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Cancer Discov DOI:10.1158/2159-8290.CD-12-0592

Systematic interrogation of 3q26 identifies TLOC1 and SKIL as cancer drivers.

Publication TypeJournal Article
Year of Publication2013
AuthorsHagerstrand, D, Tong, A, Schumacher, SE, Ilic, N, Shen, RR, Cheung, HWing, Vazquez, F, Shrestha, Y, Kim, SYoung, Giacomelli, AO, Rosenbluh, J, Schinzel, AC, Spardy, NA, Barbie, DA, Mermel, CH, Weir, BA, Garraway, LA, Tamayo, P, Mesirov, JP, Beroukhim, R, Hahn, WC
JournalCancer Discov
Volume3
Issue9
Pages1044-57
Date Published2013 Sep
ISSN2159-8290
KeywordsBreast Neoplasms, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Proliferation, Chromosomes, Human, Pair 3, DEAD-box RNA Helicases, DNA Copy Number Variations, Epithelial-Mesenchymal Transition, Female, Gene Amplification, Gene Expression Regulation, Neoplastic, Humans, Intracellular Signaling Peptides and Proteins, Lung Neoplasms, Mammary Glands, Human, Membrane Transport Proteins, Neoplasm Invasiveness, Neoplasms, Ovarian Neoplasms, Protein Binding, Proto-Oncogene Proteins, RNA Interference, RNA, Small Interfering, Snail Family Transcription Factors, Transcription Factors
Abstract

UNLABELLED: 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.

SIGNIFICANCE: 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.

URLhttp://cancerdiscovery.aacrjournals.org/cgi/pmidlookup?view=long&pmid=23764425
DOI10.1158/2159-8290.CD-12-0592
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/23764425?dopt=Abstract

Alternate JournalCancer Discov
PubMed ID23764425
PubMed Central IDPMC3770815
Grant ListR01 GM074024 / GM / NIGMS NIH HHS / United States
K08 CA138918 / CA / NCI NIH HHS / United States
R01 CA130988 / CA / NCI NIH HHS / United States
U01 CA176058 / CA / NCI NIH HHS / United States
R01 CA109467 / CA / NCI NIH HHS / United States
R01 CA154480 / CA / NCI NIH HHS / United States
U54 CA112962 / CA / NCI NIH HHS / United States
RC2 CA148268 / CA / NCI NIH HHS / United States
P01 CA050661 / CA / NCI NIH HHS / United States