The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups

被引：4398

作者：

Curtis, Christina ^{[1
,2
]}

Shah, Sohrab P. ^{[3
,4
]}

Chin, Suet-Feung ^{[1
,2
]}

Turashvili, Gulisa ^{[3
,4
]}

Rueda, Oscar M. ^{[1
,2
]}

Dunning, Mark J. ^{[2
]}

Speed, Doug ^{[2
,5
]}

Lynch, Andy G. ^{[1
,2
]}

Samarajiwa, Shamith ^{[1
,2
]}

Yuan, Yinyin ^{[1
,2
]}

Graef, Stefan ^{[1
,2
]}

Ha, Gavin ^{[3
]}

Haffari, Gholamreza ^{[3
]}

Bashashati, Ali ^{[3
]}

Russell, Roslin ^{[2
]}

McKinney, Steven ^{[3
,4
]}

Langerod, Anita ^{[6
]}

Green, Andrew ^{[7
]}

Provenzano, Elena ^{[8
]}

Wishart, Gordon ^{[8
]}

Pinder, Sarah ^{[9
,10
]}

Watson, Peter ^{[3
,4
,11
]}

Markowetz, Florian ^{[1
,2
]}

Murphy, Leigh ^{[11
]}

Ellis, Ian ^{[7
]}

Purushotham, Arnie ^{[9
,12
]}

Borresen-Dale, Anne-Lise ^{[6
,10
,13
]}

Brenton, James D. ^{[2
,14
]}

Tavare, Simon ^{[1
,2
,5
,15
]}

Caldas, Carlos ^{[1
,2
,8
,14
]}

Aparicio, Samuel ^{[3
,4
]}

机构：

[1] Univ Cambridge, Dept Oncol, Cambridge CB2 2XZ, England

[2] Canc Res UK, Cambridge Res Inst, Li Ka Shing Ctr, Cambridge CB2 0RE, England

[3] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V6T 2B5, Canada

[4] British Columbia Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada

[5] Univ Cambridge, Dept Appl Math & Theoret Phys, Ctr Math Sci, Cambridge CB3 0WA, England

[6] Radiumhosp, Dept Genet, Inst Canc Res, Oslo Univ Hosp, N-0310 Oslo, Norway

[7] Univ Nottingham, Dept Histopathol, Sch Mol Med Sci, Nottingham NG5 1PB, England

[8] Cambridge Univ Hosp NHS Fdn Trust, Cambridge Breast Unit, Addenbrookes Hosp, Cambridge CB2 2QQ, England

[9] Kings Coll London, Breakthrough Breast Canc Res Unit, London WC2R 2LS, England

[10] NIHR Cambridge Biomed Res Ctr, London WC2R 2LS, England

[11] Univ Manitoba, Manitoba Inst Cell Biol, Winnipeg, MB R3E 0V9, Canada

[12] Guys & St Thomas NHS Fdn Trust, NIHR Comprehens Biomed Res Ctr, London WC2R 2LS, England

[13] Univ Oslo, Inst Clin Med, Fac Med, N-0316 Oslo, Norway

[14] Cambridge Expt Canc Med Ctr, Cambridge CB2 0RE, England

[15] Univ So Calif, Mol & Computat Biol Program, Los Angeles, CA 90089 USA

来源：

NATURE | 2012年 / 486卷 / 7403期

基金：

美国国家卫生研究院;

关键词：

GENE-EXPRESSION; CANCER; PROTEIN; SUPPRESSOR; CARCINOMA; SUBTYPE;

