A region-based gene association study combined with a leave-one-out sensitivity analysis identifies SMG1 as a pancreatic cancer susceptibility gene.
Adenocarcinoma
/ genetics
Adult
BRCA2 Protein
/ genetics
Carcinoma
/ genetics
Female
Genes, BRCA2
Genetic Association Studies
/ methods
Genetic Predisposition to Disease
/ genetics
Germ-Line Mutation
/ genetics
Humans
Male
Middle Aged
Pancreas
/ pathology
Pancreatic Neoplasms
/ genetics
Protein Serine-Threonine Kinases
/ genetics
Sequence Analysis, DNA
/ methods
Pancreatic Neoplasms
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
21
03
2019
accepted:
03
08
2019
revised:
12
09
2019
pubmed:
31
8
2019
medline:
7
1
2020
entrez:
31
8
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31469826
doi: 10.1371/journal.pgen.1008344
pii: PGENETICS-D-19-00472
pmc: PMC6742418
doi:
Substances chimiques
BRCA2 Protein
0
BRCA2 protein, human
0
Protein Serine-Threonine Kinases
EC 2.7.11.1
SMG1 protein, human
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008344Subventions
Organisme : NCI NIH HHS
ID : P50 CA062924
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA102701
Pays : United States
Organisme : NCI NIH HHS
ID : P20 CA102701
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA097075
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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