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

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 and . For the latter, CRISPR interference (CRISPRi) further identified as a target gene (16.0 - 24.0% reduced expression, = 0.023-0.0047) with disrupted KLF9 binding likely mediating the effect. Our integrative approach provides a catalog of potentially functional noncoding driver mutations and nominates as a PDAC driver gene.