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 language | English |
|---|---|
| Pages (from-to) | 61-70 |
| Number of pages | 10 |
| Journal | Nature |
| Volume | 490 |
| Issue number | 7418 |
| DOIs | |
| State | Published - 4 Oct 2012 |
| Externally published | Yes |
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In: Nature, Vol. 490, No. 7418, 04.10.2012, p. 61-70.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Comprehensive molecular portraits of human breast tumours
AU - Koboldt, Daniel C.
AU - Fulton, Robert S.
AU - McLellan, Michael D.
AU - Schmidt, Heather
AU - Kalicki-Veizer, Joelle
AU - McMichael, Joshua F.
AU - Fulton, Lucinda L.
AU - Dooling, David J.
AU - Ding, Li
AU - Mardis, Elaine R.
AU - Wilson, Richard K.
AU - Ally, Adrian
AU - Balasundaram, Miruna
AU - Butterfield, Yaron S.N.
AU - Carlsen, Rebecca
AU - Carter, Candace
AU - Chu, Andy
AU - Chuah, Eric
AU - Chun, Hye Jung E.
AU - Coope, Robin J.N.
AU - Dhalla, Noreen
AU - Guin, Ranabir
AU - Hirst, Carrie
AU - Hirst, Martin
AU - Holt, Robert A.
AU - Lee, Darlene
AU - Li, Haiyan I.
AU - Mayo, Michael
AU - Moore, Richard A.
AU - Mungall, Andrew J.
AU - Pleasance, Erin
AU - Robertson, A. Gordon
AU - Schein, Jacqueline E.
AU - Shafiei, Arash
AU - Sipahimalani, Payal
AU - Slobodan, Jared R.
AU - Stoll, Dominik
AU - Tam, Angela
AU - Thiessen, Nina
AU - Varhol, Richard J.
AU - Wye, Natasja
AU - Zeng, Thomas
AU - Zhao, Yongjun
AU - Birol, Inanc
AU - Jones, Steven J.M.
AU - Marra, Marco A.
AU - Cherniack, Andrew D.
AU - Saksena, Gordon
AU - Onofrio, Robert C.
AU - Pho, Nam H.
AU - Carter, Scott L.
AU - Schumacher, Steven E.
AU - Tabak, Barbara
AU - Hernandez, Bryan
AU - Gentry, Jeff
AU - Nguyen, Huy
AU - Crenshaw, Andrew
AU - Ardlie, Kristin
AU - Beroukhim, Rameen
AU - Winckler, Wendy
AU - Getz, Gad
AU - Gabriel, Stacey B.
AU - Meyerson, Matthew
AU - Chin, Lynda
AU - Kucherlapati, Raju
AU - Hoadley, Katherine A.
AU - Auman, J. Todd
AU - Fan, Cheng
AU - Turman, Yidi J.
AU - Shi, Yan
AU - Li, Ling
AU - Topal, Michael D.
AU - He, Xiaping
AU - Chao, Hann Hsiang
AU - Prat, Aleix
AU - Silva, Grace O.
AU - Iglesia, Michael D.
AU - Zhao, Wei
AU - Usary, Jerry
AU - Berg, Jonathan S.
AU - Adams, Michael
AU - Booker, Jessica
AU - Wu, Junyuan
AU - Gulabani, Anisha
AU - Bodenheimer, Tom
AU - Hoyle, Alan P.
AU - Simons, Janae V.
AU - Soloway, Matthew G.
AU - Mose, Lisle E.
AU - Jefferys, Stuart R.
AU - Balu, Saianand
AU - Parker, Joel S.
AU - Hayes, D. Neil
AU - Perou, Charles M.
AU - Malik, Simeen
AU - Mahurkar, Swapna
AU - Shen, Hui
AU - Weisenberger, Daniel J.
AU - Triche, Timothy
AU - Lai, Phillip H.
AU - Bootwalla, Moiz S.
AU - Maglinte, Dennis T.
AU - Berman, Benjamin P.
AU - Van Den Berg, David J.
AU - Baylin, Stephen B.
AU - Laird, Peter W.
AU - Creighton, Chad J.
AU - Donehower, Lawrence A.
AU - Noble, Michael
AU - Voet, Doug
AU - Gehlenborg, Nils
AU - Di Cara, Daniel
AU - Zhang, Juinhua
AU - Zhang, Hailei
AU - Wu, Chang Jiun
AU - Yingchun Liu, Spring
AU - Lawrence, Michael S.
