Prevalence and impact of germline mutations in pancreatic ductal adenocarcinoma

Abstract

Background:

Germline pathogenic variants are increasingly recognized as critical determinants of pancreatic ductal adenocarcinoma (PDAC) susceptibility, prognosis, and response to targeted therapies such as PARP inhibitors. Recent guidelines recommend germline testing for all PDAC patients, regardless of family history, to identify hereditary cancer syndromes and guide treatment decisions. However, data from populations underrepresented in genomic studies, such as the Turkish population, remain limited.

Methods:

We retrospectively analyzed 151 unselected PDAC patients who underwent germline testing using a next-generation sequencing (NGS) panel between January 2023 and April 2025. The panel covered established cancer susceptibility genes. Clinical parameters—including age, sex, tumor location and stage, diabetes status, and cancer family history—were reviewed. Variants were classified as pathogenic/likely pathogenic (P/LP), variants of uncertain significance (VUS), or benign.

Results:

Among the 151 patients, 17 (11.3%) harbored P/LP variants, most frequently in ATM (n=3), BRCA1 (n=2), BRCA2 (n=2), and CDKN2A (n=2). An additional 33 patients (21.9%) carried VUS, again most commonly affecting ATM. No benign variants were reported. Notably, 70.6% of P/LP carriers had a first- or second-degree family history of cancer. Most tumors originated in the pancreatic head (72.8%), and 41.1% of patients had metastatic disease at diagnosis.

Conclusions:

Our findings confirm the relevance of multigene panel testing in PDAC and reveal a germline mutation spectrum consistent with global data. These results support universal germline screening and emphasize the need for continued VUS interpretation, particularly in genomically understudied populations.

Graphical Abstract

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