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Updated: Jun 11, 2025

Discovery of Driver Genes in Colorectal HT29-derived Cancer Stem-Like Tumorspheres
Published on: July 22, 2020
Large-scale multi-omic analysis identifies noncoding somatic driver mutations and nominates ZFP36L2 as a driver gene
Jun Zhong1, Aidan O'Brien1,2, Minal Patel1
1Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA.
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 ZFP36L2. For the latter, CRISPR interference (CRISPRi) further identified ZFP36L2 as a target gene (16.0 - 24.0% reduced expression, P = 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 ZFP36L2 as a PDAC driver gene.
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