AU - Zou, Lihua
AU - Sivachenko, Andrey
AU - Lin, Pei
AU - Stojanov, Petar
AU - Jing, Rui
AU - Cho, Juok
AU - Sinha, Raktim
AU - Park, Richard W.
AU - Nazaire, Marc Danie
AU - Robinson, Jim
AU - Thorvaldsdottir, Helga
AU - Mesirov, Jill
AU - Park, Peter J.
AU - Reynolds, Sheila
AU - Kreisberg, Richard B.
AU - Bernard, Brady
AU - Bressler, Ryan
AU - Erkkila, Timo
AU - Lin, Jake
AU - Thorsson, Vesteinn
AU - Zhang, Wei
AU - Shmulevich, Ilya
AU - Ciriello, Giovanni
AU - Weinhold, Nils
AU - Schultz, Nikolaus
AU - Gao, Jianjiong
AU - Cerami, Ethan
AU - Gross, Benjamin
AU - Jacobsen, Anders
AU - Sinha, Rileen
AU - Aksoy, B. Arman
AU - Antipin, Yevgeniy
AU - Reva, Boris
AU - Shen, Ronglai
AU - Taylor, Barry S.
AU - Ladanyi, Marc
AU - Sander, Chris
AU - Anur, Pavana
AU - Spellman, Paul T.
AU - Lu, Yiling
AU - Liu, Wenbin
AU - Verhaak, Roel R.G.
AU - Mills, Gordon B.
AU - Akbani, Rehan
AU - Zhang, Nianxiang
AU - Broom, Bradley M.
AU - Casasent, Tod D.
AU - Wakefield, Chris
AU - Unruh, Anna K.
AU - Baggerly, Keith
AU - Coombes, Kevin
AU - Weinstein, John N.
AU - Haussler, David
AU - Benz, Christopher C.
AU - Stuart, Joshua M.
AU - Benz, Stephen C.
AU - Zhu, Jingchun
AU - Szeto, Christopher C.
AU - Scott, Gary K.
AU - Yau, Christina
AU - Paull, Evan O.
AU - Carlin, Daniel
AU - Wong, Christopher
AU - Sokolov, Artem
AU - Thusberg, Janita
AU - Mooney, Sean
AU - Ng, Sam
AU - Goldstein, Theodore C.
AU - Ellrott, Kyle
AU - Grifford, Mia
AU - Wilks, Christopher
AU - Ma, Singer
AU - Craft, Brian
AU - Yan, Chunhua
AU - Hu, Ying
AU - Meerzaman, Daoud
AU - Gastier-Foster, Julie M.
AU - Bowen, Jay
AU - Ramirez, Nilsa C.
AU - Black, Aaron D.
AU - Pyatt, Robert E.
AU - White, Peter
AU - Zmuda, Erik J.
AU - Frick, Jessica
AU - Lichtenberg, Tara M.
AU - Brookens, Robin
AU - George, Myra M.
AU - Gerken, Mark A.
AU - Harper, Hollie A.
AU - Leraas, Kristen M.
AU - Wise, Lisa J.
AU - Tabler, Teresa R.
AU - McAllister, Cynthia
AU - Barr, Thomas
AU - Hart-Kothari, Melissa
AU - Tarvin, Katie
AU - Saller, Charles
AU - Sandusky, George
AU - Mitchell, Colleen
AU - Iacocca, Mary V.
AU - Brown, Jennifer
AU - Rabeno, Brenda
AU - Czerwinski, Christine
AU - Petrelli, Nicholas
AU - Dolzhansky, Oleg
AU - Abramov, Mikhail
AU - Voronina, Olga
AU - Potapova, Olga
AU - Marks, Jeffrey R.
AU - Suchorska, Wiktoria M.
AU - Murawa, Dawid
AU - Kycler, Witold
AU - Ibbs, Matthew
AU - Korski, Konstanty
AU - Spychała, Arkadiusz
AU - Murawa, Paweł
AU - Brzeziński, Jacek J.
AU - Perz, Hanna
AU - Łaźniak, Radosław
AU - Teresiak, Marek
AU - Tatka, Honorata
AU - Leporowska, Ewa
AU - Bogusz-Czerniewicz, Marta
AU - Malicki, Julian
AU - Mackiewicz, Andrzej
AU - Wiznerowicz, Maciej
AU - Van Le, Xuan
AU - Kohl, Bernard
AU - Viet Tien, Nguyen
AU - Thorp, Richard
AU - Van Bang, Nguyen
AU - Sussman, Howard
AU - Phu, Bui Duc
AU - Hajek, Richard
AU - Hung, Nguyen Phi
AU - Phuong, Tran Viet The
AU - Thang, Huynh Quyet
AU - Khan, Khurram Zaki
AU - Penny, Robert
AU - Mallery, David
AU - Curley, Erin
AU - Shelton, Candace
AU - Yena, Peggy
AU - Ingle, James N.
AU - Couch, Fergus J.
AU - Lingle, Wilma L.
AU - King, Tari A.
AU - Gonzalez-Angulo, Ana Maria
AU - Dyer, Mary D.
AU - Liu, Shuying
AU - Meng, Xiaolong
AU - Patangan, Modesto
AU - Waldman, Frederic
AU - Stöppler, Hubert
AU - Rathmell, W. Kimryn
AU - Thorne, Leigh
AU - Huang, Mei
AU - Boice, Lori
AU - Hill, Ashley
AU - Morrison, Carl
AU - Gaudioso, Carmelo
AU - Bshara, Wiam
AU - Daily, Kelly
AU - Egea, Sophie C.
AU - Pegram, Mark D.
AU - Gomez-Fernandez, Carmen
AU - Dhir, Rajiv
AU - Bhargava, Rohit
AU - Brufsky, Adam
AU - Shriver, Craig D.
AU - Hooke, Jeffrey A.
AU - Campbell, Jamie Leigh
AU - Mural, Richard J.
AU - Hu, Hai
AU - Somiari, Stella
AU - Larson, Caroline
AU - Deyarmin, Brenda
AU - Kvecher, Leonid
AU - Kovatich, Albert J.
AU - Ellis, Matthew J.
AU - Stricker, Thomas
AU - White, Kevin
AU - Olopade, Olufunmilayo
AU - Luo, Chunqing
AU - Chen, Yaqin
AU - Bose, Ron
AU - Chang, Li Wei
AU - Beck, Andrew H.
AU - Pihl, Todd
AU - Jensen, Mark
AU - Sfeir, Robert
AU - Kahn, Ari
AU - Chu, Anna
AU - Kothiyal, Prachi
AU - Wang, Zhining
AU - Snyder, Eric
AU - Pontius, Joan
AU - Ayala, Brenda
AU - Backus, Mark
AU - Walton, Jessica
AU - Baboud, Julien
AU - Berton, Dominique
AU - Nicholls, Matthew
AU - Srinivasan, Deepak
AU - Raman, Rohini
AU - Girshik, Stanley
AU - Kigonya, Peter
AU - Alonso, Shelley
AU - Sanbhadti, Rashmi
AU - Barletta, Sean
AU - Pot, David
AU - Sheth, Margi
AU - Demchok, John A.
AU - Shaw, Kenna R.Mills
AU - Yang, Liming
AU - Eley, Greg
AU - Ferguson, Martin L.
AU - Tarnuzzer, Roy W.
AU - Zhang, Jiashan
AU - Dillon, Laura A.L.
AU - Buetow, Kenneth
AU - Fielding, Peter
AU - Ozenberger, Bradley A.
AU - Guyer, Mark S.
AU - Sofia, Heidi J.
AU - Palchik, Jacqueline D.
N1 - Funding Information: Acknowledgements WethankM.Sheth andS.Lucasfor administrative coordination of TCGA activities, and C. Gunter for critical reading of the manuscript. This work was supported by the following grants from the USA National Institutes of Health: U24CA143883, U24CA143858, U24CA143840, U24CA143799, U24CA143835, U24CA143845, U24CA143882, U24CA143867, U24CA143866, U24CA143848, U24CA144025, U54HG003079, P50CA116201 and P50CA58223. Additional support was provided by the Susan G. Komen for the Cure, the US Department of Defense through the Henry M. Jackson Foundation for the Advancement of Military Medicine, and the Breast Cancer Research Foundation. The views expressed in this paper are those of the authors and do not reflect the official policy of the Department of Defense, or US Government.
PY - 2012/10/4
Y1 - 2012/10/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84877028141&partnerID=8YFLogxK
U2 - 10.1038/nature11412
DO - 10.1038/nature11412
M3 - Article
AN - SCOPUS:84877028141
SN - 0028-0836
VL - 490
SP - 61
EP - 70
JO - Nature
JF - Nature
IS - 7418
ER -