title: Systematic interrogation of 3q26 identifies TLOC1 and SKIL as cancer drivers.
abstract: 3q26 is frequently amplified in several cancer types with a common amplified region containing 20 genes. To identify cancer driver genes in this region, we interrogated the function of each of these genes by loss- and gain-of-function genetic screens. Specifically, we found that TLOC1 (SEC62) was selectively required for the proliferation of cell lines with 3q26 amplification. Increased TLOC1 expression induced anchorage-independent growth, and a second 3q26 gene, SKIL (SNON), facilitated cell invasion in immortalized human mammary epithelial cells. Expression of both TLOC1 and SKIL induced subcutaneous tumor growth. Proteomic studies showed that TLOC1 binds to DDX3X, which is essential for TLOC1-induced transformation and affected protein translation. SKIL induced invasion through upregulation of SLUG (SNAI2) expression. Together, these studies identify TLOC1 and SKIL as driver genes at 3q26 and more broadly suggest that cooperating genes may be coamplified in other regions with somatic copy number gain.
  
  
  CONCLUSIONS
  These studies identify TLOC1 and SKIL as driver genes in 3q26. These observations provide evidence that regions of somatic copy number gain may harbor cooperating genes of different but complementary functions.
authors.affiliation: 1Departments of Medical Oncology and 2Cancer Biology; 3Center for Cancer Genome Discovery, Dana-Farber Cancer Institute;4Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston; 5Broad Institute of Harvard and MIT, Cambridge, Massachusetts; and 6Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hagerstrand
authors.forename: Alexander
authors.initials: A
authors.lastname: Tong
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schumacher
authors.forename: Nina
authors.initials: N
authors.lastname: Ilic
authors.forename: Rhine R
authors.initials: RR
authors.lastname: Shen
authors.forename: Hiu Wing
authors.initials: HW
authors.lastname: Cheung
authors.forename: Francisca
authors.initials: F
authors.lastname: Vazquez
authors.forename: Yashaswi
authors.initials: Y
authors.lastname: Shrestha
authors.forename: So Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Giacomelli
authors.forename: Joseph
authors.initials: J
authors.lastname: Rosenbluh
authors.forename: Anna C
authors.initials: AC
authors.lastname: Schinzel
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Spardy
authors.forename: David A
authors.initials: DA
authors.lastname: Barbie
authors.forename: Craig H
authors.initials: CH
authors.lastname: Mermel
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Weir
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.forename: Pablo
authors.initials: P
authors.lastname: Tamayo
authors.forename: Jill P
authors.initials: JP
authors.lastname: Mesirov
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D056915:DNA Copy Number Variations / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D005784:Gene Amplification / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics; D042361:Mammary Glands, Human / Q000166:cytology; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D026901:Membrane Transport Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; C103676:SEC62 protein, human; C060615:SKIL protein, human; C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases