biostudies-literatureWong CCancer Research SocietyNCI NIH HHSe1008344https://www.ebi.ac.uk/biostudies/studies/S-EPMC6742418biostudies-literatureUnknown15(8)Pancreatic adenocarcinoma (PC) is a lethal malignancy that is familial or associated with genetic syndromes in 10% of cases. Gene-based surveillance strategies for at-risk individuals may improve clinical outcomes. However, familial PC (FPC) is plagued by genetic heterogeneity and the genetic basis for the majority of FPC remains elusive, hampering the development of gene-based surveillance programs. The study was powered to identify genes with a cumulative pathogenic variant prevalence of at least 3%, which includes the most prevalent PC susceptibility gene, BRCA2. Since the majority of known PC susceptibility genes are involved in DNA repair, we focused on genes implicated in these pathways. We performed a region-based association study using the Mixed-Effects Score Test, followed by leaPLoS geneticsA region-based gene association study combined with a leave-one-out sensitivity analysis identifies SMG1 as a pancreatic cancer susceptibility gene.PMC674241822504P50 CA102701R01 CA097075P30 CA008748P20 CA102701P50 CA062924Borgida AZogopoulos GChen FOlson SHHolter SKlein APRustgi AKCuggia AAlzheimer’s Disease Neuroimaging InitiativeWong CRoberts NJGreenwood CMTAlirezaie NDomecq CGallinger SBrand RAkbari MRPetersen GMWang YSyngal SStoffel EMajewski JLenko TCote MLfalseA region-based gene association study combined with a leave-one-out sensitivity analysis identifies SMG1 as a pancreatic cancer susceptibility gene.Pancreatic adenocarcinoma (PC) is a lethal malignancy that is familial or associated with genetic syndromes in 10% of cases. Gene-based surveillance strategies for at-risk individuals may improve clinical outcomes. However, familial PC (FPC) is plagued by genetic heterogeneity and the genetic basis for the majority of FPC remains elusive, hampering the development of gene-based surveillance programs. The study was powered to identify genes with a cumulative pathogenic variant prevalence of at least 3%, which includes the most prevalent PC susceptibility gene, BRCA2. Since the majority of known PC susceptibility genes are involved in DNA repair, we focused on genes implicated in these pathways. We performed a region-based association study using the Mixed-Effects Score Test, followed by lea2019-01-01T00:00:00Z2019 Aug2025-04-04T22:11:13.955Z2019-10-03T07:04:36ZS-EPMC67424183146982610.1371/journal.pgen.1008344