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2. An OpenData portal to share COVID-19 drug repurposing data in real time

Author

Manisha Pradhan, Amit Viraktamath, Stephen C. Kales, Alexey V. Zakharov, Alex Renn, Tongan Zhao, Miao Xu, Bolormaa Baljinnyam, Catherine Z. Chen, Ke Wang, Sam Michael, Mark Backus, Zina Itkin, Donald C. Lo, Anton Simeonov, Kyle R. Brimacombe, Tara Eicher, Quinlin M Hanson, Carleen Klumpp-Thomas, Wei Zhu, Ying Fu, Tim Mierzwa, Kirill Gorshkov, Min Shen, Emily M. Lee, Xin Hu, Wei Zheng, Lu Chen, Ewy Mathé, Matthew D. Hall, Paul Shinn, Kelli M. Wilson, Richard T. Eastman, Andrew Patt, Hui Guo, Jonathan H. Shrimp, and Marc Ferrer

Subjects
World Wide Web, Drug repositioning, Open data, Coronavirus disease 2019 (COVID-19), Computer science, Small Molecule Libraries, Translational science, Approved drug, Article, Repurposing
Abstract

The National Center for Advancing Translational Sciences (NCATS) has developed an online open science data portal for its COVID-19 drug repurposing campaign – named OpenData – with the goal of making data across a range of SARS-CoV-2 related assays available in real-time. The assays developed cover a wide spectrum of the SARS-CoV-2 life cycle, including both viral and human (host) targets. In total, over 10,000 compounds are being tested in full concentration-response ranges from across multiple annotated small molecule libraries, including approved drug, repurposing candidates and experimental therapeutics designed to modulate a wide range of cellular targets. The goal is to support research scientists, clinical investigators and public health officials through open data sharing and analysis tools to expedite the development of SARS-CoV-2 interventions, and to prioritize promising compounds and repurposed drugs for further development in treating COVID-19.

Published
2020
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3. The ISB Cancer Genomics Cloud: A Flexible Cloud-Based Platform for Cancer Genomics Research

Author

Matthew Bookman, Suzanne M. Paquette, Varsha Dhankani, Michael Miller, Kalle Leinonen, Nicole A. Deflaux, Mark Backus, Todd Pihl, Madelyn Reyes, Sheila Reynolds, Joseph Slagel, Jonathan Bingham, David L Gibbs, David Pot, William J.R. Longabaugh, Abigail Hahn, Zack Rodebaugh, Ilya Shmulevich, and Phyliss Lee

Subjects
0301 basic medicine, Cancer Research, SQL, Computer science, Datasets as Topic, Cloud computing, Bioinformatics, Article, 03 medical and health sciences, 0302 clinical medicine, Documentation, Neoplasms, Humans, Web application, computer.programming_language, Internet, Genome, Human, business.industry, GENCODE, Research, Computational Biology, Genomics, Cloud Computing, Data science, National Cancer Institute (U.S.), United States, ComputingMethodologies_PATTERNRECOGNITION, 030104 developmental biology, Workflow, Oncology, 030220 oncology & carcinogenesis, Data as a service, business, computer, Software
Abstract

The ISB Cancer Genomics Cloud (ISB-CGC) is one of three pilot projects funded by the National Cancer Institute to explore new approaches to computing on large cancer datasets in a cloud environment. With a focus on Data as a Service, the ISB-CGC offers multiple avenues for accessing and analyzing The Cancer Genome Atlas, TARGET, and other important references such as GENCODE and COSMIC using the Google Cloud Platform. The open approach allows researchers to choose approaches best suited to the task at hand: from analyzing terabytes of data using complex workflows to developing new analysis methods in common languages such as Python, R, and SQL; to using an interactive web application to create synthetic patient cohorts and to explore the wealth of available genomic data. Links to resources and documentation can be found at www.isb-cgc.org. Cancer Res; 77(21); e7–10. ©2017 AACR.

Published
2017
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4. 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

5. 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

6. 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

7. 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

8. Microprobe analysis of Tc-MIBI in heart cells: calculation of mitochondrial membrane potential

Author

Melvyn Lieberman, David Piwnica-Worms, J. Kronauge, Daniel Hockett, Ann LeFurgey, Peter Ingram, and Mark Backus

Subjects
Technetium Tc 99m Sestamibi, Cations, Divalent, Physiology, Cell, Analytical chemistry, Contrast Media, Chick Embryo, Mitochondrion, Mitochondria, Heart, Membrane Potentials, Electrolytes, Organelle, Extracellular, medicine, Animals, Inner membrane, Tissue Distribution, Cells, Cultured, Membrane potential, Chemistry, Myocardium, Phosphorus, Cell Biology, Transmembrane protein, medicine.anatomical_structure, Biophysics, Ultrastructure, Sulfur, Electron Probe Microanalysis, Subcellular Fractions
Abstract

