{"doi":"10.1101/2024.09.22.24314165","title":"Large-scale multi-omic analysis identifies noncoding somatic driver mutations and nominates <i>ZFP36L2</i> as a driver gene for pancreatic ductal adenocarcinoma","abstract":"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.","journal":"medRxiv","year":2024,"id":491944,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.887,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":692025,"name":"Aidan O’Brien","orcid":"0000-0003-2188-4223","position":1,"is_corresponding":false},{"id":108790,"name":"Minal Patel","orcid":null,"position":2,"is_corresponding":false},{"id":692936,"name":"Daina Eiser","orcid":null,"position":3,"is_corresponding":false},{"id":987891,"name":"Michael Mobaraki","orcid":null,"position":4,"is_corresponding":false},{"id":692027,"name":"Irene Collins","orcid":"0000-0001-5434-4659","position":5,"is_corresponding":false},{"id":1337830,"name":"Wang Li","orcid":"0000-0002-7618-7524","position":6,"is_corresponding":false},{"id":1242873,"name":"Konnie Guo","orcid":null,"position":7,"is_corresponding":false},{"id":1331627,"name":"Thucnhi Truongvo","orcid":null,"position":8,"is_corresponding":false},{"id":516127,"name":"Ashley Jermusyk","orcid":"0000-0003-1553-039X","position":9,"is_corresponding":false},{"id":327323,"name":"Maura O’Neill","orcid":null,"position":10,"is_corresponding":false},{"id":775214,"name":"Courtney D. Dill","orcid":"0000-0002-7293-8968","position":11,"is_corresponding":false},{"id":1337831,"name":"Andrew Wells","orcid":"0000-0003-2345-9677","position":12,"is_corresponding":false},{"id":45183,"name":"Michelle E. Leonard","orcid":null,"position":13,"is_corresponding":false},{"id":45170,"name":"James A. Pippin","orcid":"0000-0002-6850-8164","position":14,"is_corresponding":false},{"id":40827,"name":"Struan F.A. Grant","orcid":"0000-0003-2025-5302","position":15,"is_corresponding":false},{"id":240367,"name":"Tongwu Zhang","orcid":"0000-0003-2124-2706","position":16,"is_corresponding":false},{"id":276014,"name":"Þorkell Andrésson","orcid":"0000-0002-9545-2450","position":17,"is_corresponding":false},{"id":692023,"name":"Katelyn E. Connelly","orcid":"0000-0002-1693-5519","position":18,"is_corresponding":false},{"id":5285,"name":"Jianxin Shi","orcid":"0000-0001-8606-4707","position":19,"is_corresponding":false},{"id":264848,"name":"H. Efsun Arda","orcid":"0000-0002-5294-2521","position":20,"is_corresponding":false},{"id":692026,"name":"Jason W. Hoskins","orcid":"0000-0001-6944-1996","position":21,"is_corresponding":false},{"id":264809,"name":"Laufey T. Ámundadóttir","orcid":"0000-0003-1859-8971","position":22,"is_corresponding":false},{"id":319490,"name":"Jun Zhong","orcid":null,"position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-19T02:08:49.768795Z","pmid":"39371173","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}