang, Joseph Paulauskis, Thomas M. Harris, Jaegil Kim, Alan P. Hoyle, Marc Ladanyi, Anthony Saleh, Mark C. Weissler, Scott L. Carter, Kai Wang, Jonathan G. Seidman, Corbin D. Jones, Wojciech Golusiński, Robert Penny, Margi Sheth, and Lori Boice

Subjects
Cervical Cancer, Genome, head and neck, Cancer Genome Atlas Network, 2.1 Biological and endogenous factors, 2.2 Factors relating to the physical environment, Papillomaviridae, Aetiology, Genetics, Multidisciplinary, biology, HPV infection, virus diseases, Biological Sciences, integration sites, female genital diseases and pregnancy complications, Gene Expression Regulation, Neoplastic, Infectious Diseases, Head and Neck Neoplasms, DNA methylation, Host-Pathogen Interactions, HIV/AIDS, Infection, Human, Virus Integration, Molecular Sequence Data, DNA sequencing, Rare Diseases, medicine, Humans, cancer, Dental/Oral and Craniofacial Disease, Gene, genome rearrangement, Neoplastic, Base Sequence, Genome, Human, Human Genome, DNA Methylation, biology.organism_classification, medicine.disease, Human genetics, Gene Expression Regulation, Genes, Neoplasm, Sexually Transmitted Infections, Human genome, Genes, Neoplasm, papilloma virus
Abstract

Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.

Published
2014

11. The Somatic Genomic Landscape of Chromophobe Renal Cell Carcinoma

Author

Caleb F. Davis, Christopher J. Ricketts, Min Wang, Lixing Yang, Andrew D. Cherniack, Hui Shen, Christian Buhay, Hyojin Kang, Sang Cheol Kim, Catherine C. Fahey, Kathryn E. Hacker, Gyan Bhanot, Dmitry A. Gordenin, Andy Chu, Preethi H. Gunaratne, Michael Biehl, Sahil Seth, Benny A. Kaipparettu, Christopher A. Bristow, Lawrence A. Donehower, Eric M. Wallen, Angela B. Smith, Satish K. Tickoo, Pheroze Tamboli, Victor Reuter, Laura S. Schmidt, James J. Hsieh, Toni K. Choueiri, A. Ari Hakimi, Lynda Chin, Matthew Meyerson, Raju Kucherlapati, Woong-Yang Park, A. Gordon Robertson, Peter W. Laird, Elizabeth P. Henske, David J. Kwiatkowski, Peter J. Park, Margaret Morgan, Brian Shuch, Donna Muzny, David A. Wheeler, W. Marston Linehan, Richard A. Gibbs, W. Kimryn Rathmell, Chad J. Creighton, Sabina Signoretti, Christopher Ricketts, Michael Seiler, Hsu Chao, Mike Dahdouli, Liu Xi, Nipun Kakkar, Jeffrey G. Reid, Brittany Downs, Jennifer Drummond, Donna Morton, Harsha Doddapaneni, Lora Lewis, Adam English, Qingchang Meng, Christie Kovar, Qiaoyan Wang, Walker Hale, Alicia Hawes, Divya Kalra, Kimberly Walker, Bradley A. Murray, Carrie Sougnez, Gordon Saksena, Scott L. Carter, Steven E. Schumacher, Barbara Tabak, Travis I. Zack, Gad Getz, Rameen Beroukhim, Stacey B. Gabriel, Adrian Ally, Miruna Balasundaram, Inanc Birol, Denise Brooks, Yaron S.N. Butterfield, Eric Chuah, Amanda Clarke, Noreen Dhalla, Ranabir Guin, Robert A. Holt, Katayoon Kasaian, Darlene Lee, Haiyan I. Li, Emilia Lim, Yussanne Ma, Michael Mayo, Richard A. Moore, Andrew J. Mungall, Jacqueline E. Schein, Payal Sipahimalani, Angela Tam, Nina Thiessen, Tina Wong, Steven J.M. Jones, Marco A. Marra, J. Todd Auman, Donghui Tan, Shaowu Meng, Corbin D. Jones, Katherine A. Hoadley, Piotr A. Mieczkowski, Lisle E. Mose, Stuart R. Jefferys, Jeffrey Roach, Umadevi Veluvolu, Matthew D. Wilkerson, Scot Waring, Elizabeth Buda, Junyuan Wu, Tom Bodenheimer, Alan P. Hoyle, Janae V. Simons, Mathew G. Soloway, Saianand Balu, Joel S. Parker, D. Neil Hayes, Charles M. Perou, Daniel J. Weisenberger, Moiz S. Bootwalla, Timothy Triche, Phillip H. Lai, David J. Van Den Berg, Stephen B. Baylin, Fengju Chen, Cristian Coarfa, Michael S. Noble, Daniel DiCara, Hailei Zhang, Juok Cho, David I. Heiman, Nils Gehlenborg, Doug Voet, Pei Lin, Scott Frazer, Petar Stojanov, Yingchun Liu, Lihua Zou, Jaegil Kim, Michael S. Lawrence, Alexei Protopopov, Xingzhi Song, Jianhua Zhang, Angeliki Pantazi, Angela Hadjipanayis, Eunjung Lee, Lovelace J. Luquette, Semin Lee, Michael Parfenov, Netty Santoso, Jonathan Seidman, Andrew W. Xu, Junehawk Lee, Steven A. Roberts, Leszek J. Klimczak, David Fargo, Martin Lang, Yoon-La Choi, June-Koo Lee, Wenyi Wang, Yu Fan, Jaeil Ahn, Rehan Akbani, John N. Weinstein, David Haussler, Singer Ma, Amie Radenbaugh, Jingchun Zhul, Tara M. Lichtenberg, Erik Zmuda, Aaron D. Black, Benjamin Hanf, Nilsa C. Ramirez, Lisa Wise, Jay Bowen, Kristen M. Leraas, Tracy M. Hall, Julie M. Gastier-Foster, William G. Kaelin, Leigh Thorne, Lori Boice, Mei Huang, Cathy Vocke, James Peterson, Robert Worrell, Maria Merino, Bogdan A. Czerniak, Kenneth D. Aldape, Christopher G. Wood, Paul T. Spellman, Michael B. Atkins, John Cheville, R. Houston Thompson, Mark A. Jensen, Todd Pihl, Yunhu Wan, Brenda Ayala, Julien Baboud, Sudhakar Velaga, Jessica Walton, Jia Liu, Sudha Chudamani, Ye Wu, Margi Sheth, Kenna R. Mills Shaw, John A. Demchok, Tanja Davidsen, Liming Yang, Zhining Wang, Roy W. Tarnuzzer, Jiashan Zhang, Greg Eley, Ina Felau, Jean Claude Zenklusen, Carolyn M. Hutter, Mark S. Guyer, Bradley A. Ozenberger, Heidi J. Sofia, and Intelligent Systems

Subjects
Mitochondrial DNA, Cancer Research, DNA Copy Number Variations, Somatic cell, Chromophobe Renal Cell Carcinoma, DNA Mutational Analysis, Molecular Sequence Data, Chromophobe cell, Biology, DNA, Mitochondrial, Article, Chromosome Breakpoints, Chromosomes, Human, Humans, Exome, Promoter Regions, Genetic, Carcinoma, Renal Cell, Telomerase, Genetics, Base Sequence, Genome, Human, Point mutation, Cell Biology, DNA Methylation, Kidney Neoplasms, Oncology, Kataegis, DNA methylation, Chromosome Deletion, Transcriptome
Abstract

We describe the landscape of somatic genomic alterations of 66 chromophobe renal cell carcinomas (ChRCCs) based on multidimensional and comprehensive characterization, including mitochondrial DNA (mtDNA) and whole genome sequencing. The result is consistent that ChRCC originates from the distal nephron compared to other kidney cancers with more proximal origins. Combined mtDNA and gene expression analysis implicates changes in mitochondrial function as a component of the disease biology, while suggesting alternative roles for mtDNA mutations in cancers relying on oxidative phosphorylation. Genomic rearrangements lead to recurrent structural breakpoints within TERT promoter region, which correlates with highly elevated TERT expression and manifestation of kataegis, representing a mechanism of TERT up-regulation in cancer distinct from previously-observed amplifications and point mutations.

