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

By C. Rudin, S. Durinck, Eric W. Stawiski, J. Poirier, Z. Modrusan, D. Shames, E. Bergbower, Y. Guan, James Shin, Joseph Guillory and 27 more. Nature Genetics, 2012

1,002 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/7c8e6a0417b81daf83f21fcfb051cac82a7249b7

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In Molecular Biology

Citations in the corpus

Tumor Mutation Burden and Efficacy of Nivolumab Monotherapy and in Combination With Ipilimumab in Small Cell Lung Cancer (2018, neutral): “SCLC is characterized by high somatic mutational burden (George et al., 2015; Peifer et al., 2012; Rudin et al., 2012) due to the nearly universal association of SCLCwith smoking (Alexandrov et al., 2013; Byers and Rudin, 2015); mutations can affect diverse pathways, includingDNA repair mechanisms…”
Early Detection of Molecular Residual Disease in Localized Lung Cancer by Circulating Tumor DNA Profiling (2017, background): “Candidate driver genes were defined as genes that were found to be statistically significantly mutated in NSCLC or SCLC in prior studies (Supplemental Methods, Supplemental Table S6) (12-15).”
The Evaluation of Tools Used to Predict the Impact of Missense Variants Is Hindered by Two Types of Circularity (2015, background): “They are widely used for separating pathogenic variants from neutral variants in sequencing studies [Leongamornlert et al., 2012; Rudin et al., 2012; Kim et al., 2013; Thevenon et al., 2014; Weinreb et al., 2014; Zhao et al., 2015].”
The Sox Family of Transcription Factors: Versatile Regulators of Stem and Progenitor Cell Fate (2013, positive): “For instance, knockdown of SOX2 in human cell lines, derived from squamous cell caricinomas and small cell lung cancer, compromises growth (Bass et al., 2009; Rudin et al., 2012).”