A 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 leave-one-out characterization of PC-associated gene regions and variants to identify the genes and variants driving risk associations. We evaluated 398 cases from two case series and 987 controls without a personal history of cancer. The first case series consisted of 109 patients with either FPC (n = 101) or PC at ≤50 years of age (n = 8). The second case series was composed of 289 unselected PC cases. We validated this discovery strategy by identifying known pathogenic BRCA2 variants, and also identified SMG1, encoding a serine/threonine protein kinase, to be significantly associated with PC following correction for multiple testing (p = 3.22x10-7). The SMG1 association was validated in a second independent series of 532 FPC cases and 753 controls (p G SMG1 variant in 3 affected relatives in a FPC kindred, and we found c.103G>A to be a recurrent SMG1 variant associating with PC in both the discovery and validation series. These results suggest that SMG1 is a novel PC susceptibility gene, and we identified specific SMG1 gene variants associated with PC risk.Author summary: Pancreatic cancer (PC) remains one of the most lethal malignancies, with a 5-year survival rate of only 9%. Approximately 10% of PC occurs in families or in patients with hereditary mutations that are known to cause PC. The genetic causes of familial PC remain largely unknown. Using a new statistical method, we tested 398 patients with PC and 987 individuals without cancer (discovery series) to identify hereditary genetic variabilities that associate with PC. As a proof of principle for our methodology, we identified mutations in the BRCA2 gene, which is known to cause PC. We also identified SMG1 as a novel gene that associates with PC risk. To support this finding, we confirmed our observations in a separate group of 532 patients with PC and 753 individuals without cancer (validation series). In addition, we provide additional genetic evidence to support our findings by showing that a SMG1 genetic change is present in three relatives with PC in a family. We also identified a recurrent SMG1 variant that associated with PC in both the discovery and validation series. Our observations suggest that SMG1 is a novel PC susceptibility gene.