Published
2014

12. Multiplatform analysis of 12 cancer types reveals molecular classification within and across tissues of origin

Author

Hoadley, Katherine A., Yau, Christina, Wolf, Denise M., Cherniack, Andrew D., Tamborero, David, Sam, Ng, Leiserson, Max D. M., Niu, Beifang, Mclellan, Michael D., Uzunangelov, Vladislav, Zhang, Jiashan, Kandoth, Cyriac, Akbani, Rehan, Shen, Hui, Omberg, Larsson, Chu, Andy, Margolin, Adam A., Van'T Veer, Laura J., Lopez Bigas, Nuria, Laird, Peter W., Raphael, Benjamin J., Ding, Li, Robertson, A. Gordon, Byers, Lauren A., Mills, Gordon B., Weinstein, John N., Van Waes, Carter, Chen, Zhong, Collisson, Eric A., Benz, Christopher C, Perou, Charles M., Stuart, Joshua M., Rachel, Abbott, Scott, Abbott, Arman Aksoy, B., Kenneth, Aldape, Adrian, Ally, Samirku mar Amin, Dimitris, Anastassiou, Todd Auman, J., Baggerly, Keith A., Miruna, Balasundaram, Saianand, Balu, Baylin, Stephen B., Benz, Stephen C., Berman, Benjamin P., Brady, Bernard, Bhatt, Ami S., Inanc, Birol, Black, Aaron D., Tom, Bodenheimer, Bootwalla, Moiz S., Jay, Bowen, Ryan, Bressler, Bristow, Christopher A., Brooks, Angela N., Bradley, Broom, Elizabeth, Buda, Robert, Burton, Butterfield, Yaron S. N., Daniel, Carlin, Carter, Scott L., Casasent, Tod D., Kyle, Chang, Stephen, Chanock, Lynda, Chin, Dong Yeon Cho, Juok, Cho, Eric, Chuah, Chun, Hye Jung E., Kristian, Cibulskis, Giovanni, Ciriello, James Cle land, Melisssa, Cline, Brian, Craft, Creighton, Chad J., Ludmila, Danilova, Tanja, Davidsen, Caleb, Davis, Dees, Nathan D., Kim, Delehaunty, Demchok, John A., Noreen, Dhalla, Daniel, Dicara, Huyen, Dinh, Dobson, Jason R., Deepti, Dodda, Harshavardhan, Doddapaneni, Lawrence, Donehower, Dooling, David J., Gideon, Dresdner, Jennifer, Drummond, Andrea, Eakin, Mary, Edgerton, Eldred, Jim M., Greg, Eley, Kyle, Ellrott, Cheng, Fan, Suzanne, Fei, Ina, Felau, Scott, Frazer, Freeman, Samuel S., Jessica, Frick, Fronick, Catrina C., Ful ton, Lucinda L., Robert, Fulton, Gabriel, Stacey B., Jianjiong, Gao, Gastier Foster, Julie M., Nils, Gehlenborg, Myra, George, Gad, Getz, Richard, Gibbs, Mary, Goldman, Abel Gonzalez Perez, Benjamin, Gross, Ranabir, Guin, Preethi, Gunaratne, Angela, Hadjipanayis, Hamilton, Mark P., Hamilton, Stanley R., Leng, Han, Han, Yi, Harper, Hollie A., Psalm, Haseley, David, Haussler, Neil Hayes, D., Heiman, David I., Elena, Helman, Carmen, Helsel, Herbrich, Shelley M., Her man, James G., Toshinori, Hinoue, Carrie, Hirst, Martin, Hirst, Holt, Robert A., Hoyle, Alan P., Lisa, Iype, Anders, Jacobsen, Jeffreys, Stuart R., Jensen, Mark A., Jones, Corbin D., Jones, Steven J. M., Zhenlin, Ju, Joonil, Jung, Andre, Kahles, Ari, Kahn, Joelle Kalicki Veizer, Divya, Kalra, Krishna Latha Kanchi, Kane, David W., Hoon, Kim, Jaegil, Kim, Theo, Knijnenburg, Koboldt, Daniel C., Christie, Kovar, Roger, Kramer, Richard, Kreisberg, Raju, Kucherlapati, Marc, Ladanyi, Lander, Eric S., Larson, David E., Lawrence, Michael S., Darlene, Lee, Eunjung, Lee, Semin, Lee, William, Lee, Kjong Van Lehmann, Kalle, Leinonen, Ler aas, Kristen M., Seth, Lerner, Levine, Douglas A., Lora, Lewis, Ley, Timothy J., Haiyan I., Li, Jun, Li, Wei, Li, Han, Liang, Lichtenberg, Tara M., Jake, Lin, Ling, Lin, Pei, Lin, Wen bin Liu, Yingchun, Liu, Yuexin, Liu, Lorenzi, Philip L., Charles, Lu, Yiling, Lu, Luquette, Love lace J., Singer, Ma, Magrini, Vincent J., Mahadeshwar, Harshad S., Mardis, Elaine R., Adam, Margolin, Marra, Marco A., Michael, Mayo, Cynthia, Mcallister, Mcguire, Sean E., Mcmichael, Joshua F., James, Melott, Shaowu, Meng, Matthew, Meyerson, Mieczkowski, Piotr A., Miller, Christopher A., Miller, Martin L., Michael, Miller, Moore, Richard A., Margaret, Morgan, Donna, Morton, Mose, Lisle E., Mungall, Andrew J., Donna, Muzny, Lam, Nguyen, Noble, Michael S., Houtan, Noushmehr, Michelle, O’Laughlin, Ojesina, Akinyemi I., Tai Hsien Ou Yang, Brad, Ozenberger, Angeliki, Pantazi, Michael, Parfenov, Park, Peter J., Parker, Joel S., Evan, Paull, Chandra Sekhar Pedamallu, Todd, Pihl, Craig, Pohl, David, Pot, Alexei, Protopopov, Teresa, Przytycka, Amie Raden baugh, Ramirez, Nilsa C., Ricardo, Ramirez, Gunnar Ra, ̈ tsch, Jeffrey, Reid, Xiao jia Ren, Boris, Reva, Reynolds, Sheila M., Rhie, Suhn K., Jeffrey, Roach, Hector, Rovira, Michael, Ryan, Gordon, Saksena, Sofie, Salama, Chris, Sander, Netty, Santoso, Schein, Jacqueline E., Heather, Schmidt, Nikolaus, Schultz, Schumacher, Steven E., Jonathan, Seidman, Yasin, Senbabaoglu, Sahil, Seth, Saman tha Sharpe, Ronglai, Shen, Margi, Sheth, Yan, Shi, Ilya, Shmulevich, Silva, Grace O., Simons, Janae V., Rileen, Sinha, Payal, Sipahimalani, Smith, Scott M., Sofia, Heidi J., Artem, Sokolov, Soloway, Mathew G., Xingzhi, Song, Carrie Soug nez, Paul, Spellman, Louis, Staudt, Chip, Stewart, Petar, Stojanov, Xiaoping, Su, Onur Sumer, S., Yichao, Sun, Teresa, Swatloski, Barbara, Tabak, Angela, Tam, Donghui, Tan, Jiabin, Tang, Roy, Tarnuzzer, Taylor, Barry S., Nina, Thiessen, Ves teinn Thorsson, Timothy Triche, J. r., Van Den Berg, David J., Vandin, Fabio, Varhol, Richard J., Vaske, Charles J., Umadevi, Veluvolu, Roeland, Verhaak, Doug, Voet, Jason, Walker, Wallis, John W., Peter, Waltman, Yunhu, Wan, Min, Wang, Wenyi, Wang, Zhining, Wang, Scot, Waring, Nils, Weinhold, Weisenberger, Daniel J., Wendl, Michael C., David, Wheeler, Wilkerson, Matthew D., Wilson, Richard K., Lisa, Wise, Andrew, Wong, Chang Jiun Wu, Chia Chin Wu, Hsin Ta Wu, Junyuan, Wu, Todd, Wylie, Liu, Xi, Ruibin, Xi, Zheng, Xia, Andrew W., Xu, Yang, Da, Liming, Yang, Lixing, Yang, Yang, Yang, Jun, Yao, Rong, Yao, Kai, Ye, Ko suke Yoshihara, Yuan, Yuan, Yung, Alfred K., Travis, Zack, Dong, Zeng, Jean Claude Zenklusen, Hailei, Zhang, Jianhua, Zhang, Nianxiang, Zhang, Qunyuan, Zhang, Wei, Zhang, Wei, Zhao, Siyuan, Zheng, Jing, Zhu, Erik, Zmuda, and Lihua, Zou

Subjects
Genetics and Molecular Biology (all), Cluster Analysis, Humans, Neoplasms, Transcriptome, Biochemistry, Genetics and Molecular Biology (all), Extramural, Biochemistry, Genetics and Molecular Biology(all), Cancer, Computational biology, Disease, Biology, medicine.disease, Bioinformatics, Biochemistry, General Biochemistry, Genetics and Molecular Biology, Article, 3. Good health, Molecular classification, TP63, CLUSTERS (ANÁLISE), medicine, Head and neck, Gene
Abstract

Summary Recent genomic analyses of pathologically defined tumor types identify "within-a-tissue" disease subtypes. However, the extent to which genomic signatures are shared across tissues is still unclear. We performed an integrative analysis using five genome-wide platforms and one proteomic platform on 3,527 specimens from 12 cancer types, revealing a unified classification into 11 major subtypes. Five subtypes were nearly identical to their tissue-of-origin counterparts, but several distinct cancer types were found to converge into common subtypes. Lung squamous, head and neck, and a subset of bladder cancers coalesced into one subtype typified by TP53 alterations, TP63 amplifications, and high expression of immune and proliferation pathway genes. Of note, bladder cancers split into three pan-cancer subtypes. The multiplatform classification, while correlated with tissue-of-origin, provides independent information for predicting clinical outcomes. All data sets are available for data-mining from a unified resource to support further biological discoveries and insights into novel therapeutic strategies.

Published
2014

13. The Cancer Genome Atlas Pan-Cancer analysis project

Author

Qunyuan Zhang, B. Arman Aksoy, Fabio Vandin, Eric A. Collisson, Larsson Omberg, S. Onur Sumer, John A. Demchok, Sven Nelander, Vladislav Uzunangelov, Michael C. Wendl, Roger Kramer, John W. Wallis, Brian Craft, Angeliki Pantazi, Leng Han, W. K. Alfred Yung, Brad Ozenberger, Philip L. Lorenzi, James G. Herman, Andy Chu, Sahil Seth, Richard A. Gibbs, Angela Hadjipanayis, Hector Rovira, Peter W. Laird, Inanc Birol, Richard K. Wilson, James Cleland, Peter J. Park, Jiashan Zhang, Payal Sipahimalani, Stanley R. Hamilton, Liming Yang, Seth Lerner, Amie Radenbaugh, Barry S. Taylor, Carrie Hirst, David Tamborero, Stephen B. Baylin, Gad Getz, Tanja Davidsen, Miruna Balasundaram, Cheng Fan, Yuan Yuan, Kristian Cibulskis, Yan Shi, Angela Tam, Divya Kalra, Chris Sander, Scott Abbott, Catrina Fronick, Margi Sheth, Chip Stewart, Angela N. Brooks, Noreen Dhalla, Lam Nguyen, Hui Shen, Travis I. Zack, Andrew J. Mungall, Artem Sokolov, Douglas A. Levine, Carrie Sougnez, Paul T. Spellman, Greg Eley, Deepti Dodda, Wenbin Liu, Michael B. Ryan, Liu Xi, Aaron D. Black, Rong Yao, Saianand Balu, Benjamin P. Berman, Raju Kucherlapati, James M. Melott, Xingzhi Song, Boris Reva, Huyen Dinh, David A. Pot, Michael D. McLellan, Kjong-Van Lehmann, Wenyi Wang, Petar Stojanov, Bradley McIntosh Broom, Timothy J. Ley, Da Yang, Mary Elizabeth Edgerton, Houtan Noushmehr, Mathew G. Soloway, Nina Thiessen, Zhenlin Ju, Mark D.M. Leiserson, Michael Parfenov, Laura van 't Veer, Scott L. Carter, Ludmila Danilova, Adrian Ally, Hailei Zhang, Ina Felau, Carmen Helsel, Kenneth Aldape, Teresia Kling, Charles Lu, Psalm Haseley, A. Gordon Robertson, Andrew Wei Xu, Jessica Frick, Benjamin Gross, Louis M. Staudt, Craig Pohl, Dimitris Anastassiou, Netty Santoso, Donna Muzny, Chad J. Creighton, Donghui Tan, Ryan Bressler, Andrew J. Wong, Barbara Tabak, Yasin Senbabaoglu, Daniel C. Koboldt, Darlene Lee, Doug Voet, Joonil Jung, Hollie A. Harper, Jianhua Zhang, Kyle Chang, Wei Zhao, Marc Ladanyi, Lisa Iype, Ricardo Ramirez, Ami S. Bhatt, Lisle E. Mose, Singer Ma, Abel Gonzalez-Perez, Jonathan G. Seidman, Kosuke Yoshihara, Denise M. Wolf, Corbin D. Jones, Patrik Johansson, Siyuan Zheng, André Kahles, Stacey Gabriel, John N. Weinstein, Han Liang, Samantha Sharpe, Steven E. Schumacher, Matthew Meyerson, D. Neil Hayes, David Haussler, Krishna L. Kanchi, Julie M. Gastier-Foster, Umadevi Veluvolu, Ari B. Kahn, Brady Bernard, Tod D. Casasent, Christopher A. Bristow, Akinyemi I. Ojesina, Sam Ng, Charles M. Perou, Moiz S. Bootwalla, Cyriac Kandoth, Lixing Yang, Joel S. Parker, Alan P. Hoyle, Timothy J. Triche, Dong Zeng, Sean E. McGuire, Christie Kovar, Kim D. Delehaunty, Juok Cho, Alexei Protopopov, Shaowu Meng, Ling Lin, Heather Schmidt, Nils Gehlenborg, Yuexin Liu, Elaine R. Mardis, Martin L. Miller, Jake Lin, Jason Walker, Lisa Wise, Suzanne S. Fei, Jacqueline E. Schein, Semin Lee, Christina Yau, Melisssa Cline, Tara M. Lichtenberg, David I. Heiman, Scot Waring, Richard A. Moore, Margaret B. Morgan, Robert S. Fulton, David E. Larson, Xiaoping Su, Kalle Leinonen, Samirkumar B. Amin, Joshua M. Stuart, J. Todd Auman, Rebecka Jörnsten, Rileen Sinha, Andrew D. Cherniack, Caleb F. Davis, Stephen J. Chanock, Nathan D. Dees, Adam Margolin, Haiyan I. Li, Yaron S.N. Butterfield, Daniel E. Carlin, Tai Hsien Ou Yang, Rameen Beroukhim, Vincent Magrini, Mark P. Hamilton, Grace O. Silva, Nils Weinhold, Harshad S. Mahadeshwar, Michael S. Lawrence, Eric Chuah, Jun Li, Wei Li, Robert A. Burton, Teresa M. Przytycka, Katherine A. Hoadley, Keith A. Baggerly, Sheila M. Reynolds, Daniel DiCara, Tom Bodenheimer, Charles J. Vaske, James M. Eldred, Richard Varhol, Mark A. Jensen, David W. Kane, Xiaojia Ren, Christopher A. Miller, Elizabeth Buda, Li Ding, Michael Mayo, Hsin-Ta Wu, Joelle Kalicki-Veizer, Shelley M. Herbrich, Eunjung Lee, Yingchun Liu, Joshua F. McMichael, Jennifer Drummond, Teresa Swatloski, Harshavardhan Doddapaneni, William Lee, Daniel J. Weisenberger, David A. Wheeler, Chia Chin Wu, Richard Kreisberg, Roeland Verhaak, Elena Helman, Piotr A. Mieczkowski, Mary Goldman, Ilya Shmulevich, Nikolaus Schultz, Min Wang, Lovelace J. Luquette, Marco A. Marra, Todd Pihl, Roy Tarnuzzer, Ronglai Shen, Donna Morton, Yichao Sun, Lawrence A. Donehower, Jun Yao, Theo A. Knijnenburg, Benjamin J. Raphael, Lora Lewis, Peter Waltman, Andrea Eakin, Martin Hirst, Jaegil Kim, Lihua Zou, Ranabir Guin, Yi Han, Scott M. Smith, Hoon Kim, Kristen M. Leraas, Heidi J. Sofia, Erik Zmuda, Matthew D. Wilkerson, Michelle O'Laughlin, Jianjiong Gao, Jeffrey G. Reid, Jing Zhu, Toshinori Hinoue, Gunnar Rätsch, Hye Jung E. Chun, Anders Jacobsen, Stephen C. Benz, Kenna R. Mills Shaw, Gordon B. Mills, Zhining Wang, Cynthia McAllister, Michael S. Noble, Christopher C. Benz, Rehan Akbani, Ruibin Xi, Nianxiang Zhang, Jay Bowen, Wei Zhang, Chandra Sekhar Pedamallu, Eric S. Lander, Yunhu Wan, David J. Dooling, Dong Yeon Cho, Preethi Gunaratne, Todd Wylie, Pei Lin, Chang-Jiun Wu, Jeffrey Roach, Scott Frazer, Samuel S. Freeman, Rachel Abbott, Zheng Xia, Lucinda Fulton, Kyle Ellrott, Nuria Lopez-Bigas, Yang Yang, Michael Miller, Nilsa C. Ramirez, Evan O. Paull, Janae V. Simons, Junyuan Wu, Lynda Chin, Gordon Saksena, Jiabin Tang, Vesteinn Thorsson, Robert A. Holt, Suhn K. Rhie, Steven J.M. Jones, Stuart R. Jeffreys, Giovanni Ciriello, Sofie R. Salama, Gideon Dresdner, Yiling Lu, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., and Park, Peter J.

