Germline Testing for Prostate Cancer Patients: Evidence-Based Evaluation of Genes Recommended by NCCN Guidelines.

Abstract

Background: Approximately 50% of prostate cancer (PCa) patients meet the National Comprehensive Cancer Network (NCCN) guidelines for germline testing at diagnosis. However, the selection of genes for testing, their supporting evidence, and clinical interpretation remain poorly understood.

Methods: An evidence-based evaluation of the recommended genes was conducted using data from the UK Biobank and Johns Hopkins School of Medicine, including 22,052 PCa patients and 191,055 unaffected controls. Association of germline pathogenic/likely pathogenic (P/LP) variants in each gene was tested using logistic regression, adjusting for age and genetic background.

Results: Among the 11 NCCN-recommended PCa-related genes, significant associations (p < 0.0045) were identified between germline P/LP variants of five genes (HOXB13, BRCA2, ATM, CHEK2, and MSH2) and PCa risk. Additionally, BRCA2 and ATM variants were significantly associated with PCa aggressiveness. Of the 19 NCCN-recommended genes related to PARPi sensitivity, consistent evidence supported an enhanced response to PARPi therapy in patients with BRCA2 alterations, with weaker evidence for BRCA1, and limited supporting evidence for the remaining genes. Germline P/LP variants in BRCA2 and BRCA1 were observed in 0.77% and 0.14% of unselected PCa patients, respectively. Notably, no published study specifically assessed the efficacy of germline alterations, which were considerably rarer than somatic mutations.

Conclusion: Supporting statistical evidence is available for only a subset of the NCCN-recommended genes for germline testing. This evidence-based analysis may aid urologists-particularly those without specialized genetics training-in understanding germline testing for PCa risk assessment, prognosis, and treatment decision-making in clinical practice.