Prevalence and Clinical Associations of Germline DDR Variants in Prostate Cancer: Real-World Evidence from a...

Germline alterations in DNA damage repair (DDR) genes represent a clinically important subset of prostate cancer (PCa), but real-world data from Middle Eastern and Turkish populations remain limited. We evaluated the prevalence and clinicopathologic associations of germline DDR variants in a single-center Turkish cohort.

We retrospectively analyzed 122 men with histologically confirmed PCa who underwent germline multigene panel testing. Variants were classified according to ACMG/ClinVar criteria. Patients were grouped as pathogenic/likely pathogenic (P/LP), variants of uncertain significance (VUS), or variant-negative. Patients were grouped as variant-positive (P/LP or VUS/uncategorized) or clinically actionable variant-negative (benign/likely benign or no variant detected). Group comparisons used t-tests, chi-square or Fisher's exact tests as appropriate.

The median age at diagnosis was 65.2 years (mean 64.6 ± 8.78). Overall, 37 patients (30.3%) carried at least one germline variant, including 12 (9.8%) with P/LP alterations and 24 (19.7%) with VUS; one patient (0.8%) harbored an uncategorized variant. The most frequently affected genes were CHEK2 (n = 8), BRCA1 (n = 6), BRCA2 (n = 6), ATM (n = 5), and APC (n = 4). Variant-positive status increased from 10.8% in ISUP 1-2 to 21.6% in ISUP 3 and 76.0% in ISUP 4-5, although this trend was not statistically significant (p = 0.391). Mean age at diagnosis and the prevalence of metastatic disease did not differ between variant-positive and clinically actionable variant-negative patients (64.2 vs. 65.7 years, p = 0.390; 66.7% vs. 64.6%, p = 0.842). Truncating DDR variants (RAD50, BRCA2, MSH3, NBN, CHEK2, ATM) occurred predominantly in ISUP 4-5 tumors.

Germline DDR alterations-most notably in BRCA2, CHEK2, and ATM-were present in a substantial subset of Turkish men with PCa and showed a non-significant trend toward clustering in higher-grade disease. The high prevalence of VUS reflects limited genomic annotation in under-represented populations and underscores the need for longitudinal reinterpretation. These data support the clinical value of incorporating germline DDR testing into risk assessment and familial counseling, while larger cohorts integrating somatic profiling are needed to refine genotype-phenotype associations.