Germline Mutations in DNA Repair Genes in Patients with Pancreatic Neuroendocrine Neoplasms: Diagnostic and Therapeutic Implications

TL;DR

This study found that 25% of Polish patients with pancreatic neuroendocrine tumors had germline DNA repair gene mutations, suggesting these mutations may play a role in tumor development even without family history.

Contribution

The study is the first to report germline DNA repair gene mutations in Polish patients with pancreatic neuroendocrine neoplasms, including those without family cancer history.

Findings

Germline DNA repair gene mutations were found in 24.6% of patients with pancreatic neuroendocrine neoplasms.

Pathogenic variants in BRCA2 and CHEK2 were identified in two patients, and seven had variants of uncertain significance.

The mutations are linked to multiple cancer types, indicating potential broader genetic risk for these patients.

Abstract

Pancreatic neuroendocrine neoplasms (pNENs) are the second most common type of pancreatic cancer after ductal adenocarcinoma. While germline mutations in DNA repair genes are known to contribute to various hereditary and sporadic cancers, their role in pNENs remains unclear. This pilot study aimed to evaluate the frequency and clinical relevance of such mutations in Polish patients with pNENs, regardless of family cancer history. Germline DNA from 57 individuals was analyzed using targeted next-generation sequencing covering a panel of DNA repair genes. Mutations were found in 14 patients (24.6%). Pathogenic variants in BRCA2 and CHEK2 were identified in two cases, while seven patients carried variants of uncertain significance (VUS). The detected alterations are associated with multiple malignancies, including breast, ovarian, prostate, gastric, colorectal, and pancreatic cancers. These findings suggest that germline DNA repair gene mutations may contribute to pNEN pathogenesis, even without familial predisposition. Broader germline testing and population-specific studies are warranted.

Pancreatic neuroendocrine neoplasms (pNENs) are the second most common type of pancreatic cancer after pancreatic ductal adenocarcinoma. Germline mutations in DNA repair genes drive several hereditary and sporadic cancers; however, their role in pNENs remains poorly defined. This pilot study aimed to assess the frequency and clinical relevance of germline DNA repair gene mutations in patients with pNENs, both with and without a family history of cancer. Germline DNA from 57 Polish patients with pNENs was analyzed using targeted next-generation sequencing to identify variants in a panel of DNA repair genes. Variant classification followed the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines. Germline mutations were identified in 14 patients (24.6%), both with and without a family history of malignancy. Two patients carried pathogenic variants in BRCA2 and CHEK2, while seven carried variants of uncertain significance (VUS). The identified variants have been implicated in various cancer types, including breast, ovarian, prostate, gastric, colorectal, and pancreatic cancers. These findings indicate that germline mutations in DNA repair genes may contribute to the pathogenesis of pNENs, even in patients without a family history. Broader germline testing and population-specific studies are needed to clarify the genetic landscape and clinical implications of these alterations.

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