The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.
The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups.
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DOI：
10.1038/nature10983
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发表时间：
2012-04-18
期刊：
影响因子：
64.8
通讯作者：
Aparicio, Samuel
中科院分区：
文献类型：
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作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
乳腺癌亚组及其分子驱动因素的阐明需要来自代表性数量的患者的基因组和转录组的综合视图。我们分别对997和995例原发性乳腺肿瘤的发现和验证集进行了拷贝数和基因表达的综合分析，并进行了长期临床随访。遗传变异（拷贝数变异和单核苷酸多态性）和获得性体细胞拷贝数畸变（CNA）与约40%的基因表达相关，顺式和反式作用CNA占主导地位。通过描绘由CNA顺式驱动的表达异常基因，我们鉴定了推定的癌症基因，包括PPP 2 R2 A、MTAP和MAP 2K 4中的缺失。配对DNA-RNA谱的无监督分析揭示了具有不同临床结果的新亚组，其在验证队列中重现。这些包括一个高风险，雌激素受体阳性11 q13/14顺式作用亚组和一个良好的预后亚组没有CNAs。发现反式作用畸变热点可以调节亚组特异性基因网络，包括“缺乏CNA”亚组中的TCR缺失介导的适应性免疫反应和基底细胞特异性5号染色体缺失相关的有丝分裂网络。我们的研究结果提供了一种新的乳腺癌人群的分子分层，来自体细胞CNA对转录组的影响。
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 ~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.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5.8
作者：
Teschendorff, Andrew E.;Naderi, Ali;Caldas, Carlos
通讯作者：
Caldas, Carlos
影响因子：
11.1
作者：
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
通讯作者：
Caldas, Carlos
影响因子：
50.3
作者：
Tan, Jing;Lee, Puay Leng;Yu, Qiang
通讯作者：
Yu, Qiang
影响因子：
45.3
作者：
Mahmoud, Sahar M. A.;Paish, Emma Claire;Green, Andrew R.
通讯作者：
Green, Andrew R.