Subjects
Genetics, medicine.medical_specialty, Genome, Gene Expression Profiling, Genomics, Computational biology, Biology, Humans, Neoplasms, Article, Analysis Project, Gene expression profiling, GENÉTICA MOLECULAR, Cancer genome, Genomic Profile, medicine, Medical genetics, Epigenetics
Abstract

The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile., National Cancer Institute (U.S.), National Human Genome Research Institute (U.S.)

Published
2013

14. Comprehensive molecular characterization of urothelial bladder carcinoma

Author

Elizabeth Buda, Nikolaus Schultz, Donghui Tan, Pat Swanson, Xingzhi Song, Jennifer Owens, Carmelo Gaudioso, Liming Yang, Kenna R. Mills Shaw, Sophie C. Egea, John N. Weinstein, Lihua Zou, Dmitry A. Gordenin, Gad Getz, Stuart R. Jefferys, Wiam Bshara, David Haussler, Ari B. Kahn, Mary Iacocca, Brady Bernard, Charles M. Perou, Leigh B. Thorne, Kimberly R. Christ, Eric S. Lander, Yunhu Wan, Timothy J. Triche, Dong Zeng, Bogdan Czerniak, Wenbin Liu, Jianhua Zhang, David Mallery, B. Arman Aksoy, Lynn M. Herbert, Hailei Zhang, Jennifer DiPiero, Tod D. Casasent, Sugy Kodeeswaran, Daniel DiCara, Jacqueline E. Schein, Scott L. Carter, Umadevi Veluvolu, John M. S. Bartlett, Theresa M. Koppie, Ji Yeon Yang, Ronglai Shen, Yingchun Liu, Daniel J. Weisenberger, Ranabir Guin, Myra M. George, Marc Ladanyi, J. Todd Auman, Moiz S. Bootwalla, Shaowu Meng, Mark S. Soloway, Tatjana Antic, Greg Eley, Hikmat Al-Ahmadie, Carolyn M. Hutter, Jonathan G. Seidman, Corbin D. Jones, Lori Boice, Xiaoping Su, Jay Bowen, Raju Kucherlapati, Hui Shen, Benjamin Gross, Reanne Bowlby, Lawrence A. Donehower, Phan Thi Hanh, David J. McConkey, Saianand Balu, Jiexin Zhang, Tina Wong, Juok Cho, Alexei Protopopov, Carolyn L. Smith, Yuexin Liu, Angeliki Pantazi, Jason R. Gee, Xuan Van Le, Ricardo Ramirez, Ami S. Bhatt, Samuel S. Freeman, Jaegil Kim, Bui Duc Phu, Michael Ittman, Charles C. Guo, Carmen Gomez-Fernandez, Norm D. Smith, S. Onur Sumer, Bradley A. Ozenberger, Paul M. Weinberger, George E. Sandusky, Troy Shelton, Seth P. Lerner, Charles Saller, Nicholas J. Petrelli, Nguyen Van Bang, Sahil Seth, Richard A. Gibbs, Lisle E. Mose, Aaron D. Black, Yair Lotan, Carrie Sougnez, Jessie Au, Martin L. Ferguson, Ashley Marie Regazzi, Matthew Meyerson, Joel B. Nelson, Natasja Wye, Daniel E. Carlin, Nils Weinhold, Tom Bodenheimer, Nilsa C. Ramirez, Michael Ryan, Anders Jacobsen, Eric J. Burks, Lee Lichtenstein, Erin Curley, Angela Hadjipanayis, Nils Gehlenborg, Hector Rovira, Bernard Kohl, Jean C. Zenklusen, Travis Sullivan, Margaret Morgan, Rajiv Dhir, Julie M. Gastier-Foster, Gary D. Steinberg, Mathew G. Soloway, Nina Thiessen, Jianjiong Gao, Lisa Wise, Barry S. Taylor, Gordon Saksena, Hui Yao, David Van Den Berg, Jiabin Tang, Robert Penny, Nguyen Viet Tien, Jeffrey R. Gingrich, Jing Zhu, Ronald L. Hrebinko, Dick Kreisberg, Pei Lin, Christopher A. Bristow, Andrey Sivachenko, Andy Chu, Peter W. Laird, Thomas Barr, Junyuan Wu, Robert A. Holt, Harshad S. Mahadeshwar, Piotr A. Mieczkowski, Steven A. Roberts, Victor E. Reuter, Jeffrey S. Damrauer, Roni J. Bollag, Chad J. Creighton, Johanna Gardner, Michael Parfenov, Qiang Li, Phillip H. Lai, Thomas C. Motter, Alireza Moinzadeh, Jodi K. Maranchie, Christopher C. Benz, Lynda Chin, Angela Tam, Margi Sheth, David B. Solit, Erik Zmuda, Lixing Yang, Peter J. Park, Marco A. Marra, Katherine A. Hoadley, Eila C. Skinner, Scott Frazer, Roy Tarnuzzer, Heidi J. Sofia, Bradley M. Broom, Zhining Wang, David I. Heiman, Sebrina A Tello, Lori Huelsenbeck-Dill, Steven J.M. Jones, Antonia H. Holway, Ilana Rebecca Garcia-Grossman, Merce Jorda, Roeland Verhaak, Ilya Shmulevich, W.K. Rathmell, Bernard H. Bochner, Scot Waring, Kenneth Aldape, Richard A. Moore, Toshinori Hinoue, Carrie Hirst, Mark A. Jensen, Payal Kapur, Andrew D. Cherniack, Dean F. Bajorin, Evano Paull, Cheryl M. Lewis, William Y. Kim, Giovanni Ciriello, David C. Fargo, Gordon B. Mills, Michael S. Noble, Stephanie Weaver, Whitney D. McClenden, Benjamin Davies, Payal Sipahimalani, Vina Alexopoulou, Bo Peng, Stephen B. Baylin, Michael Mayo, Rameen Beroukhim, Boris Reva, Anil V. Parwani, Joshua M. Stuart, David J. Kwiatkowski, Stacey B. Gabrie, Janae V. Simons, Rehan Akbani, Todd Pihl, Nianxiang Zhang, Suzie Carter, Michael S. Lawrence, Carmen Helsel, Carl Morrison, Xiaojia Ren, Jeffrey Roach, Peter H. O'Donnell, Miruna Balasundaram, Yevgeniy Antipin, Gideon Dresdner, Cynthia McAllister, Tanja Davidsen, Brenda Rabeno, Jolanta Bondaruk, Kristian Cibulskis, Chip Stewart, Matthew D. Wilkerson, Jonathan E. Rosenberg, Brian D. Robinson, Patricia Castro, Wei Zhang, Chandra Sekhar Pedamallu, Allison Beaver, Andrew Wei Xu, Adrian Ally, Andrea Sorcini, Andrew J. Mungall, Katherine Tarvin, Christine Czerwinski, Petar Stojanov, Philip L. Lorenzi, Alan P. Hoyle, Jay Engel, Tara M. Lichtenberg, D. Neil Hayes, John A. Demchok, Eric Chuah, Benjamin Hanf, Deepak Srinivasan, Donna E. Hansel, Noreen Dhalla, Zhenlin Ju, Leszek J. Klimczak, Trevor J. Pugh, Richard Thorp, A. Gordon Robertson, Darlene Lee, Steven E. Schumacher, Semin Lee, Sheldon I. Bastacky, Rileen Sinha, Haiyan I. Li, William Lee, Sam Ng, Joel S. Parker, Sheila Reynolds, Teresa R. Tabler, Yaron S.N. Butterfield, David Pot, Chris Sander, Wenyi Wang, Weiguo Jian, Le Quang Vinh, Netty Santoso, Doug Voet, and Joonil Jung

Subjects
Metastatic Urothelial Carcinoma, Invasive urothelial carcinoma, Virus Integration, Down-Regulation, Disease, Bioinformatics, Malignancy, Article, Phosphatidylinositol 3-Kinases, Cancer genome, medicine, Carcinoma, Humans, Molecular Targeted Therapy, RNA, Messenger, Urothelial carcinoma, Multidisciplinary, business.industry, TOR Serine-Threonine Kinases, Cell Cycle, Creative commons, medicine.disease, Chromatin, 3. Good health, Gene Expression Regulation, Neoplastic, MicroRNAs, Oxidative Stress, Urinary Bladder Neoplasms, business, Protein Kinases, Proto-Oncogene Proteins c-akt, Signal Transduction
Abstract

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.