D O I：

10.1038/nature10983

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The elucidation of breast cancer subgroups and their molecular drivers requires integrated views of the genome and transcriptome from representative numbers of patients. We present an integrated analysis of copy number and gene expression in a discovery and validation set of 997 and 995 primary breast tumours, respectively, with long-term clinical follow-up. Inherited variants (copy number variants and single nucleotide polymorphisms) and acquired somatic copy number aberrations (CNAs) were associated with expression in similar to 40% of genes, with the landscape dominated by cis-and trans-acting CNAs. By delineating expression outlier genes driven in cis by CNAs, we identified putative cancer genes, including deletions in PPP2R2A, MTAP and MAP2K4. Unsupervised analysis of paired DNA-RNA profiles revealed novel subgroups with distinct clinical outcomes, which reproduced in the validation cohort. These include a high-risk, oestrogen-receptor-positive 11q13/14 cis-acting subgroup and a favourable prognosis subgroup devoid of CNAs. Trans-acting aberration hotspots were found to modulate subgroup-specific gene networks, including a TCR deletion-mediated adaptive immune response in the 'CNA-devoid' subgroup and a basal-specific chromosome 5 deletion-associated mitotic network. Our results provide a novel molecular stratification of the breast cancer population, derived from the impact of somatic CNAs on the transcriptome.

引用

页码：346 / 352

页数：7

共 29 条

[1] Signatures of mutation and selection in the cancer genome [J].

Bignell, Graham R. ;

Greenman, Chris D. ;

Davies, Helen ;

Butler, Adam P. ;

Edkins, Sarah ;

Andrews, Jenny M. ;

Buck, Gemma ;

Chen, Lina ;

Beare, David ;

Latimer, Calli ;

Widaa, Sara ;

Hinton, Jonathon ;

Fahey, Ciara ;

Fu, Beiyuan ;

Swamy, Sajani ;

Dalgliesh, Gillian L. ;

Teh, Bin T. ;

Deloukas, Panos ;

Yang, Fengtang ;

Campbell, Peter J. ;

Futreal, P. Andrew ;

Stratton, Michael R. .

NATURE, 2010, 463 (7283) :893-U61

[2] Subtyping of Breast Cancer by Immunohistochemistry to Investigate a Relationship between Subtype and Short and Long Term Survival: A Collaborative Analysis of Data for 10,159 Cases from 12 Studies [J].

Blows, Fiona M. ;

Driver, Kristy E. ;

Schmidt, Marjanka K. ;

Broeks, Annegien ;

van Leeuwen, Flora E. ;

Wesseling, Jelle ;

Cheang, Maggie C. ;

Gelmon, Karen ;

Nielsen, Torsten O. ;

Blomqvist, Carl ;

Heikkila, Paivi ;

Heikkinen, Tuomas ;

Nevanlinna, Heli ;

Akslen, Lars A. ;

Begin, Louis R. ;

Foulkes, William D. ;

Couch, Fergus J. ;

Wang, Xianshu ;

Cafourek, Vicky ;

Olson, Janet E. ;

Baglietto, Laura ;

Giles, Graham G. ;

Severi, Gianluca ;

McLean, Catriona A. ;

Southey, Melissa C. ;

Rakha, Emad ;

Green, Andrew R. ;

Ellis, Ian O. ;

Sherman, Mark E. ;

Lissowska, Jolanta ;

Anderson, William F. ;

Cox, Angela ;

Cross, Simon S. ;

Reed, Malcolm W. R. ;

Provenzano, Elena ;

Dawson, Sarah-Jane ;

Dunning, Alison M. ;

Humphreys, Manjeet ;

Easton, Douglas F. ;

Garcia-Closas, Montserrat ;

Caldas, Carlos ;

Pharoah, Paul D. ;

Huntsman, David .

PLOS MEDICINE, 2010, 7 (05)

[3] Amplification of 11q13 in ovarian carcinoma [J].

Brown, Lindsay A. ;

Kalloger, Steve E. ;

Miller, Melinda A. ;

Shih, le-Ming ;

McKinney, Steven E. ;

Santos, Jennifer L. ;

Swenerton, Ken ;

Spellman, Paul T. ;

Gray, Joe ;

Gilks, C. Blake ;

Huntsman, David G. .

GENES CHROMOSOMES & CANCER, 2008, 47 (06) :481-489

[4] Variations in DNA elucidate molecular networks that cause disease [J].

