Abstract
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<0.0062, OR = 1.88, 95%CI 1.17–3.03). We showed segregation of the c.4249A>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.
Highlights
Pancreatic adenocarcinoma (PC) remains one of the most lethal malignancies, with a 5-year survival rate of only 9%[1,2]
10% of PC occurs in families or in patients with hereditary mutations that are known to cause PC
We identified SMG1 as a novel gene that associates with PC risk
Summary
Pancreatic adenocarcinoma (PC) remains one of the most lethal malignancies, with a 5-year survival rate of only 9%[1,2]. Since 10% of PC cases are familial (FPC) or can be accounted for by genes implicated in hereditary cancer syndromes[3,4], gene-based surveillance strategies may enable early cancer detection in at-risk individuals. Known predisposition genes account for only a minority of FPC[4] and the hereditary basis underlying the remaining fraction of FPC remains unknown[5]. Several studies have attempted to identify the hereditary basis for the fraction of FPC unexplained by known predisposition genes[5,6,7]. We previously reported a candidate gene list using a filter-based approach focusing on protein truncating variants (PTVs) to prioritize candidate DNA repair genes[6]. Roberts et al used a similar filter-based approach to prioritize
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