Published
2013

15. Comprehensive molecular profiling of lung adenocarcinoma

Author

Amie Radenbaugh, Noreen Dhalla, Christina Williamson, Charles Saller, James Suh, Ramaswamy Govindan, Travis I. Zack, Paul T. Spellman, Daniel DiCara, Harvey I. Pass, Deepak Srinivasan, William G. Richards, Robert J. Cerfolio, Igor Letovanec, A. Gordon Robertson, Gabriel Sica, Chad J. Creighton, Hendrik Dienemann, Jeffrey A. Borgia, Boris Reva, Bryan F. Meyers, Yiling Lu, Nikolaus Schultz, Christopher I. Amos, Dante Trusty, Carmelo Gaudioso, Michael Meister, James T. Robinson, Lihua Zou, James Shin, Jeremy Parfitt, Darlene Lee, Junyuan Wu, Carl Morrison, Scott L. Carter, Giovanni Ciriello, Nils Weinhold, Elena Nemirovich-Danchenko, Andrew Wei Xu, Christopher G. Maher, Lori Boice, Irina Zaytseva, Dennis A. Wigle, Kenna R. Mills Shaw, Matthew G. Soloway, Matthew Meyerson, Peng Chieh Chen, Frank Schneider, Troy Shelton, Douglas Voet, Steven E. Schumacher, D L Rotin, Saianand Balu, Stuart R. Jefferys, Tom Bodenheimer, Bradley A. Ozenberger, Eric S. Lander, Edward Gabrielson, Konstantin V. Fedosenko, Rehan Akbani, William D. Travis, Ari B. Kahn, Marcin Imielinski, Jacqueline E. Schein, Thomas L. Bauer, Kai Ye, Samuel A. Yousem, Robert C. Onofrio, Thomas Muley, Ayesha S. Bryant, Michael K. Asiedu, Monique Albert, Pei Lin, Corbin D. Jones, Edwina Duhig, Jean C. Zenklusen, Lucinda Fulton, Christina Yau, J. Todd Auman, Leigh B. Thorne, Elena Helman, Richard T. Cheney, William Lee, Patrick K. Kimes, Juok Cho, Alexei Protopopov, Wenbin Liu, Lee Lichtenstein, Jing Wang, Lixing Yang, W. Kimryn Rathmell, Jo Ellen Weaver, David A. Wheeler, Leslie Cope, Mark A. Watson, Heidi J. Sofia, Angeliki Pantazi, Ronglai Shen, Jeffrey Roach, Eric A. Collisson, Patrick Kwok Shing Ng, Angela Hadjipanayis, Peter S. Hammerman, David Van Den Berg, Kwun M. Fong, Nils Gehlenborg, Natasha Rekhtman, William K. Funkhouser, D. Neil Hayes, Harshad S. Mahadeshwar, Semin Lee, Martin Peifer, David Mallery, Piotr A. Mieczkowski, Ranabir Guin, Madhusmita Behera, Philipp A. Schnabel, Jill M. Siegfried, Carmen Gomez-Fernandez, Johanna Gardner, Lynn M. Herbert, Hailei Zhang, Robert S. Fulton, Travis Sullivan, Sahil Seth, Sam Ng, Chandra Sekhar Pedamallu, Barry S. Taylor, Venkatraman E. Seshan, Valerie W. Rusch, Jinze Liu, Daniel P. Raymond, Jianjiong Gao, Nathan A. Pennell, Marco A. Marra, Jan F. Prins, Payal Sipahimalani, Janae V. Simons, Joel S. Parker, Rileen Sinha, Lindy Hunter, Raju Kucherlapati, Dennis T. Maglinte, Fedor Moiseenko, Eric E. Snyder, Roy Tarnuzzer, Beverly Lee, James Stephen Marron, Kristian Cibulskis, Jerome Myers, Haiyan I. Li, Robert Penny, Hartmut Juhl, Richard K. Wilson, Zhining Wang, Eran Hodis, Carrie Sougnez, Jiabin Tang, William Mallard, Bryan Hernandez, Liming Yang, Jennifer Brown, Gad Getz, Farhad Kosari, Catrina Fronick, Juliann Chmielecki, Jianhua Zhang, Suresh S. Ramalingam, Michael Parfenov, Peter J. Park, Tanja Davidsen, Philip H. Lai, Jeff Boyd, Dang Huy Quoc Thinh, Harmanjatinder S. Sekhon, Malcolm V. Brock, Mark Pool, Margi Sheth, Kimberly M. Rieger-Christ, Michael J. Liptay, E. Getz, S. Onur Sumer, Ian A. Yang, B. Arman Aksoy, Douglas B. Flieder, Bradley M. Broom, Carrie Hirst, Solange Peters, Joshua M. Stuart, Khurram Z. Khan, Scott Morris, Donghui Tan, Andrew J. Mungall, Ming-Sound Tsao, Gordon B. Mills, Stephen B. Baylin, Rebecca Carlsen, Sanja Dacic, Julien Baboud, Brenda Rabeno, Richard A. Hajek, Lauren Averett Byers, Yaron S.N. Butterfield, Miruna Balasundaram, Chip Stewart, Katherine Tarvin, Peter B. Illei, James G. Herman, David J. Kwiatkowski, Andy Chu, David Haussler, Natasja Wye, Charles M. Perou, Peter W. Laird, Timothy J. Triche, Yan Shi, Jill P. Mesirov, Angela N. Brooks, Lori Huelsenbeck-Dill, Steven J.M. Jones, Antonia H. Holway, Lixia Diao, Anthony A. Gal, David G. Beer, Angela Tam, Ashley H. Salazar, Mark A. Jensen, Robert A. Holt, Katherine A. Hoadley, John A. Demchok, Sandra McDonald, Chandra Goparaju, David Pot, Belinda E. Clarke, Gordon Robertson, Michael C. Wendl, Helga Thorvaldsdottir, Kristen Rogers, Joshua D. Campbell, Chris Sander, Rayleen V. Bowman, Marc Danie Nazaire, Michael Mayo, Olga Voronina, Ludmila Danilova, Paul Zippile, Netty Santoso, John V. Heymach, Matthew D. Wilkerson, John Eckman, Morgan Windsor, Cureline Oleg Dolzhanskiy, Nina Thiessen, Mara Rosenberg, Gideon Dresdner, Levi A. Garraway, Eric Chuah, Richard Varhol, Elizabeth Buda, Li Ding, Alice H. Berger, Xingzhi Song, John M. S. Bartlett, Michael D. McLellan, Olga Potapova, Joseph Paulauskis, Igor Jurisica, Benjamin Gross, Jaegil Kim, John N. Weinstein, Kevin Lau, Christopher R. Cabanski, Philip Bonomi, Michael S. Noble, Maureen F. Zakowski, George E. Sandusky, Mary Iacocca, Eric J. Burks, Erin Curley, Lynda Chin, Rajiv Dhir, Singer Ma, Sophie C. Egea, Umadevi Veluvolu, Sugy Kodeeswaran, Christopher A. Miller, Moiz S. Bootwalla, Daniel J. Weisenberger, Shaowu Meng, Mei Huang, Elaine R. Mardis, Gordon Saksena, Nicholas J. Petrelli, Yvonne Owusu-Sarpong, Christopher C. Benz, Bernard Kohl, Jingchun Zhu, David I. Heiman, Carol Farver, Scot Waring, Richard A. Moore, Darshan Singh, Andrew D. Cherniack, Rameen Beroukhim, Michael S. Lawrence, Xiaojia Ren, Marc Ladanyi, Stacey Gabriel, Christine Czerwinski, Alan P. Hoyle, Cancer Genome Atlas Research Network, Collisson, E. A., Campbell, J.D., Brooks, A.N., Berger, A.H., Lee, W., Chmielecki, J., Beer, D.G., Cope, L., Creighton, C.J., Danilova, L., Ding, L., Getz, G., Hammerman, P.S., Hayes, D.N., Hernandez, B., Herman, J.G., Heymach, J.V., Jurisica, I., Kucherlapati, R., Kwiatkowski, D., Ladanyi, M., Robertson, G., Schultz, N., Shen, R., Sinha, R., Sougnez, C., Tsao, M.S., Travis, W.D., Weinstein, J.N., Wigle, D.A., Wilkerson, M.D., Chu, A., Cherniack, A.D., Hadjipanayis, A., Rosenberg, M., Weisenberger, D.J., Laird, P.W., Radenbaugh, A., Ma, S., Stuart, J.M., Averett Byers, L., Baylin, S.B., Govindan, R., Meyerson, M., Gabriel, S.B., Cibulskis, K., Kim, J., Stewart, C., Lichtenstein, L., Lander, E.S., Lawrence, M.S., Kandoth, C., Fulton, R., Fulton, L.L., McLellan, M.D., Wilson, R.K., Ye, K., Fronick, C.C., Maher, C.A., Miller, C.A., Wendl, M.C., Cabanski, C., Mardis, E., Wheeler, D., Balasundaram, M., Butterfield, Y.S., Carlsen, R., Chuah, E., Dhalla, N., Guin, R., Hirst, C., Lee, D., Li, H.I., Mayo, M., Moore, R.A., Mungall, A.J., Schein, J.E., Sipahimalani, P., Tam, A., Varhol, R., Robertson, A., Wye, N., Thiessen, N., Holt, R.A., Jones, S.J., Marra, M.A., Imielinski, M., Onofrio, R.C., Hodis, E., Zack, T., Helman, E., Sekhar Pedamallu, C., Mesirov, J., Saksena, G., Schumacher, S.E., Carter, S.L., Garraway, L., Beroukhim, R., Lee, S., Mahadeshwar, H.S., Pantazi, A., Protopopov, A., Ren, X., Seth, S., Song, X., Tang, J., Yang, L., Zhang, J., Chen, P.C., Parfenov, M., Wei Xu, A., Santoso, N., Chin, L., Park, P.J., Hoadley, K.A., Auman, J.T., Meng, S., Shi, Y., Buda, E., Waring, S., Veluvolu, U., Tan, D., Mieczkowski, P.A., Jones, C.D., Simons, J.V., Soloway, M.G., Bodenheimer, T., Jefferys, S.R., Roach, J., Hoyle, A.P., Wu, J., Balu, S., Singh, D., Prins, J.F., Marron, J.S., Parker, J.S., Perou, C.M., Liu, J., Maglinte, D.T., Lai, P.H., Bootwalla, M.S., Van Den Berg, D.J., Triche, T., Cho, J., DiCara, D., Heiman, D., Lin, P., Mallard, W., Voet, D., Zhang, H., Zou, L., Noble, M.S., Gehlenborg, N., Thorvaldsdottir, H., Nazaire, M.D., Robinson, J., Aksoy, B.A., Ciriello, G., Taylor, B.S., Dresdner, G., Gao, J., Gross, B., Seshan, V.E., Reva, B., Sumer, S.O., Weinhold, N., Sander, C., Ng, S., Zhu, J., Benz, C.C., Yau, C., Haussler, D., Spellman, P.T., Kimes, P.K., Broom, B.M., Wang, J., Lu, Y., Kwok Shing Ng, P., Diao, L., Liu, W., Amos, C.I., Akbani, R., Mills, G.B., Curley, E., Paulauskis, J., Lau, K., Morris, S., Shelton, T., Mallery, D., Gardner, J., Penny, R., Saller, C., Tarvin, K., Richards, W.G., Cerfolio, R., Bryant, A., Raymond, D.P., Pennell, N.A., Farver, C., Czerwinski, C., Huelsenbeck-Dill, L., Iacocca, M., Petrelli, N., Rabeno, B., Brown, J., Bauer, T., Dolzhanskiy, O., Potapova, O., Rotin, D., Voronina, O., Nemirovich-Danchenko, E., Fedosenko, K.V., Gal, A., Behera, M., Ramalingam, S.S., Sica, G., Flieder, D., Boyd, J., Weaver, J., Kohl, B., Huy Quoc Thinh, D., Sandusky, G., Juhl, H., Duhig, E., Illei, P., Gabrielson, E., Shin, J., Lee, B., Rodgers, K., Trusty, D., Brock, M.V., Williamson, C., Burks, E., Rieger-Christ, K., Holway, A., Sullivan, T., Asiedu, M.K., Kosari, F., Rekhtman, N., Zakowski, M., Rusch, V.W., Zippile, P., Suh, J., Pass, H., Goparaju, C., Owusu-Sarpong, Y., Bartlett, J.M., Kodeeswaran, S., Parfitt, J., Sekhon, H., Albert, M., Eckman, J., Myers, J.B., Cheney, R., Morrison, C., Gaudioso, C., Borgia, J.A., Bonomi, P., Pool, M., Liptay, M.J., Moiseenko, F., Zaytseva, I., Dienemann, H., Meister, M., Schnabel, P.A., Muley, T.R., Peifer, M., Gomez-Fernandez, C., Herbert, L., Egea, S., Huang, M., Thorne, L.B., Boice, L., Hill Salazar, A., Funkhouser, W.K., Rathmell, W.K., Dhir, R., Yousem, S.A., Dacic, S., Schneider, F., Siegfried, J.M., Hajek, R., Watson, M.A., McDonald, S., Meyers, B., Clarke, B., Yang, I.A., Fong, K.M., Hunter, L., Windsor, M., Bowman, R.V., Peters, S., Letovanec, I., Khan, K.Z., Jensen, M.A., Snyder, E.E., Srinivasan, D., Kahn, A.B., Baboud, J., Pot, D.A., Mills Shaw, K.R., Sheth, M., Davidsen, T., Demchok, J.A., Wang, Z., Tarnuzzer, R., Zenklusen, J.C., Ozenberger, B.A., Sofia, H.J., Massachusetts Institute of Technology. Department of Biology, and Lander, Eric S.

Subjects
Male, Lung Neoplasms, Adenocarcinoma/genetics, Adenocarcinoma/pathology, Cell Cycle Proteins/genetics, Female, Gene Dosage, Gene Expression Regulation, Neoplastic, Genomics, Humans, Lung Neoplasms/genetics, Lung Neoplasms/pathology, Molecular Typing, Mutation/genetics, Oncogenes/genetics, Sex Factors, Transcriptome/genetics, Adenocarcinoma of Lung, Cell Cycle Proteins, Biology, Adenocarcinoma, Exon, Germline mutation, microRNA, Adenocarcinoma of the lung, medicine, Gene, Multidisciplinary, Oncogene, Oncogenes, medicine.disease, MET Exon 14 Skipping Mutation, Molecular biology, 3. Good health, Mutation, Transcriptome
Abstract

Adenocarcinoma of the lung is the leading cause of cancer death worldwide. Here we report molecular profiling of 230 resected lung adenocarcinomas using messenger RNA, microRNA and DNA sequencing integrated with copy number, methylation and proteomic analyses. High rates of somatic mutation were seen (mean 8.9 mutations per megabase). Eighteen genes were statistically significantly mutated, including RIT1 activating mutations and newly described loss-of-function MGA mutations which are mutually exclusive with focal MYC amplification. EGFR mutations were more frequent in female patients, whereas mutations in RBM10 were more common in males. Aberrations in NF1, MET, ERBB2 and RIT1 occurred in 13% of cases and were enriched in samples otherwise lacking an activated oncogene, suggesting a driver role for these events in certain tumours. DNA and mRNA sequence from the same tumour highlighted splicing alterations driven by somatic genomic changes, including exon 14 skipping in MET mRNA in 4% of cases. MAPK and PI(3)K pathway activity, when measured at the protein level, was explained by known mutations in only a fraction of cases, suggesting additional, unexplained mechanisms of pathway activation. These data establish a foundation for classification and further investigations of lung adenocarcinoma molecular pathogenesis.

Published
2013

16. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia

Author

Ley, Timothy, Miller, Christopher, Ding, Li, Raphael, Benjamin J., Mungall, Andrew J., Robertson, A. Gordon, Hoadley, Katherine, Triche, Timothy J., Laird, Peter W., Baty, Jack D., Fulton, Lucinda L., Fulton, Robert, Heath, Sharon E., Kalicki Veizer, Joelle, Kandoth, Cyriac, Klco, Jeffery M., Koboldt, Daniel C., Kanchi, Krishna Latha, Shashikant, Kulkarni, M. S., P. h. D., F. A. C. M. G., Lamprecht, Tamara L., B. S., Washington, University, Louis, S. t., Larson, David E., P. h. D., Ling, Lin, M. S., Charles, Lu, Mclellan, Michael D., Mcmichael, Joshua F., the Genome Institute at Washington University, Jacqueline, Payton, M. D., P. h. D., Heather, Schmidt, Spencer, David H., Tomasson, Michael H., M. D., Siteman Cancer Center, S. t. Louis, Wallis, John W., Wartman, Lukas D., Watson, Mark A., John, Welch, Wendl, Michael C., Adrian, Ally, B. S. c., Miruna, Balasundaram, B. A. S. c., Inanc, Birol, Yaron, Butterfield, Readman, Chiu, M. S. c., Andy, Chu, Eric, Chuah, Hye Jung Chun, Richard, Corbett, Noreen, Dhalla, Ranabir, Guin, An, He, Carrie, Hirst, Martin, Hirst, Holt, Robert A., Steven, Jones, Aly, Karsan, Darlene, Lee, Haiyan I., Li, Marra, Marco A., Michael, Mayo, Moore, Richard A., Karen, Mungall, Jeremy, Parker, Erin, Pleasance, Patrick, Plettner, Jacquie, Schein, Dominik, Stoll, Lucas, Swanson, Angela, Tam, Nina, Thiessen, Richard, Varhol, Natasja, Wye, Yongjun, Zhao, M. S. c., D. V. M., British Columbia Cancer Agency's Genome Sciences Centre, Vancouver, Canada, Stacey, Gabriel, Gad, Getz, Carrie, Sougnez, Lihua, Zou, Broad Institute of Harvard, Massachusetts Institute of Technology, Cambridge, Ma, Mark D. M. Leiserson, B. A., Vandin, Fabio, Hsin Ta Wu, Brown, University, Center for Computational Molecular Biology, Providence, Ri, Frederick, Applebaum, Fred Hutchinson Cancer Research Center, Division of Medical Oncology, Seattle Cancer Care Alliance, Seattle, Baylin, Stephen B., Johns Hopkins University, Baltimore, Rehan, Akbani, Broom, Bradley M., Ken, Chen, Motter, Thomas C., B. A., Khanh, Nguyen, Weinstein, John N., Nianziang, Zhang, Anderson Cancer Center, University of Texas M. D., Houston, Ferguson, Martin L., Mlf, Consulting, Biotechnology Consultant, Boston, Christopher, Adams, Aaron, Black, Jay, Bowen, Julie Gastier Foster, Thomas, Grossman, Tara, Lichtenberg, Lisa, Wise, the Research Institute at Nationwide Children's Hospital, Columbus, Oh, Tanja, Davidsen, Demchok, John A., Mills Shaw, Kenna R., Margi, Sheth, National Cancer Institute, Bethesda, Md, Sofia, Heidi J., P. h. D., M. P. H., National Human Genome Research Institute, Liming, Yang, Downing, James R., Jude Children's Research Hospital, S. t., Memphis, Greg, Eley, Sciementis, Llc, Statham, Ga, Shelley, Alonso, Brenda, Ayala, Julien, Baboud, Mark, Backus, Barletta, Sean P., Berton, Dominique L., M. S. C. S., Chu, Anna L., Stanley, Girshik, Jensen, Mark A., Ari, Kahn, Prachi, Kothiyal, Nicholls, Matthew C., Pihl, Todd D., Pot, David A., Rohini, Raman, B. E., Sanbhadti, Rashmi N., Snyder, Eric E., Deepak, Srinivasan, Jessica, Walton, Yunhu, Wan, Zhining, Wang, Sra, International, Fairfax, Va, Issa, Jean Pierre J., Temple, University, Philadelphia, Michelle Le Beau, University of Chicago, Chicago, Martin, Carroll, University of Pennsylvania, Hagop Kantarjian, M. D., Steven, Kornblau, Bootwalla, Moiz S., B. S. c., M. S., Lai, Phillip H., Hui, Shen, Van Den Berg, David J., Weisenberger, Daniel J., University of Southern California, Epigenome, Center, Los, Angeles, Daniel C. Link, M. D., Walter, Matthew J., Ozenberger, Bradley A., Mardis, Elaine R., Peter, Westervelt, Graubert, Timothy A., Dipersio, John F., and Wilson, Richard K.

Subjects
Myeloid, Adult, Epigenomics, Male, NPM1, Gene Expression, CpG Islands, DNA Methylation, Female, Gene Fusion, Genome, Human, Humans, Leukemia, Myeloid, Acute, MicroRNAs, Middle Aged, Sequence Analysis, DNA, Mutation, Acute, Enasidenib, Biology, CEBPA, Genetics, Genome, Leukemia, Massive parallel sequencing, MicroRNA sequencing, Myeloid leukemia, DNA, General Medicine, KMT2A, biology.protein, Sequence Analysis, Nucleophosmin, Human, Comparative genomic hybridization
Abstract

BACKGROUND—Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. METHODS—We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. RESULTS—AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcriptionfactor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumorsuppressor genes (16%), DNA-methylation–related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. CONCLUSIONS—We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.) The molecular pathogenesis of acute myeloid leukemia (AML) has been studied with the use of cytogenetic analysis for more than three decades. Recurrent chromosomal structural variations are well established as diagnostic and prognostic markers, suggesting that acquired genetic abnormalities (i.e., somatic mutations) have an essential role in pathogenesis. 1,2 However, nearly 50% of AML samples have a normal karyotype, and many of these genomes lack structural abnormalities, even when assessed with high-density comparative genomic hybridization or single-nucleotide polymorphism (SNP) arrays 3-5 (see Glossary). Targeted sequencing has identified recurrent mutations in FLT3, NPM1, KIT, CEBPA, and TET2. 6-8 Massively parallel sequencing enabled the discovery of recurrent mutations in DNMT3A 9,10 and IDH1. 11 Recent studies have shown that many patients with

