Targeted Germline Sequencing Identifies Ultra-Rare DDR Variants in High-Risk Prostate Cancer
Background: Prostate cancer (PCa) is a biologically heterogeneous disease, with a subset of cases driven by hereditary germline alterations. Methods: Targeted germline sequencing using the Twist Fixed Panel was performed in nine high-risk PCa patients (median age 47; range 30–61). Variants were classified based on ClinVar, gnomAD, and in silico prediction tools. Results: Pathogenic and likely pathogenic variants in DNA damage repair (DDR) genes were identified, including BRCA2, BRIP1, PALB2, and BRCA1. A homozygous ATM variant was observed in one patient. Several ultra-rare variants in MLH3 and BARD1 were also detected. Most variants had allele frequencies <10-6. Conclusions: High-risk and early-onset PCa is associated with rare germline DDR alterations. These findings support expanded germline testing in younger patients and suggest potential relevance for precision oncology approaches, although functional validation is required..