Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer

被引：906

作者：

Rudin, Charles M. ^{[1
]}

Durinck, Steffen ^{[2
,3
]}

Stawiski, Eric W. ^{[2
,3
]}

Poirier, John T. ^{[1
]}

Modrusan, Zora ^{[2
]}

Shames, David S. ^{[4
]}

Bergbower, Emily A. ^{[1
]}

Guan, Yinghui ^{[2
]}

Shin, James ^{[1
]}

Guillory, Joseph ^{[2
]}

Rivers, Celina Sanchez ^{[2
]}

Foo, Catherine K. ^{[2
]}

Bhatt, Deepali ^{[2
]}

Stinson, Jeremy ^{[2
]}

Gnad, Florian ^{[3
]}

Haverty, Peter M. ^{[3
]}

Gentleman, Robert ^{[3
]}

Chaudhuri, Subhra ^{[2
]}

Janakiraman, Vasantharajan ^{[2
]}

Jaiswal, Bijay S. ^{[2
]}

Parikh, Chaitali ^{[2
]}

Yuan, Wenlin ^{[2
]}

Zhang, Zemin ^{[3
]}

Koeppen, Hartmut ^{[5
]}

Wu, Thomas D. ^{[3
]}

Stern, Howard M. ^{[5
]}

Yauch, Robert L. ^{[4
]}

Huffman, Kenneth E. ^{[6
]}

Paskulin, Diego D. ^{[7
]}

Illei, Peter B. ^{[1
]}

Varella-Garcia, Marileila ^{[7
]}

Gazdar, Adi F. ^{[6
]}

de Sauvage, Frederic J. ^{[2
]}

Bourgon, Richard ^{[3
]}

Minna, John D. ^{[6
]}

Brock, Malcolm V. ^{[1
]}

Seshagiri, Somasekar ^{[2
]}

机构：

[1] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21218 USA

[2] Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Bioinformat & Computat Biol, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Oncol Biomarker Dev, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA

[6] Univ Texas SW Med Ctr Dallas, Hamon Ctr Therapeut Oncol Res, Dallas, TX 75390 USA

[7] Univ Colorado, Ctr Canc, Div Med Oncol, Aurora, CO USA

来源：

NATURE GENETICS | 2012年 / 44卷 / 10期

关键词：

NONSMALL CELL; MUTATIONS; CARCINOMA; KINASE; TARGET; GROWTH; DIFFERENTIATION; REARRANGEMENTS; PATHWAY; COMPLEX;

D O I：

10.1038/ng.2405

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

Small-cell lung cancer (SCLC) is an exceptionally aggressive disease with poor prognosis. Here, we obtained exome, transcriptome and copy-number alteration data from approximately 53 samples consisting of 36 primary human SCLC and normal tissue pairs and 17 matched SCLC and lymphoblastoid cell lines. We also obtained data for 4 primary tumors and 23 SCLC cell lines. We identified 22 significantly mutated genes in SCLC, including genes encoding kinases, G protein-coupled receptors and chromatin-modifying proteins. We found that several members of the SOX family of genes were mutated in SCLC. We also found SOX2 amplification in similar to 27% of the samples. Suppression of SOX2 using shRNAs blocked proliferation of SOX2-amplified SCLC lines. RNA sequencing identified multiple fusion transcripts and a recurrent RLF-MYCL1 fusion. Silencing of MYCL1 in SCLC cell lines that had the RLF-MYCL1 fusion decreased cell proliferation. These data provide an in-depth view of the spectrum of genomic alterations in SCLC and identify several potential targets for therapeutic intervention.

引用

页码：1111 / +

页数：8

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