Published
2013

17. Comprehensive genomic characterization of squamous cell lung cancers

Author

Charles J. Vaske, Ying Du, Theodore C. Goldstein, Ping Yang, Yufeng Liu, Bryan Hernandez, Daniel R. Zerbino, Kenneth H. Buetow, Khurram Z. Khan, Semin Lee, Martin Peifer, Kristin G. Ardlie, James G. Herman, Sanja Dacic, Ashley Hill, Christopher Szeto, Jianjiong Gao, Singer Ma, Peng Chieh Chen, Carl F. Schaefer, David G. Beer, Kerstin David, Brent W. Zanke, Karen Mungall, Beverly Lee, Daniel DiCara, Kristen Rogers, Rui Jing, Christina Liquori, Carrie Sougnez, Ron Bose, Brian O'Connor, Piotr A. Mieczkowski, Scott L. Carter, Andy Chu, Peter W. Laird, David J. Kwiatkowski, R. Craig Cason, Marie Christine Aubry, Rileen Sinha, Dennis T. Maglinte, Chad J. Creighton, Howard H. Sussman, Jill M. Siegfried, Laura A.L. Dillon, Agnes Viale, Marco A. Marra, Stephen E. Schumacher, Dennis A. Wigle, Yongjun Zhao, Robert C. Onofrio, Heidi J. Sofia, Ranabir Guin, Lori Boice, Ling Li, Mark Backus, Pei Lin, Prachi Kothiyal, Jan F. Prins, Lauren Averett Byers, Haiyan I. Li, An He, Ka Ming Nip, Chang-Jiun Wu, Peter Dolina, James A. Robinson, Saianand Balu, Collisson E, Jinze Liu, Nicholas D. Socci, Erin Pleasance, Joan Pontius, Christina Yau, Eric E. Snyder, Shaowu Meng, Mei Huang, Aaron McKenna, Corbin D. Jones, Carl Morrison, Malcolm V. Brock, Chris Wakefield, Jared R. Slobodan, Ethan Cerami, Angela Tam, Jane Peterson, Michael D. Topal, Jacob M. Kaufman, Elena Helman, Richard T. Cheney, Dominik Stoll, Cristiane M. Ida, Dante Trusty, Peter S. Hammerman, Yevgeniy Antipin, D. Neil Hayes, Anders Jacobsen, Anna K. Unruh, Noreen Dhalla, Candace Shelton, Peter Waltman, Chris Sander, Zhining Wang, Derek Y. Chiang, Elizabeth J. Thomson, Vonn Walter, JoEllen Weaver, Elena Nemirovich-Danchenko, Jacqueline E. Schein, Bradley M. Broom, Sandra C. Tomaszek, Peter A. Kigonya, Tod D. Casasent, Ari B. Kahn, Joanne Yi, Kyle Ellrott, John M. S. Bartlett, Payal Sipahimalani, William D. Travis, Douglas Voet, Sean P. Barletta, Elizabeth Chun, J. Todd Auman, Ludmila Danilova, Katherine A. Hoadley, Marcin Imielinski, Ramaswamy Govindan, David P. Carbone, Leigh B. Thorne, David A. Wheeler, Carrie Hirst, Barbara Tabak, Sugy Kodeeswaran, Ijeoma A. Azodo, James Stephen Marron, Michael S. Noble, Jianjua John Zhang, Paul K. Paik, Deepak Srinivasan, Boris Reva, B. Arman Aksoy, Kristian Cibulskis, Douglas B. Flieder, Fei Pan, Daniel J. Weisenberger, Ronglai Shen, Jinhua Zhang, Nils Weinhold, Harman Sekhon, David Van Den Berg, Mark S. Guyer, Robert Penny, Hartmut Juhl, Marc Danie Nazaire, Yiqun Zhang, Eric A. Collisson, Robin J.N. Coope, Tom Bodenheimer, Richard Thorp, Junyuan Wu, Matthew Meyerson, Nguyen Phi Hung, Jerome Myers, Artem Sokolov, Yidi J. Turman, Thomas Muley, Stephen B. Baylin, Anisha Gulabani, A. Gordon Robertson, Lynda Chin, Eric Chuah, Richard Varhol, Margi Sheth, Janae V. Simons, Nils Gehlenborg, Tanja Davidsen, Psalm Haseley, Miruna Balasundaram, Olga Potapova, Spring Yingchun Liu, W. Kimryn Rathmell, Bizhan Bandarchi-Chamkhaleh, Wendy Winckler, David Mallery, Nicholas J. Petrelli, Nicole Todaro, Alex E. Lash, James Shin, Travis Brown, Igor Jurisica, Benjamin Gross, Hailei Zhang, Nikolaus Schultz, Kenna R. Mills Shaw, Nam Pho, William Pao, Darlene Lee, Zhen Fan, Troy Shelton, Yan Shi, Shelley Alonso, Carmelo Gaudioso, Peter B. Illei, Stuart R. Jefferys, Maureen F. Zakowski, Marian Rutledge, Bruce E. Johnson, Andrew J. Mungall, Eric S. Lander, Matthew G. Soloway, Michael Mayo, Christopher G. Maher, John V. Heymach, Lihua Zou, Dominique L. Berton, Nina Thiessen, Gary K. Scott, Anna L. Chu, Richard A. Hajek, Ming-Sound Tsao, Liming Yang, Qianxing Mo, Nguyen Van Bang, Martin Hirst, John Eckman, Erin Curley, Rajiv Dhir, Gad Getz, Stanley Girshik, Xuan Van Le, Jeff Boyd, Roman K. Thomas, Konstantin V. Fedosenko, Juok Cho, Alexei Protopopov, Nguyen Viet Tien, Lixing Yang, Laetitia Borsu, Steven J.M. Jones, Matthew D. Wilkerson, Mark Sherman, Andrew Crenshaw, Doug Voet, Elizabeth Buda, Jennifer Brown, Yaron S.N. Butterfield, Rehan Akbani, Todd Pihl, Ruibin Xi, Nianxiang Zhang, Jessica Walton, Ricardo Ramirez, Lisle E. Mose, Leslie Cope, Greg Eley, Mark A. Jensen, John N. Weinstein, Li Ding, Li-Wei Chang, Matthew C. Nicholls, Peter J. Park, Bui Duc Phu, Christopher R. Cabanski, Bernard Kohl, Julien Baboud, Joseph Paulauskis, David Pot, Gordon Robertson, Jingchun Zhu, John A. Demchok, Eunjung Lee, Giovanni Ciriello, Mary Iacocca, Gordon Saksena, Jesse Walsh, Yupu Liang, William K. Funkhouser, Rashmi N. Sanbhadti, Sam Ng, Venkatraman E. Seshan, Valerie W. Rusch, Robert A. Holt, Robert Sfeir, Jung E. Hye-Chun, Kai Wang, Helga Thorvaldsdottir, Huy V. Nguyen, Christopher Wilks, Brian Craft, Donghui Tan, David Haussler, Charles M. Perou, Timothy J. Triche, Christopher C. Benz, Scot Waring, Peggy Yena, Richard A. Moore, Darshan Singh, Andrew D. Cherniack, Rameen Beroukhim, Michael S. Lawrence, Xiaojia Ren, Stacey Gabriel, Martha Hatfield, Christine Czerwinski, Alan P. Hoyle, Marc Ladanyi, Joshua M. Stuart, Andrey Sivachenko, Jacqueline D. Palchik, Thomas Zeng, Inanc Birol, Rohini Raman, Ijeoma Azodo, Jianhua Zhang, Adam B. Olshen, Bradley A. Ozenberger, Angela Hadjipanayis, Sachet A. Shukla, Barry S. Taylor, John M. Greene, Jill P. Mesirov, Petar Stojanov, Raju Kucherlapati, Richard Corbett, Farhad Kosari, Martin L. Ferguson, Natasha Rekhtman, Keith A. Baggerly, Scott Morris, Brenda Rabeno, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., and Park, Peter J.

Subjects
Lung Neoplasms, Squamous Differentiation, DNA Mutational Analysis, Adenocarcinoma of Lung, Biology, Adenocarcinoma, Article, Phosphatidylinositol 3-Kinases, Gefitinib, Mutation Rate, CDKN2A, Carcinoma, medicine, Humans, Molecular Targeted Therapy, Lung cancer, Multidisciplinary, Genome, Human, Gene Expression Profiling, Genes, p16, Genomics, medicine.disease, Genes, p53, Gene expression profiling, Gene Expression Regulation, Neoplastic, Mutation, Cancer research, Carcinoma, Squamous Cell, Gene Deletion, medicine.drug, Necitumumab, Signal Transduction
Abstract

Lung squamous cell carcinoma is a common type of lung cancer, causing approximately 400,000 deaths per year worldwide. Genomic alterations in squamous cell lung cancers have not been comprehensively characterized, and no molecularly targeted agents have been specifically developed for its treatment. As part of The Cancer Genome Atlas, here we profile 178 lung squamous cell carcinomas to provide a comprehensive landscape of genomic and epigenomic alterations. We show that the tumour type is characterized by complex genomic alterations, with a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumour. We find statistically recurrent mutations in 11 genes, including mutation of TP53 in nearly all specimens. Previously unreported loss-of-function mutations are seen in the HLA-A class I major histocompatibility gene. Significantly altered pathways included NFE2L2 and KEAP1 in 34%, squamous differentiation genes in 44%, phosphatidylinositol-3-OH kinase pathway genes in 47%, and CDKN2A and RB1 in 72% of tumours. We identified a potential therapeutic target in most tumours, offering new avenues of investigation for the treatment of squamous cell lung cancers., National Institutes of Health (U.S.) (Grant U24 CA126561), National Institutes of Health (U.S.) (Grant U24 CA126551), National Institutes of Health (U.S.) (Grant U24 CA126554), National Institutes of Health (U.S.) (Grant U24 CA126543), National Institutes of Health (U.S.) (Grant U24 CA126546), National Institutes of Health (U.S.) (Grant U24 CA126563), National Institutes of Health (U.S.) (Grant U24 CA126544), National Institutes of Health (U.S.) (Grant U24 CA143845), National Institutes of Health (U.S.) (Grant U24 CA143858), National Institutes of Health (U.S.) (Grant U24 CA144025), National Institutes of Health (U.S.) (Grant U24 CA143882), National Institutes of Health (U.S.) (Grant U24 CA143866), National Institutes of Health (U.S.) (Grant U24 CA143867), National Institutes of Health (U.S.) (Grant U24 CA143848), National Institutes of Health (U.S.) (Grant U24 CA143840), National Institutes of Health (U.S.) (Grant U24 CA143835), National Institutes of Health (U.S.) (Grant U24 CA143799), National Institutes of Health (U.S.) (Grant U24 CA143883), National Institutes of Health (U.S.) (Grant U24 CA143843), National Institutes of Health (U.S.) (Grant U54 HG003067), National Institutes of Health (U.S.) (Grant U54 HG003079), National Institutes of Health (U.S.) (Grant U54 HG003273)

Published
2012

18. Mutations of the VHL tumour suppressor gene in renal carcinoma

Author

C. Florence, K. Tory, Rudy Pozzatti, Michael I. Lerman, James D. Brooks, James R. Gnarra, W. M. Linehan, Berton Zbar, S. Liu, Haiyan I. Li, F. Chen, Yongkai Weng, S. Pomer, H.B. Grossman, Fuh Mei Duh, William B. Isaacs, D. R. Duan, Laura S. Schmidt, Farida Latif, M. M. Walther, Irina A. Lubensky, Ming-Hui Wei, Hiltrud Brauch, and Neil H. Bander

Subjects
medicine.medical_specialty, von Hippel-Lindau Disease, endocrine system diseases, DNA Mutational Analysis, Molecular Sequence Data, Biology, urologic and male genital diseases, Loss of heterozygosity, Internal medicine, Von Hippel–Lindau tumor suppressor, Genetics, medicine, Carcinoma, Humans, Genes, Tumor Suppressor, Von Hippel–Lindau disease, neoplasms, Sequence Deletion, Kidney, Base Sequence, Epithelioma, Neoplasms, Second Primary, DNA, Neoplasm, medicine.disease, Kidney Neoplasms, female genital diseases and pregnancy complications, medicine.anatomical_structure, Endocrinology, Organ Specificity, Mutation, Cancer research, biology.protein, Adenocarcinoma, VHL Gene Mutation, Polymorphism, Restriction Fragment Length, Adenocarcinoma, Clear Cell
Abstract

Multiple, bilateral renal carcinomas are a frequent occurrence in von Hippel-Lindau (VHL) disease. To elucidate the aetiological role of the VHL gene in human kidney tumorigenesis, localized and advanced tumours from 110 patients with sporadic renal carcinoma were analysed for VHL mutations and loss of heterozygosity (LOH). VHL mutations were identified in 57% of clear cell renal carcinomas analysed and LOH was observed in 98% of those samples. Moreover, VHL was mutated and lost in a renal tumour from a patient with familial renal carcinoma carrying the constitutional translocation, t(3;8)(p14;q24). The identification of VHL mutations in a majority of localized and advanced sporadic renal carcinomas and in a second form of hereditary renal carcinoma indicates that the VHL gene plays a critical part in the origin of this malignancy.

