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

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. JaiswalChaitali 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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1111-1116
Number of pages6
JournalNature genetics
Volume44
Issue number10
DOIs
StatePublished - Oct 1 2012

ASJC Scopus subject areas

  • Genetics

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    Rudin, C. M., Durinck, S., Stawiski, E. W., Poirier, J. T., Modrusan, Z., Shames, D. S., Bergbower, E. A., Guan, Y., Shin, J., Guillory, J., Rivers, C. S., Foo, C. K., Bhatt, D., Stinson, J., Gnad, F., Haverty, P. M., Gentleman, R., Chaudhuri, S., Janakiraman, V., ... Seshagiri, S. (2012). Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nature genetics, 44(10), 1111-1116. https://doi.org/10.1038/ng.2405