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


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.

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Figure 1: SCLC somatic mutations.
Figure 2: Significantly mutated genes in SCLC.
Figure 3: SOX2 is amplified in SCLC and drives proliferation.
Figure 4: SOX2 gene amplification and protein expression in SCLC.
Figure 5: Kinase fusions.


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The authors would like to thank Genentech DNA Sequencing and Oligo groups for their help with the project. We thank M.A. Huntley and J. Degenhardt for bioinformatics support and the Pathology Core Labs for providing histology, IHC and tissue management support. This work was also supported by grants from the Burroughs Wellcome Fund, the Flight Attendant Medical Research Institute, the Johns Hopkins Specialized Programs of Research Excellence (SPORE) NCI P50CA058184 (M.V.B. and C.M.R.), the Colorado SPORE NCI P50 CA058187 (M.V.-G) and the University of Texas SPORE NCI P50CA70907 (J.D.M., A.F.G. and K.E.H.). D.D.P. is supported by the Coordenacao de Aperfeicoamento de Passoal de Nivel Superior (CAPES) Foundation and the Ministry of Education of Brazil.

Author information

C.M.R. and S.S. conceived the study and designed the experiments. E.W.S. and S.D. performed the exome and whole-genome sequencing, RNA-seq and copy-number analysis. Z.M. and Y.G. performed validation of the fusions. Z.M. managed exome capture. J.T.P., E.A.B., S.C., V.J., B.S.J., W.Y. and C.P. performed biological validated studies. J. Shin, D.D.P., P.B.I. and M.V.-G. performed SOX2 IHC and FISH studies. K.E.H., A.F.G. and J.D.M. provided reagents and analysis support. J. Stinson, C.K.F., D.B., C.S.R. and J.G. collected sequencing data and performed mutation validation. F.G. and Z.Z. predicted the functional effects of mutations. E.W.S., P.M.H., R.B., T.D.W. and R.G. provided bioinformatics support, including the algorithm for variant calling, fusion detection and copy-number calling. R.B. and P.M.H. analyzed SNP array data. H.K., H.M.S., P.B.I., M.V.B. and A.F.G. provided pathology support. F.J.d.S., D.S.S., R.L.Y. and J.D.M. provided critical analysis and organizational support. D.S.S., E.W.S., S.D., Z.M., C.M.R. and J.T.P. wrote the manuscript, which was reviewed and edited by the other coauthors.

Correspondence to Charles M Rudin or Somasekar Seshagiri.

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Competing interests

C.M.R. has previously consulted for Genentech. P.B.I. is a consultant for Leica Microsystems, the manufacturer of a device used in this study. The terms of these arrangements are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. Some of the authors, as indicated in the author affiliations, are employees of Genentech and hold shares in Roche.

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Rudin, C., Durinck, S., Stawiski, E. et al. Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer. Nat Genet 44, 1111–1116 (2012).

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