Authors:
Charles M Rudin, Steffen Durinck, Eric W Stawiski, John T Poirier, Zora Modrusan, David S Shames, Emily A Bergbower, Yinghui Guan, James Shin, Joseph Guillory, Celina Sanchez Rivers, Catherine K Foo, Deepali Bhatt, Jeremy Stinson, Florian Gnad, Peter M Haverty, Robert Gentleman, Subhra Chaudhuri, Vasantharajan Janakiraman, Bijay S Jaiswal, Chaitali Parikh, Wenlin Yuan, Zemin Zhang, Hartmut Koeppen, Thomas D Wu, Howard M Stern, Robert L Yauch, Kenneth E Huffman, Diego D Paskulin, Peter B Illei, Marileila Varella-Garcia, Adi F Gazdar, Frederic J de Sauvage, Richard Bourgon, John D Minna, Malcolm V Brock, & Somasekar Seshagiri
Summary:
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 ~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.
Source:
Nature Genetics; 44, 1111-1116 (09/02/12)