Hexakis (2-methoxyisobutylisonitrile) technetium-99m (99mTc-MIBI) is a gamma-emitting radiopharmaceutical probe currently in clinical use to evaluate myocardial perfusion. Biochemical and cellular pharmacological studies have suggested that Tc-MIBI, a lipophilic cation, is sequestered in mitochondria in response to transmembrane potentials. To assess directly the subcellular distribution of the probe in heart tissue, cultured chick heart cells were analyzed by electron-probe X-ray microanalysis (EPXMA) following equilibration in micromolar concentrations of carrier-added 99Tc-MIBI, the ground-state radiopharmaceutical. Quantitation of the physiological elements Na, Ca, Mg, K, S, P, and Cl was correlated with exposure to increasing concentrations of 99Tc-MIBI. EPXMA signals indicated that 99Tc-MIBI was concentrated up to 1,000 times into mitochondria in a dose-dependent fashion based on measured Tc content in the mitochondria. Inner membrane potential (delta psi) of individual mitochondria was calculated as -117 mV using the Nernst equation. Concentrations of 99Tc-MIBI > 36 microM caused a significant efflux of K and Mg from the cell, as well as an increase in Cl in the mitochondria. Comparison of cell ultrastructure with conventional electron microscopy at extracellular 99Tc-MIBI concentrations of 36-72 microM showed no changes compared with control. 99Tc-MIBI allows valuable in situ investigation of cellular bioenergetics with EPXMA by quantitation of delta psi.

Published
1993
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9. Mitochondrial localization and characterization of 99Tc-SESTAMIBI in heart cells by electron probe X-ray microanalysis and 99Tc-NMR spectroscopy

Author

David Piwnica-Worms, James F. Kronauge, B. Leonard Holman, Alun G. Jones, Peter Ingram, Daniel Hockett, Mark Backus, Melvyn Lieberman, Alan Davison, and Ann LeFurgey

Subjects
In situ, Technetium Tc 99m Sestamibi, Cytoplasm, Magnetic Resonance Spectroscopy, Biomedical Engineering, Biophysics, Chick Embryo, Microanalysis, Mitochondria, Heart, Nuclear magnetic resonance, Animals, Radiology, Nuclear Medicine and imaging, Spectroscopy, Cells, Cultured, Cell Nucleus, Cryopreservation, Chemistry, Myocardium, Sodium, Technetium, Nuclear magnetic resonance spectroscopy, Subcellular localization, Chemical state, Microscopy, Electron, Potassium, Quantitative analysis (chemistry), Electron Probe Microanalysis
Abstract

As the development of targeted intracellular magnetic resonance contrast agents proceeds, techniques for the quantitative analysis of the subcellular compartmentation and characterization of metallopharmaceuticals must also advance. To this end, the subcellular distribution and chemical state of hexakis (2-methoxyisobutyl isonitrile) technetium-99 ( 99 Tc-SESTAMIBI), the ground state of the organotechnetium radiopharmaceutical used for the noninvasive evaluation of myocardial perfusion and viability by scintigraphy, has been determined by a novel application of electron probe X-ray microanalysis (EPXMA) and 99 Tc-NMR spectroscopy. In cryopreserved cultured chick heart cells equilibrated in 36 μM 99 Tc-SESTAMIBI, EPXMA imaging of mitochondria yielded a respiratory uncoupler-sensitive characteristic 99 Tc X-ray peak representing 32.0 ± 2.9 nmoles Tc/mg dry weight, while EPXMA of cytoplasm or nucleus showed no peak significantly greater than the threshold detectability limit of ∼ 1 nmole/mg dry weight. Technetium-99 NMR spectroscopy of heart cells equilibrated with 99 Tc-SESTAMIBI showed a single peak at −45.5 ppm with no evidence of significant line broadening or chemical shift compared to aqueous chemical standards, indicating that the majority of the complex exists unbound within the mitochondrial matrix. These data quantitatively demonstrate the localization of this lipophilic cationic organometallic complex within mitochondria in situ, consistent with a sequestration mechanism dependent on membrane potentials. Furthermore, this study establishes the general feasibility of combined EPXMA and NMR spectroscopy for the direct subcellular localization and characterization of metallopharmaceuticals, techniques that are readily applicable to MR contrast agents.

Published
1994

10. Microprobe analysis of technetium-mibi accumulation in cultured heart cell mitochondria: Correlation of structure and membrane potential

Author

Daniel Hockett, Ann LeFurgey, Peter Ingram, David Piwnica-Worms, Mark Backus, and Melvyn Lieberman

Subjects
Membrane potential, 0303 health sciences, Microprobe, Chemistry, Cell, chemistry.chemical_element, 02 engineering and technology, General Medicine, Mitochondrion, 021001 nanoscience & nanotechnology, Technetium, 03 medical and health sciences, medicine.anatomical_structure, medicine, Biophysics, 0210 nano-technology, 030304 developmental biology
Abstract

Hexakis (methoxyisobutylisonitrile)99mTechnetium (Tc-MTBI) is a gamma emitting radiopharmaceutical currently in clinical use for evaluating myocardial perfusion. Because Tc-MIBI exists as a lipophilic cation with a single positive charge, it has been shown to concentrate in mitochondria in response to membrane potential in a Nernstian fashion similar to rhodamine 123. Use of electron probe x-ray microanalysis (EPXMA) for localization and quantitation of the element technetium in mitochondria and calculation of membrane potential allows correlation for the first time between mitochondrial structure and membrane potential in intact cells.Heart cells from 11-day-old chick embryos were cultured into spherical aggregates 50 -100 μm in diameter after Ebihara et al. Aggregates were then incubated for 60 minutes in HEPES balanced buffer salt solution containing either 0, 36,72, or 144 μMTc99-MIBI as well as 20 mCi metastable Tc99m-MIBI. Some aggregates were prepared for conventional fixation and subsequent electron microscopic evaluation, while other aggregates were plunge frozen in liquid propane and cryosectioned for quantitative EPXMA.

Published
1992
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11. 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.

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