Open AccessA region-based gene association study combined with a leave-one-out sensitivity analysis identifies SMG1 as a pancreatic cancer susceptibility gene
Author(s) -
Cavin Wong,
Fei Chen,
Najmeh Alirezaie,
Yifan Wang,
Adeline Cuggia,
Ayelet Borgida,
Spring Holter,
Tatiana Lenko,
Céline Domecq,
Alzheimer’s Disease Neuroimaging Initiative,
Gloria M. Petersen,
Sapna Syngal,
Randall E. Brand,
Anil K. Rustgi,
Michele L. Coté,
Elena M. Stoffel,
Sara H. Olson,
Nicholas J. Roberts,
Mohammad Reza Akbari,
Jacek Majewski,
Alison P. Klein,
Celia Greenwood,
Steven Gallinger,
George Zogopoulos
Publication year - 2019
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1008344
Subject(s) - biology , pancreatic cancer , gene , genetics , genetic predisposition , genetic testing , cancer , bioinformatics
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.