Published
1994

19. Comprehensive molecular characterization of human colon and rectal cancer

Author

Donghui Tan, Nils Gehlenborg, Robert S. Fulton, Pat Swanson, Pei Lin, Chang-Jiun Wu, Piotr A. Mieczkowski, David Haussler, Marco A. Marra, Stephen E. Schumacher, Bernard Kohl, Jingchun Zhu, Lucinda Fulton, Charles M. Perou, Timothy J. Triche, Madhumati Gundapuneni, Mark Backus, Eve Shinbrot, Yonghong Xiao, Xuan Van Le, Liming Yang, Gad Getz, Stanley Girshik, Jessica Walton, Barbara Tabak, Greg Eley, Brian O'Connor, Larissa K. Temple, Saianand Balu, Eric A. Collisson, Tanja Davidsen, Elizabeth Buda, Janae V. Simons, Anisha Gulabani, Joseph Willis, Tod D. Casasent, Scott Morris, Doug Voat, Jireh Santibanez, Jennifer Drummond, Li Ding, Nicholas J. Petrelli, Andrew J. Mungall, Michael Mayo, Aaron D. Black, Gerald C. Chu, Elizabeth N. Medina, Huy V. Nguyen, Aaron E. Cozen, Yongjun Zhao, Hui Shen, Christopher Szeto, Brenda Rabeno, Martin Hirst, Bogumil Kaczkowski, Lisle E. Mose, Lora Lewis, Brian Craft, Joseph Paulauskis, Ari B. Kahn, Andy Chu, Peter W. Laird, Benjamin Gross, Matthew D. Wilkerson, Raju Kucherlapati, Matthew C. Nicholls, David Van Den Berg, Vesteinn Thorsson, Richard W. Park, Ethan Cerami, David A. Wheeler, Laura A.L. Dillon, Angela Tam, Julien Baboud, Kim D. Delehaunty, Katherine A. Hoadley, Ranabir Guin, Donna M. Muzny, Gordon Saksena, Shaowu Meng, Richard Kreisberg, Kenneth H. Buetow, Rajiv Dhir, Inanc Birol, Timo Erkkilä, Martin L. Ferguson, Robert A. Holt, Elaine R. Mardis, Aaron McKenna, Rohini Raman, Robert Sfeir, Mark Sherman, Andrew Crenshaw, J. Zachary Sanborn, Spring Yingchun Liu, Yuan Qing Wu, Jane Peterson, Eric E. Snyder, Lisa Iype, John N. Weinstein, Helga Thorvaldsdottir, Adam J. Bass, Dominik Stoll, Brady Bernard, Steven J.M. Jones, Peter Dolina, Julie M. Gastier-Foster, Jared R. Slobodan, Mark A. Jensen, Jacqueline E. Schein, Christie Kovar, Anders Jacobsen, Stephen C. Benz, J. Todd Auman, Juinhua Zhang, Peter Fielding, Paul T. Spellman, Jacqueline D. Palchik, Jay Bowen, Thomas Zeng, Douglas Voet, Arnulf Dörner, Joshua M. Stuart, Ryan Demeter, Theodore C. Goldstein, Keith A. Baggerly, Jorma J. de Ronde, Deepak Srinivasan, Boris Reva, Robert E. Pyatt, Andrew Kaufman, Timothy A. Chan, Alexei Protopopov, William G. Richards, Daniel R. Zerbino, Brenda Ayala, Martin R. Weiser, Psalm Haseley, Margaret Morgan, Mary Iacocca, Thomas Robinson, Chad J. Creighton, Dominique L. Berton, Da Yang, Peng Chieh Chen, Carl F. Schaefer, Peter White, Fred Denstman, Giovanni Ciriello, Matthew N. Bainbridge, Heidi J. Sofia, Irene Newsham, Jill P. Mesirov, Ling Li, Benjamin P. Berman, Daniel J. Weisenberger, Garrett M. Nash, Jason Walker, Nina Thiessen, Narayanan Sathiamoorthy, James A. Robinson, Petar Stojanov, Todd Wylie, Derek Y. Chiang, Kristin G. Ardlie, Jianjiong Gao, Lisa Wise, Bradley A. Ozenberger, Jeffrey G. Reid, Angela Hadjipanayis, Sachet A. Shukla, Barry S. Taylor, John M. Greene, Eric Chuah, Richard Varhol, Lisa R. Trevino, Charles J. Vaske, Ying Du, Arthur P. Goldberg, Rui Jing, Jon Whitmore, Joan Pontius, Yevgeniy Antipin, Kyle Ellrott, Nilsa C. Ramirez, Tom Bodenheimer, Junyuan Wu, Lynda Chin, Scott L. Carter, Hailei Zhang, Ryan Bressler, Adam Norberg, Stacey Gabriel, Martha Hatfield, Jonathan G. Seidman, Corbin D. Jones, Huyen Dinh, D. Neil Hayes, Christine Czerwinski, Gerald R. Fowler, Mark S. Guyer, Robert Penny, Alan P. Hoyle, Hartmut Juhl, Catrina Fronick, Margi Sheth, Christopher C. Benz, Scot Waring, Peggy Yena, Richard A. Moore, Darshan Singh, Toshinori Hinoue, Yaron S.N. Butterfield, Andrew D. Cherniack, Maria C. Mariano, Rameen Beroukhim, Michael S. Lawrence, Xiaojia Ren, Marc Ladanyi, Anna K. Unruh, Noreen Dhalla, Candace Shelton, Gary Witkin, Andrey Sivachenko, David Pot, Michael J. Zinner, Richard Thorp, Jan F. Prins, Eunjung Lee, A. Gordon Robertson, Wendy Winckler, Efsevia Vakiani, Chris Wakefield, Alex H. Ramos, Semin Lee, Zhining Wang, Sam Ng, Lihua Zhou, Christina Liquori, Rileen Sinha, Dennis T. Maglinte, Michael S. Noble, Haiyan I. Li, B. Arman Aksoy, Preethi H. Gunaratne, Michael Meyers, Daniel C. Koboldt, Lawrence A. Donehower, Darlene Lee, Jake Lin, Gary K. Scott, Hye Jung E. Chun, Sheila Reynolds, Anna L. Chu, Rehan Akbani, Todd Pihl, Ruibin Xi, Charles S. Fuchs, Nianxiang Zhang, Stanley R. Hamilton, Bradley M. Broom, Wei Zhang, Chris Sander, Marc Danie Nazaire, Carrie Hirst, Stephen B. Baylin, Joel E. Tepper, Kyle Chang, Miruna Balasundaram, Jen Brown, Yan Shi, Matthew G. Soloway, Richard A. Gibbs, Richard K. Wilson, Peter J. Park, Zhaoshi Zeng, John A. Demchok, Jesse Walsh, Rashmi N. Sanbhadti, Troy Shelton, Lixing Yang, Prachi Kothiyal, Monica M. Bertagnolli, Sean P. Barletta, Kristian Cibulskis, Yidi J. Turman, Nikolaus Schultz, Min Wang, Shelley Alonso, Carsten Zornig, P. Paty, Elizabeth J. Thomson, Peter A. Kigonya, Fei Pan, Yuexin Liu, Matthew Meyerson, Kenna R. Mills Shaw, Nam Pho, Stuart R. Jefferys, Daniel DiCara, Robert C. Onofrio, Erin Pleasance, Eric S. Lander, David J. Dooling, Christina Yau, Michael D. Topal, David B. Solit, Christopher Wilks, Ilya Shmulevich, Robin J.N. Coope, Ronglai Shen, Jose G. Guillem, R. Craig Cason, Massachusetts Institute of Technology. Department of Biology, and Lander, Eric S.

Subjects
DNA Copy Number Variations, Colorectal cancer, Biology, medicine.disease_cause, MLH1, Polymorphism, Single Nucleotide, 03 medical and health sciences, 0302 clinical medicine, Mutation Rate, microRNA, medicine, Humans, Exome, 030304 developmental biology, 0303 health sciences, Multidisciplinary, POLD1, Rectal Neoplasms, Gene Expression Profiling, Microsatellite instability, Sequence Analysis, DNA, DNA Methylation, medicine.disease, 3. Good health, 030220 oncology & carcinogenesis, DNA methylation, Colonic Neoplasms, Mutation, Cancer research, KRAS
Abstract

To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression., National Institutes of Health (U.S.) (Grant U24CA143799), National Institutes of Health (U.S.) (Grant U24CA143835), National Institutes of Health (U.S.) (Grant U24CA143840), National Institutes of Health (U.S.) (Grant U24CA143843), National Institutes of Health (U.S.) (Grant U24CA143845), National Institutes of Health (U.S.) (Grant U24CA143848), National Institutes of Health (U.S.) (Grant U24CA143858), National Institutes of Health (U.S.) (Grant U24CA143866), National Institutes of Health (U.S.) (Grant U24CA143867), National Institutes of Health (U.S.) (Grant U24CA143882), National Institutes of Health (U.S.) (Grant U24CA143883), National Institutes of Health (U.S.) (Grant U24CA144025), National Institutes of Health (U.S.) (Grant U54HG003067), National Institutes of Health (U.S.) (Grant U54HG003079), National Institutes of Health (U.S.) (Grant U54HG003273)

Published
2011

20. Purification and unique properties of mammary epithelial stem cells

Author

David H. Choi, Haiyan I. Li, Ian Ricketson, Peter Eirew, Mark Shackleton, François Vaillant, John Stingl, and Connie J. Eaves

Subjects
Cellular differentiation, Population, Mammary gland, Cell Separation, Biology, Mice, Mammary Glands, Animal, Animals, Congenic, medicine, Animals, Progenitor cell, education, Coloring Agents, Cell Proliferation, Sexual Abstinence, education.field_of_study, Multidisciplinary, Stem Cells, Cell Differentiation, Epithelial Cells, Cell biology, Mice, Inbred C57BL, medicine.anatomical_structure, Phenotype, Mammary Epithelium, Adipose Tissue, Female, Stem cell, Mammary gland morphogenesis, Adult stem cell
Abstract

Elucidation of the cellular and molecular mechanisms that maintain mammary epithelial tissue integrity is of broad interest and paramount to the design of more effective treatments for breast cancer. Evidence from both in vitro and in vivo experiments suggests that mammary cell differentiation is a hierarchical process originating in an uncommitted stem cell with self-renewal potential. However, analysis of the properties and regulation of mammary stem cells has been limited by a lack of methods for their prospective isolation. Here we report the use of multi-parameter cell sorting and limiting dilution transplant analysis to demonstrate the purification of a rare subset of adult mouse mammary cells that are able individually to regenerate an entire mammary gland within 6 weeks in vivo while simultaneously executing up to ten symmetrical self-renewal divisions. These mammary stem cells are phenotypically distinct from and give rise to mammary epithelial progenitor cells that produce adherent colonies in vitro. The mammary stem cells are also a rapidly cycling population in the normal adult and have molecular features indicative of a basal position in the mammary epithelium.

Published
2005

21. Differentially Expressed and Novel Transcripts in Highly Purified Chronic Phase CML Stem Cells

Author

Haiyan I. Li, Connie J. Eaves, Allen Delaney, Yun Zhao, Marco A. Marra, Xiaoyan Jiang, Allen C. Eaves, Angelique Schnerch, Kamini Raghuram, and Afshin Raouf

Subjects
Genetics, Immunology, CD34, Cell Biology, Hematology, Biology, CD38, Biochemistry, Molecular biology, Transcriptome, Haematopoiesis, Cell culture, hemic and lymphatic diseases, Cord blood, Serial analysis of gene expression, Stem cell
Abstract

The chronic phase of CML is sustained by rare BCR-ABL+ stem cells. These cells share many properties with normal pluripotent hematopoietic stem cells, but also differ in critical ways that alter their growth, drug responsiveness and genome stability. Understanding the molecular mechanisms underlying the biological differences between normal and CML stem cells is key to the development of more effective CML therapies. To obtain new insights into these mechanisms, we generated Long Serial Analysis of Gene Expression (SAGE) libraries from paired isolates of highly purified lin-CD34+CD45RA-CD36- CD71-CD7-CD38+ and lin-CD34+CD45RA-CD36-CD71-CD7-CD38- cells from 3 chronic phase CML patients (all with predominantly Ph+/BCR-ABL+ cells in both subsets) and from 3 control samples: a pool of 10 normal bone marrows (BMs), a single normal BM and a pool of G-CSF-mobilized blood cells from 9 donors. In vitro bioassays showed the CD34+CD38+ cells were enriched in CFCs (CML: 3–20% pure; normal: 4–19% pure) and the CD34+CD38- cells were enriched in LTC-ICs (CML: 0.2–26% pure; normal: 12–52% pure). Each of the 12 libraries was then sequenced to a depth of ~200,000 tags and tags from libraries prepared from like phenotypes were compared between genotypes using DiscoverySpace software and hierarchical clustering. 1687 (355 with clustering) and 1258 (316 with clustering) transcripts were thus identified as differentially expressed in the CML vs control CD34+CD38− and CD34+CD38+ subsets, respectively. 266 of these transcripts (11 with clustering) were differentially expressed in both subsets. The differential expression of 5 genes (GAS2, IGF2BP2, IL1R1, DUSP1 & SELL) was confirmed by real-time PCR analysis of lin-CD34+ cells isolated from an additional 5 normal BMs and 11 CMLs, and lin-CD34+CD38− cells from an additional 2 normal BMs and 2 CMLs (with dominant Ph+ cells). GAS2 and IL1R1 transcript levels were correlated with BCR-ABL transcript levels in both primitive subsets, and predicted differences in expression of IL1R1 and SELL were apparent within 3 days in CD34+ cord blood cells transduced with a lenti-BCR-ABL-IRES-GFP vs a control lenti-GFP vector (n=3). These findings support a direct role of BCR-ABL in perturbing the expression of these 3 genes. Further comparison of the meta CD34+CD38− and CD34+CD38+ CML cell libraries with most publicly accessible SAGE data revealed 69 novel tags in the CD34+ CML cells that correspond to unique but conserved genomic sequences. Nine of these were recovered by 5′- and 3′- RACE applied to cDNAs pooled from several human leukemic cell lines. These results illustrate the power of SAGE to reveal key components of the transcriptomes of rare human CML stem cell populations including transcripts of genes not previously known to exist. Continuing investigation of their biological roles in primary CML cells and primitive BCR-ABL-transduced human cells offer important strategies for delineating their potential as therapeutic targets.

