Germline mutations in penetrant cancer predisposition genes are rare in men with prostate cancer selecting active surveillance

Abstract

Background: Pathogenic germline mutations in several rare penetrant cancer predisposition genes are associated with an increased risk of aggressive prostate cancer (PC). Our objectives were to determine the prevalence of pathogenic germline mutations in men with low-risk PC on active surveillance, and assess whether pathogenic germline mutations associate with grade reclassification or adverse pathology, recurrence, or metastases, in men treated after initial surveillance.

Methods: Men prospectively enrolled in the Canary Prostate Active Surveillance Study (PASS) were retrospectively sampled for the study. Germline DNA was sequenced utilizing a hereditary cancer gene panel. Mutations were classified according to the American College of Clinical Genetics and Genomics' guidelines. The association of pathogenic germline mutations with grade reclassification and adverse characteristics was evaluated by weighted Cox proportional hazards modeling and conditional logistic regression, respectively.

Results: Overall, 29 of 437 (6.6%) study participants harbored a pathogenic germline mutation of which 19 occurred in a gene involved in DNA repair (4.3%). Eight participants (1.8%) had pathogenic germline mutations in three genes associated with aggressive PC: ATM, BRCA1, and BRCA2. The presence of pathogenic germline mutations in DNA repair genes did not associate with adverse characteristics (univariate analysis HR = 0.87, 95% CI: 0.36-2.06, p = 0.7). The carrier rates of pathogenic germline mutations in ATM, BRCA1, and BRCA2did not differ in men with or without grade reclassification (1.9% vs. 1.8%).

Conclusion: The frequency of pathogenic germline mutations in penetrant cancer predisposition genes is extremely low in men with PC undergoing active surveillance and pathogenic germline mutations had no apparent association with grade reclassification or adverse characteristics.

Keywords: active surveillance; adverse pathology; germline mutations; prostate cancer.

FIGURE 1

Cancer prostate cancer active surveillance study participant characteristics. cases (in bold font; N = 169) in the Canary PASS cohort that developed adverse characteristics after initial active surveillance. Controls (N = 268) with no adverse characteristics were matched to cases at the time of the earliest event. RP = radical prostatectomy; AP = adverse pathology; BRC = biochemical recurrence; Met = metastasis. *244 participants with insufficient germline DNA available were excluded prior to selection. **4 AP cases included pN1, 1 which subsequently recurred. The 3 pN1 that did not recur were included in secondary endpoint of recurrence and/or metastasis (N = 55)