title: Comprehensive genomic analysis identifies SOX2 as a frequently amplified gene in small-cell lung cancer.
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.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, USA. rudin@jhmi.edu
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Steffen
authors.initials: S
authors.lastname: Durinck
authors.forename: Eric W
authors.initials: EW
authors.lastname: Stawiski
authors.forename: John T
authors.initials: JT
authors.lastname: Poirier
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: David S
authors.initials: DS
authors.lastname: Shames
authors.forename: Emily A
authors.initials: EA
authors.lastname: Bergbower
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Guan
authors.forename: James
authors.initials: J
authors.lastname: Shin
authors.forename: Joseph
authors.initials: J
authors.lastname: Guillory
authors.forename: Celina Sanchez
authors.initials: CS
authors.lastname: Rivers
authors.forename: Catherine K
authors.initials: CK
authors.lastname: Foo
authors.forename: Deepali
authors.initials: D
authors.lastname: Bhatt
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stinson
authors.forename: Florian
authors.initials: F
authors.lastname: Gnad
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haverty
authors.forename: Robert
authors.initials: R
authors.lastname: Gentleman
authors.forename: Subhra
authors.initials: S
authors.lastname: Chaudhuri
authors.forename: Vasantharajan
authors.initials: V
authors.lastname: Janakiraman
authors.forename: Bijay S
authors.initials: BS
authors.lastname: Jaiswal
authors.forename: Chaitali
authors.initials: C
authors.lastname: Parikh
authors.forename: Wenlin
authors.initials: W
authors.lastname: Yuan
authors.forename: Zemin
authors.initials: Z
authors.lastname: Zhang
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Wu
authors.forename: Howard M
authors.initials: HM
authors.lastname: Stern
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yauch
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Huffman
authors.forename: Diego D
authors.initials: DD
authors.lastname: Paskulin
authors.forename: Peter B
authors.initials: PB
authors.lastname: Illei
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.forename: Richard
authors.initials: R
authors.lastname: Bourgon
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Malcolm V
authors.initials: MV
authors.lastname: Brock
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
mesh_terms: D001483:Base Sequence; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D059472:Exome; D005784:Gene Amplification; D015870:Gene Expression; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics; D055748:SOXB1 Transcription Factors / Q000235:genetics* / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000378:metabolism
chemical_list: D015514:Oncogene Proteins, Fusion; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D011494:Protein Kinases