Whole-exome Sequencing Reveals New Potential Susceptibility Genes for Japanese Familial Pancreatic Cancer.
Journal
Annals of surgery
ISSN: 1528-1140
Titre abrégé: Ann Surg
Pays: United States
ID NLM: 0372354
Informations de publication
Date de publication:
01 04 2022
01 04 2022
Historique:
pubmed:
23
8
2020
medline:
27
4
2022
entrez:
23
8
2020
Statut:
ppublish
Résumé
The primary objective of this study was to identify novel genes that predispose people in the Japanese population to FPC. Familial history of pancreatic cancer is an important risk factor but, to date, few genes predisposing individuals to increased risk of developing FPC have been identified. We performed whole-exome sequencing of germline DNA from 81 Japanese FPC patients. We also investigated somatic gene alterations in 21 matched tumor tissues through whole-exome sequencing and copy number analysis. Our germline variants identified previously known FPC susceptibility genes such as ATM and BRCA2, and several novel tumor suppressor genes with potentially deleterious variants for FPC. Interestingly, somatic whole-exome analysis demonstrated that most tumor samples with suspicious loss of heterozygosity of candidate genes were KRAS wild-types, implying that these cases may not have required KRAS activation as a driver event for carcinogenesis. Our findings indicate that FPC patients harbor potentially deleterious causative germline variants in tumor suppressor genes, which are known to acquire somatic mutations in pancreatic cancer, and that somatic loss of heterozygosity of some FPC susceptibility genes may contribute to the development of FPC in the absence of somatic KRAS-activating mutation. Genetic testing for a wider variety of FPC-predisposition genes could provide better screening approach for high-risk groups of pancreatic cancer.
Sections du résumé
OBJECTIVE
The primary objective of this study was to identify novel genes that predispose people in the Japanese population to FPC.
SUMMARY OF BACKGROUND DATA
Familial history of pancreatic cancer is an important risk factor but, to date, few genes predisposing individuals to increased risk of developing FPC have been identified.
METHODS
We performed whole-exome sequencing of germline DNA from 81 Japanese FPC patients. We also investigated somatic gene alterations in 21 matched tumor tissues through whole-exome sequencing and copy number analysis.
RESULTS
Our germline variants identified previously known FPC susceptibility genes such as ATM and BRCA2, and several novel tumor suppressor genes with potentially deleterious variants for FPC. Interestingly, somatic whole-exome analysis demonstrated that most tumor samples with suspicious loss of heterozygosity of candidate genes were KRAS wild-types, implying that these cases may not have required KRAS activation as a driver event for carcinogenesis.
CONCLUSIONS
Our findings indicate that FPC patients harbor potentially deleterious causative germline variants in tumor suppressor genes, which are known to acquire somatic mutations in pancreatic cancer, and that somatic loss of heterozygosity of some FPC susceptibility genes may contribute to the development of FPC in the absence of somatic KRAS-activating mutation. Genetic testing for a wider variety of FPC-predisposition genes could provide better screening approach for high-risk groups of pancreatic cancer.
Identifiants
pubmed: 32826389
pii: 00000658-202204000-00035
doi: 10.1097/SLA.0000000000004213
doi:
Substances chimiques
Proto-Oncogene Proteins p21(ras)
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e652-e658Informations de copyright
Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.
Déclaration de conflit d'intérêts
The authors report no conflicts of interest.
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