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

ABSTRACT: Identification of somatic driver mutations in the noncoding genome remains challenging. To comprehensively characterize noncoding driver mutations for pancreatic ductal adenocarcinoma (PDAC), 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). Functional assessment using massively parallel reporter assays (MPRA) identified 178 NCSMs impacting reporter activity (19.45% of those tested). Focused luciferase validation confirmed negative effects on gene regulatory activity for NCSMs near CDKN2A and ZFP3

SUBMITTER: Zhong J 

PROVIDER: S-EPMC11451821 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature