Comprehensive Genomic Analysis Identifies SOX2 As a Frequently Amplified Gene in Small-cell Lung Cancer

Overview

Journal Nat Genet

Specialty Genetics

Date 2012 Sep 4

PMID 22941189

Citations 580

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Small cell lung carcinoma with YAP1 expression and SMARCA4-deficient undifferentiated tumors.

Hayashi T Transl Cancer Res. 2025; 14(1):7-10.

PMID: 39974377 PMC: 11833380. DOI: 10.21037/tcr-24-1952.

Polo-like Kinase 1 Inhibitors Demonstrate In Vitro and In Vivo Efficacy in Preclinical Models of Small Cell Lung Cancer.

Zhang G, Pannucci A, Ivanov A, Switchenko J, Sun S, Sica G Cancers (Basel). 2025; 17(3).

PMID: 39941812 PMC: 11815996. DOI: 10.3390/cancers17030446.

Development and validation of a glycolysis-associated gene signature for predicting the prognosis, immune landscape, and drug sensitivity in bladder cancer.

Shen C, Suo Y, Guo J, Su W, Zhang Z, Yang S Front Immunol. 2025; 15:1430583.

PMID: 39867879 PMC: 11757262. DOI: 10.3389/fimmu.2024.1430583.

Neuroendocrine Transformation as a Mechanism of Resistance to Targeted Lung Cancer Therapies: Emerging Mechanisms and Their Therapeutic Implications.

Joshi A, Bhaskar N, Pearson J Cancers (Basel). 2025; 17(2).

PMID: 39858043 PMC: 11763869. DOI: 10.3390/cancers17020260.

Recent Advances in the Clinical Translation of Small-Cell Lung Cancer Therapeutics.

Das S, Samaddar S Cancers (Basel). 2025; 17(2).

PMID: 39858036 PMC: 11764476. DOI: 10.3390/cancers17020255.

References

Seshagiri S, Stawiski E, Durinck S, Modrusan Z, Storm E, Conboy C . Recurrent R-spondin fusions in colon cancer. Nature. 2012; 488(7413):660-4. PMC: 3690621. DOI: 10.1038/nature11282. View

Mermel C, Schumacher S, Hill B, Meyerson M, Beroukhim R, Getz G . GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 2011; 12(4):R41. PMC: 3218867. DOI: 10.1186/gb-2011-12-4-r41. View

Gonzalez-Perez A, Lopez-Bigas N . Improving the assessment of the outcome of nonsynonymous SNVs with a consensus deleteriousness score, Condel. Am J Hum Genet. 2011; 88(4):440-9. PMC: 3071923. DOI: 10.1016/j.ajhg.2011.03.004. View

Martincorena I, Seshasayee A, Luscombe N . Evidence of non-random mutation rates suggests an evolutionary risk management strategy. Nature. 2012; 485(7396):95-8. DOI: 10.1038/nature10995. View

DePristo M, Banks E, Poplin R, Garimella K, Maguire J, Hartl C . A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011; 43(5):491-8. PMC: 3083463. DOI: 10.1038/ng.806. View

Pleasance E, Stephens P, OMeara S, McBride D, Meynert A, Jones D . A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature. 2009; 463(7278):184-90. PMC: 2880489. DOI: 10.1038/nature08629. View

Phelps R, Johnson B, Ihde D, Gazdar A, Carbone D, McClintock P . NCI-Navy Medical Oncology Branch cell line data base. J Cell Biochem Suppl. 1996; 24:32-91. DOI: 10.1002/jcb.240630505. View

Ng P, Henikoff S . Accounting for human polymorphisms predicted to affect protein function. Genome Res. 2002; 12(3):436-46. PMC: 155281. DOI: 10.1101/gr.212802. View

Lujan E, Chanda S, Ahlenius H, Sudhof T, Wernig M . Direct conversion of mouse fibroblasts to self-renewing, tripotent neural precursor cells. Proc Natl Acad Sci U S A. 2012; 109(7):2527-32. PMC: 3289376. DOI: 10.1073/pnas.1121003109. View

10.

Molderings G, Kolck U, Scheurlen C, Bruss M, Homann J, von Kugelgen I . Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell activation disorder. Scand J Gastroenterol. 2007; 42(9):1045-53. DOI: 10.1080/00365520701245744. View

11.

Tatematsu A, Shimizu J, Murakami Y, Horio Y, Nakamura S, Hida T . Epidermal growth factor receptor mutations in small cell lung cancer. Clin Cancer Res. 2008; 14(19):6092-6. DOI: 10.1158/1078-0432.CCR-08-0332. View

12.

Yokomizo A, Tindall D, Drabkin H, Gemmill R, Franklin W, Yang P . PTEN/MMAC1 mutations identified in small cell, but not in non-small cell lung cancers. Oncogene. 1998; 17(4):475-9. DOI: 10.1038/sj.onc.1201956. View

13.

Barbieri C, Baca S, Lawrence M, Demichelis F, Blattner M, Theurillat J . Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet. 2012; 44(6):685-9. PMC: 3673022. DOI: 10.1038/ng.2279. View

14.

Onuki N, Wistuba I, Travis W, Virmani A, Yashima K, Brambilla E . Genetic changes in the spectrum of neuroendocrine lung tumors. Cancer. 1999; 85(3):600-7. DOI: 10.1002/(sici)1097-0142(19990201)85:3<600::aid-cncr10>3.0.co;2-w. View

15.

Siegel R, Ward E, Brawley O, Jemal A . Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011; 61(4):212-36. DOI: 10.3322/caac.20121. View

16.

Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S . RET, ROS1 and ALK fusions in lung cancer. Nat Med. 2012; 18(3):378-81. DOI: 10.1038/nm.2658. View

17.

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

18.

Medina P, Castillo S, Blanco S, Sanz-Garcia M, Largo C, Alvarez S . The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer. Hum Mol Genet. 2009; 18(7):1343-52. DOI: 10.1093/hmg/ddp034. View

19.

Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-76. DOI: 10.1016/j.cell.2006.07.024. View

20.

Wegner M . SOX after SOX: SOXession regulates neurogenesis. Genes Dev. 2011; 25(23):2423-8. PMC: 3243053. DOI: 10.1101/gad.181487.111. View