Published
2008

22. Comprehensive molecular portraits of human breast tumours

Author

Julie M. Gastier-Foster, Nguyen Van Bang, Christopher Szeto, Daoud Meerzaman, Nguyen Viet Tien, Richard K. Wilson, Jennifer Brown, Singer Ma, Andrew H. Beck, Sam Ng, Phillip H. Lai, Peter J. Park, Khurram Z. Khan, Gordon B. Mills, Joel S. Parker, Li Ding, Ying Hu, Jill P. Mesirov, Rebecca Carlsen, Kevin P. White, Benjamin P. Berman, Michael C. Adams, Laura A.L. Dillon, Jake Lin, Giovanni Ciriello, Simeen Malik, Moiz S. Bootwalla, Sheila Reynolds, Petar Stojanov, B. Arman Aksoy, Jerry Usary, Mei Huang, Andrzej Mackiewicz, Prachi Kothiyal, Keith A. Baggerly, Hann Hsiang Chao, Timo Erkkilä, Elaine R. Mardis, Nils Gehlenborg, Bradley M. Broom, Tara M. Lichtenberg, Jeff Gentry, Payal Sipahimalani, Chris Wakefield, Zhining Wang, Anna Chu, Konstanty Korski, Michael S. Noble, Lawrence A. Donehower, Pavana Anur, Janita Thusberg, Rohit Bhargava, Chris Sander, Lori Boice, Juok Cho, Charles Saller, Sophie C. Egea, Marc Danie Nazaire, Heather Schmidt, Bui Duc Phu, Hye Jung E. Chun, Bradley A. Ozenberger, Robert S. Fulton, Carrie Hirst, Stephen B. Baylin, Miruna Balasundaram, Peter White, Fergus J. Couch, Saianand Balu, Christina Yau, Yevgeniy Antipin, Jacek J. Brzeziński, Rehan Akbani, Todd Pihl, Ari B. Kahn, Nianxiang Zhang, Sean P. Barletta, Mary Iacocca, Kelly Daily, Wiam Bshara, Marc Ladanyi, Michael D. Topal, Huy Nguyen, Theodore C. Goldstein, Tari A. King, Bernard Kohl, Jingchun Zhu, Wiktoria Maria Suchorska, Xuan Van Le, Wei Zhang, Yan Shi, Marta Bogusz-Czerniewicz, Barry S. Taylor, Li-Wei Chang, Matthew C. Nicholls, Julien Baboud, Honorata Tatka, Doug Voet, Vesteinn Thorsson, Richard W. Park, Aaron D. Black, Pawel Murawa, Leonid Kvecher, Raju Kucherlapati, Colleen Mitchell, Wei Zhao, Leigh B. Thorne, Artem Sokolov, Modesto Patangan, Yidi J. Turman, Teresa R. Tabler, Kyle Ellrott, Yaron S.N. Butterfield, Gordon Saksena, Ronglai Shen, Yaqin Chen, Olga Voronina, Candace Carter, Yiling Lu, Cynthia McAllister, Thomas Stricker, Chunqing Luo, Dominique L. Berton, Thomas Barr, Robert A. Holt, Christopher Wilks, David Van Den Berg, Robert Sfeir, Ilya Shmulevich, Ranabir Guin, Nilsa C. Ramirez, Hollie A. Harper, John A. Demchok, Matthew J. Ellis, David Haussler, Katherine A. Hoadley, Eric Chuah, Richard J. Mural, Charles M. Perou, Timothy J. Triche, Steven J.M. Jones, Mark A. Jensen, Jeffrey R. Marks, Hanna Perz, Rashmi N. Sanbhadti, Robin J.N. Coope, Brian Craft, Andy Chu, Peter W. Laird, Eric E. Snyder, Chunhua Yan, Martin L. Ferguson, Junyuan Wu, Richard Varhol, Daniel J. Weisenberger, Yongjun Zhao, Ewa Leporowska, Ashley Hill, Katie Tarvin, M. Teresiak, David Pot, Nguyen Phi Hung, Helga Thorvaldsdottir, Erik Zmuda, Spring Yingchun Liu, Melissa Hart-Kothari, Joshua M. Stuart, Caroline Larson, Erin Pleasance, Nikolaus Schultz, Matthew Ibbs, Hubert Stoppler, Joelle Kalicki-Veizer, Andrey Sivachenko, Christopher C. Benz, Dawid Murawa, Swapna Mahurkar, Nicholas J. Petrelli, Lynda Chin, Juinhua Zhang, Pei Lin, Michael Mayo, Wilma L. Lingle, Julian Malicki, Robin Brookens, Ethan Cerami, Angela Tam, Shelley Alonso, Carmelo Gaudioso, Dominik Stoll, Anders Jacobsen, Stephen C. Benz, Mark S. Guyer, Wendy Winckler, Roel R.G. Verhaak, Chang-Jiun Wu, Raktim Sinha, Xiaping He, Nina Thiessen, Craig D. Shriver, Kenna R. Mills Shaw, Heidi J. Sofia, Martin Hirst, Stuart R. Jefferys, Robert Penny, Adam Brufsky, Kristen M. Leraas, Joshua F. McMichael, Brenda Rabeno, Inanc Birol, David J. Dooling, Peggy Yena, Richard A. Moore, Andrew D. Cherniack, Lucinda Fulton, Jessica K. Booker, Lihua Zou, Rileen Sinha, Michael D. Iglesia, Dennis T. Maglinte, Rohini Raman, Evan O. Paull, Rameen Beroukhim, Oleg Dolzhansky, Grace O. Silva, Jiashan Zhang, Witold Kycler, Janae V. Simons, Anisha Gulabani, Michael S. Lawrence, Peter Fielding, Huynh Quyet Thang, Peter A. Kigonya, Myra M. George, Jay Bowen, Haiyan I. Li, Robert E. Pyatt, Margi Sheth, Stacey Gabriel, Ana M. Gonzalez-Angulo, Hui Shen, Andrew J. Mungall, Carmen Gomez-Fernandez, Liming Yang, Hai Hu, Radoslaw Łaźniak, Olufunmilayo I. Olopade, Christine Czerwinski, Richard A. Hajek, Michael D. McLellan, Arash Shafiei, Matthew Meyerson, Gad Getz, Stanley Girshik, Cheng Fan, Shuying Liu, Olga Potapova, Alan P. Hoyle, Mia Grifford, Daniel C. Koboldt, Jacqueline D. Palchik, Jessica Walton, Greg Eley, Jamie Leigh Campbell, Thomas Zeng, Mikhail Abramov, Benjamin Gross, Brenda Deyarmin, Maciej Wiznerowicz, Natasja Wye, Ron Bose, Darlene Lee, Carl Morrison, Albert J. Kovatich, Andrew Crenshaw, Jessica Frick, John N. Weinstein, Adrian Ally, Nam H. Pho, Brady Bernard, Scott L. Carter, Gary K. Scott, Steven E. Schumacher, Barbara Tabak, D. Neil Hayes, Robert C. Onofrio, Sean D. Mooney, Mary D. Dyer, Mark Gerken, Erin Curley, Rajiv Dhir, Anna K. Unruh, Noreen Dhalla, Candace Shelton, Kevin R. Coombes, Richard Thorp, George E. Sandusky, A. Gordon Robertson, Marco A. Marra, Roy Tarnuzzer, Mark Backus, Aleix Prat, Kristin G. Ardlie, Daniel Di Cara, Richard Kreisberg, Kenneth H. Buetow, Jacqueline E. Schein, J. Todd Auman, Jianjiong Gao, Lisa Wise, Ling Li, James A. Robinson, Jonathan S. Berg, Tod D. Casasent, James N. Ingle, Brenda Ayala, Xiaolong Meng, Boris Reva, Rui Jing, Mark D. Pegram, Arkadiusz Spychała, Joan Pontius, Jeffrey A. Hooke, Daniel E. Carlin, Nils Weinhold, Jared R. Slobodan, Tom Bodenheimer, Wenbin Liu, Christopher K. Wong, W. Kimryn Rathmell, David Mallery, Paul T. Spellman, Hailei Zhang, Ryan Bressler, Deepak Srinivasan, Lisle E. Mose, Bryan Hernandez, Stella Somiari, Chad J. Creighton, Howard H. Sussman, Frederic Waldman, Matthew G. Soloway, and Universitat de Barcelona

Subjects
Proteomics, Oncologia, DNA Mutational Analysis, Genes, BRCA1, Retinoblastoma Protein, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Breast cancer, Exome, RNA, Neoplasm, Exome sequencing, Oligonucleotide Array Sequence Analysis, Ovarian Neoplasms, Genetics, 0303 health sciences, Multidisciplinary, Triple Negative Breast Neoplasms, Genomics, 3. Good health, Gene Expression Regulation, Neoplastic, Receptors, Estrogen, Oncology, 030220 oncology & carcinogenesis, Female, DNA Copy Number Variations, Class I Phosphatidylinositol 3-Kinases, Protein Array Analysis, MAP Kinase Kinase Kinase 1, Breast Neoplasms, GATA3 Transcription Factor, Biology, Article, Càncer de mama, Genetic Heterogeneity, 03 medical and health sciences, medicine, Humans, RNA, Messenger, 030304 developmental biology, MicroRNA sequencing, Genome, Human, Genetic heterogeneity, Gene Expression Profiling, Cancer, DNA Methylation, Genes, erbB-2, Genes, p53, medicine.disease, Claudin-Low, Expressió gènica, MicroRNAs, Genòmica, Mutation, Gene expression, Genes, Neoplasm
Abstract

We analysed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, messenger RNA arrays, microRNA sequencing and reverse-phase protein arrays. Our ability to integrate information across platforms provided key insights into previously defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at >10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the luminal A subtype. We identified two novel protein-expression-defined subgroups, possibly produced by stromal/microenvironmental elements, and integrated analyses identified specific signalling pathways dominant in each molecular subtype including a HER2/phosphorylated HER2/EGFR/phosphorylated EGFR signature within the HER2-enriched expression subtype. Comparison of basal-like breast tumours with high-grade serous ovarian tumours showed many molecular commonalities, indicating a related aetiology and similar therapeutic opportunities. The biological finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biological subtypes of breast cancer.

23. Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation

Author

J M, Friedman, Agnes, Baross, Allen D, Delaney, Adrian, Ally, Laura, Arbour, Linlea, Armstrong, Jennifer, Asano, Dione K, Bailey, Sarah, Barber, Patricia, Birch, Mabel, Brown-John, Manqiu, Cao, Susanna, Chan, David L, Charest, Noushin, Farnoud, Nicole, Fernandes, Stephane, Flibotte, Anne, Go, William T, Gibson, Robert A, Holt, Steven J M, Jones, Giulia C, Kennedy, Martin, Krzywinski, Sylvie, Langlois, Haiyan I, Li, Barbara C, McGillivray, Tarun, Nayar, Trevor J, Pugh, Evica, Rajcan-Separovic, Jacqueline E, Schein, Angelique, Schnerch, Asim, Siddiqui, Margot I, Van Allen, Gary, Wilson, Siu-Li, Yong, Farah, Zahir, Patrice, Eydoux, and Marco A, Marra

Subjects
Chromosome Aberrations, Genetics, Genome, Human, Gene Dosage, Genomics, Biology, medicine.disease, Gene dosage, Genome, Trisomy 9, Article, Developmental disorder, Oligonucleotide Microarray, Intellectual Disability, Intellectual disability, medicine, Humans, Human genome, Genetics(clinical), Child, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Sequence Deletion
Abstract

The cause of mental retardation in one-third to one-half of all affected individuals is unknown. Microscopically detectable chromosomal abnormalities are the most frequently recognized cause, but gain or loss of chromosomal segments that are too small to be seen by conventional cytogenetic analysis has been found to be another important cause. Array-based methods offer a practical means of performing a high-resolution survey of the entire genome for submicroscopic copy-number variants. We studied 100 children with idiopathic mental retardation and normal results of standard chromosomal analysis, by use of whole-genome sampling analysis with Affymetrix GeneChip Human Mapping 100K arrays. We found de novo deletions as small as 178 kb in eight cases, de novo duplications as small as 1.1 Mb in two cases, and unsuspected mosaic trisomy 9 in another case. This technology can detect at least twice as many potentially pathogenic de novo copy-number variants as conventional cytogenetic analysis can in people with mental retardation.

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