Comprehensive molecular portraits of human breast tumours

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

Research output: Contribution to journalArticle

6050 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)61-70
Number of pages10
JournalNature
Volume490
Issue number7418
DOIs
StatePublished - Oct 4 2012

ASJC Scopus subject areas

  • General

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