Chen, Yanqing ;

Zhu, Jun ;

Lum, Pek Yee ;

Yang, Xia ;

Pinto, Shirly ;

MacNeil, Douglas J. ;

Zhang, Chunsheng ;

Lamb, John ;

Edwards, Stephen ;

Sieberts, Solveig K. ;

Leonardson, Amy ;

Castellini, Lawrence W. ;

Wang, Susanna ;

Champy, Marie-France ;

Zhang, Bin ;

Emilsson, Valur ;

Doss, Sudheer ;

Ghazalpour, Anatole ;

Horvath, Steve ;

Drake, Thomas A. ;

Lusis, Aldons J. ;

Schadt, Eric E. .

NATURE, 2008, 452 (7186) :429-435

[5] Genomic and transcriptional aberrations linked to breast cancer pathophysiologies [J].

Chin, Koei ;

DeVries, Sandy ;

Fridlyand, Jane ;

Spellman, Paul T. ;

Roydasgupta, Ritu ;

Kuo, Wen-Lin ;

Lapuk, Anna ;

Neve, Richard M. ;

Qian, Zuwei ;

Ryder, Tom ;

Chen, Fanqing ;

Feiler, Heidi ;

Tokuyasu, Taku ;

Kingsley, Chris ;

Dairkee, Shanaz ;

Meng, Zhenhang ;

Chew, Karen ;

Pinkel, Daniel ;

Jain, Ajay ;

Ljung, Britt Marie ;

Esserman, Laura ;

Albertson, Donna G. ;

Waldman, Frederic M. ;

Gray, Joe W. .

CANCER CELL, 2006, 10 (06) :529-541

[6] High-resolution aCGH and expression profiling identifies a novel genomic subtype of ER negative breast cancer [J].

Chin, Suet F. ;

Teschendorff, Andrew E. ;

Marioni, John C. ;

Wang, Yanzhong ;

Barbosa-Morais, Nuno L. ;

Thorne, Natalie P. ;

Costa, Jose L. ;

Pinder, Sarah E. ;

van de Wiel, Mark A. ;

Green, Andrew R. ;

Ellis, Ian O. ;

Porter, Peggy L. ;

Tavare, Simon ;

Brenton, James D. ;

Ylstra, Bauke ;

Caldas, Carlos .

GENOME BIOLOGY, 2007, 8 (10)

[7]

Christopher SA, 2002, CANCER RES, V62, P6639

[8] High levels of the Mps1 checkpoint protein are protective of aneuploidy in breast cancer cells [J].

Daniel, Jewel ;

Coulter, Jonathan ;

Woo, Ju-Hyung ;

Wilsbach, Kathleen ;

Gabrielson, Edward .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2011, 108 (13) :5384-5389

[9] Revealing the architecture of gene regulation: the promise of eQTL studies [J].

Gilad, Yoav ;

Rifkin, Scott A. ;

Pritchard, Jonathan K. .

TRENDS IN GENETICS, 2008, 24 (08) :408-415

[10] ZNF703 is a common Luminal B breast cancer oncogene that differentially regulates luminal and basal progenitors in human mammary epithelium [J].

Holland, Daniel G. ;

Burleigh, Angela ;

Git, Anna ;

Goldgraben, Mae A. ;

Perez-Mancera, Pedro A. ;

Chin, Suet-Feung ;

Hurtado, Antonio ;

Bruna, Alejandro ;

Ali, H. Raza ;

Greenwood, Wendy ;

Dunning, Mark J. ;

Samarajiwa, Shamith ;

Menon, Suraj ;

Rueda, Oscar M. ;

Lynch, Andy G. ;

McKinney, Steven ;

Ellis, Ian O. ;

Eaves, Connie J. ;

Carroll, Jason S. ;

Curtis, Christina ;

Aparicio, Samuel ;

Caldas, Carlos .

EMBO MOLECULAR MEDICINE, 2011, 3 (03) :167-180

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