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Cancer Discov. 2013 Sep;3(9):1044-57. doi: 10.1158/2159-8290.CD-12-0592. Epub 2013 Jun 13.

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

Author information

1
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.

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.

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.

PMID:
23764425
PMCID:
PMC3770815
DOI:
10.1158/2159-8290.CD-12-0592
[Indexed for MEDLINE]
Free PMC Article

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