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Nature. 2012 Oct 4;490(7418):61-70. doi: 10.1038/nature11412. Epub 2012 Sep 23.

Comprehensive molecular portraits of human breast tumours.

Collaborators (357)

Koboldt DC, Fulton RS, McLellan MD, Schmidt H, Kalicki-Veizer J, McMichael JF, Fulton LL, Dooling DJ, Ding L, Mardis ER, Wilson RK, Ally A, Balasundaram M, Butterfield YS, Carlsen R, Carter C, Chu A, Chuah E, Chun HJ, Coope RJ, Dhalla N, Guin R, Hirst C, Hirst M, Holt RA, Lee D, Li HI, Mayo M, Moore RA, Mungall AJ, Pleasance E, Robertson A, Schein JE, Shafiei A, Sipahimalani P, Slobodan JR, Stoll D, Tam A, Thiessen N, Varhol RJ, Wye N, Zeng T, Zhao Y, Birol I, Jones SJ, Marra MA, Cherniack AD, Saksena G, Onofrio RC, Pho NH, Carter SL, Schumacher SE, Tabak B, Hernandez B, Gentry J, Nguyen H, Crenshaw A, Ardlie K, Beroukhim R, Winckler W, Getz G, Gabriel SB, Meyerson M, Chin L, Park PJ, Kucherlapati R, Hoadley KA, Auman J, Fan C, Turman YJ, Shi Y, Li L, Topal MD, He X, Chao HH, Prat A, Silva GO, Iglesia MD, Zhao W, Usary J, Berg JS, Adams M, Booker J, Wu J, Gulabani A, Bodenheimer T, Hoyle AP, Simons JV, Soloway MG, Mose LE, Jefferys SR, Balu S, Parker JS, Hayes D, Perou CM, Malik S, Mahurkar S, Shen H, Weisenberger DJ, Triche T Jr, Lai PH, Bootwalla MS, Maglinte DT, Berman BP, Van Den Berg DJ, Baylin SB, Laird PW, Creighton CJ, Donehower LA, Getz G, Noble M, Voet D, Saksena G, Gehlenborg N, DiCara D, Zhang J, Zhang H, Wu CJ, Liu SY, Lawrence MS, Zou L, Sivachenko A, Lin P, Stojanov P, Jing R, Cho J, Sinha R, Park RW, Nazaire MD, Robinson J, Thorvaldsdottir H, Mesirov J, Park PJ, Chin L, Reynolds S, Kreisberg RB, Bernard B, Bressler R, Erkkila T, Lin J, Thorsson V, Zhang W, Shmulevich I, Ciriello G, Weinhold N, Schultz N, Gao J, Cerami E, Gross B, Jacobsen A, Sinha R, Aksoy B, Antipin Y, Reva B, Shen R, Taylor BS, Ladanyi M, Sander C, Anur P, Spellman PT, Lu Y, Liu W, Verhaak RR, Mills GB, Akbani R, Zhang N, Broom BM, Casasent TD, Wakefield C, Unruh AK, Baggerly K, Coombes K, Weinstein JN, Haussler D, Benz CC, Stuart JM, Benz SC, Zhu J, Szeto CC, Scott GK, Yau C, Paull EO, Carlin D, Wong C, Sokolov A, Thusberg J, Mooney S, Ng S, Goldstein TC, Ellrott K, Grifford M, Wilks C, Ma S, Craft B, Yan C, Hu Y, Meerzaman D, Gastier-Foster JM, Bowen J, Ramirez NC, Black AD, Pyatt RE, White P, Zmuda EJ, Frick J, Lichtenberg TM, Brookens R, George MM, Gerken MA, Harper HA, Leraas KM, Wise LJ, Tabler TR, McAllister C, Barr T, Hart-Kothari M, Tarvin K, Saller C, Sandusky G, Mitchell C, Iacocca MV, Brown J, Rabeno B, Czerwinski C, Petrelli N, Dolzhansky O, Abramov M, Voronina O, Potapova O, Marks JR, Suchorska WM, Murawa D, Kycler W, Ibbs M, Korski K, Spychała A, Murawa P, Brzeziński JJ, Perz H, Łaźniak R, Teresiak M, Tatka H, Leporowska E, Bogusz-Czerniewicz M, Malicki J, Mackiewicz A, Wiznerowicz M, Le XV, Kohl B, Nguyen VT, Thorp R, Nguyen VB, Sussman H, Bui DP, Hajek R, Nguyen PH, Tran VT, Huynh QT, Khan KZ, Penny R, Mallery D, Curley E, Shelton C, Yena P, Ingle JN, Couch FJ, Lingle WL, King TA, Gonzalez-Angulo AM, Mills GB, Dyer MD, Liu S, Meng X, Patangan M, Waldman F, Stöppler H, Rathmell W, Thorne L, Huang M, Boice L, Hill A, Morrison C, Gaudioso C, Bshara W, Daily K, Egea SC, Pegram M, Gomez-Fernandez C, Dhir R, Bhargava R, Brufsky A, Shriver CD, Hooke JA, Campbell JL, Mural RJ, Hu H, Somiari S, Larson C, Deyarmin B, Kvecher L, Kovatich AJ, Ellis MJ, King TA, Hu H, Couch FJ, Mural RJ, Stricker T, White K, Olopade O, Ingle JN, Luo C, Chen Y, Marks JR, Waldman F, Wiznerowicz M, Bose R, Chang LW, Beck AH, Gonzalez-Angulo AM, Pihl T, Jensen M, Sfeir R, Kahn A, Chu A, Kothiyal P, Wang Z, Snyder E, Pontius J, Ayala B, Backus M, Walton J, Baboud J, Berton D, Nicholls M, Srinivasan D, Raman R, Girshik S, Kigonya P, Alonso S, Sanbhadti R, Barletta S, Pot D, Sheth M, Demchok JA, Shaw KR, Yang L, Eley G, Ferguson ML, Tarnuzzer RW, Zhang J, Dillon LA, Buetow K, Fielding P, Ozenberger BA, Guyer MS, Sofia HJ, Palchik JD.

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.

PMID:
23000897
[PubMed - indexed for MEDLINE]
PMCID:
PMC3465532
Free PMC Article

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