MassIVE MSV000098624

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Large-scale multi-omic analysis identifies noncoding somatic driver mutations and nominates ZFP36L2 as a driver gene for pancreatic ductal adenocarcinoma

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Description

Background The identification and characterization of somatic cancer driver mutations in the noncoding genome remains challenging. Objective To broadly characterize noncoding driver mutations for pancreatic ductal adenocarcinoma (PDAC). Design Using mutation calls from whole-genome sequence (WGS) data in PDACs and genome-scale maps of accessible gene regulatory regions in normal- and tumor-derived pancreatic samples, we analyzed enrichment of noncoding mutations in gene regulatory regions relevant to normal- and tumor-derived pancreatic contexts. Functional follow up of potential driver mutations was performed using chromatin interaction analyses, massively parallel reporter assays (MPRA) and targeted analysis of selected noncoding somatic mutations. Results We first created genome-scale maps of accessible chromatin regions (ACRs) and histone modification marks (HMMs) in pancreatic cell lines and purified pancreatic acinar and duct cells. Integration with whole-genome mutation calls from 506 PDACs revealed 314 ACRs/HMMs significantly enriched with 3,614 noncoding somatic mutations (NCSMs). Chromatin interaction analysis identified 416 potential target genes and MPRA revealed 178 NCSMs impacting reporter activity (19.45% of those tested). Targeted luciferase validation confirmed negative effects on gene regulatory activity for NCSMs near ZFP36L2 and CDKN2A. For the former, CRISPR interference (CRISPRi) identified ZFP36L2 as a target gene (16.0 - 24.0% reduced expression, P = 0.023-0.0047), and growth inhibition after overexpression of ZFP36L2 (4.1 - 14.1-fold reduction, P = 6.0x10-4 - 3.2x10-3) implicates a possible tumor suppressor function. Conclusion Our integrative approach provides a catalog of potential noncoding driver mutations and nominates ZFP36L2 as a novel PDAC driver gene with a likely tumor suppressor function. [doi:10.25345/C5HH6CJ9P] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Mutations, Pancreatic Cancer, Gene Regulation, Chromatin, Epigenetics. ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Laufey Amundadottir, NCI/NIH, United States of America
Submitting User: laufey_a
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