Germline Mutations Detected by Somatic DNA Sequencing in Lethal Prostate Cancer.

Background: Germline mutations in the ataxia telangiectasia mutated () gene occur in 0.5-1% of the overall population and are associated with tumour predisposition. The clinical and pathological features of -mutated prostate cancer (PC) are poorly defined but have been associated with lethal PC.

Objective: To report on the clinical characteristics including family history and clinical outcomes of a cohort of patients with advanced metastatic castration-resistant PC (CRPC) who were found to have germline mutations after mutation detection by initial tumour DNA sequencing.

Design Setting And Participants: We acquired germline mutation data by saliva next-generation sequencing from patients with mutations in PC biopsies sequenced between January 2014 and January 2022. Demographics, family history, and clinical data were collected retrospectively.

Outcome Measurements And Statistical Analysis: Outcome endpoints were based on overall survival (OS) and time from diagnosis to CRPC. Data were analysed using R version 3.6.2 (R Foundation for Statistical Computing, Vienna, Austria).

Results And Limitations: Overall, seven patients ( = 7/1217; 0.6%) had germline mutations detected, with five of them having a family history of malignancies, including breast, prostate, pancreas, and gastric cancer; leukaemia; and lymphoma. Two patients had concomitant somatic mutations in tumour biopsies in genes other than , while two patients were found to carry more than one pathogenic mutation. Five tumours in germline variant carriers had loss of ATM by immunohistochemistry. The median OS from diagnosis was 7.1 yr (range 2.9-14 yr) and the median OS from CRPC was 5.3 yr (range 2.2-7.3 yr). When comparing these data with PC patients sequenced by The Cancer Genome Atlas, we found that the spatial localisation of mutations was similar, with distribution of alterations occurring on similar positions in the gene. Interestingly, these include a mutation within the FRAP-ATM-TRRAP (FAT) domain, suggesting that this represents a mutational hotspot for .

Conclusions: Germline mutations are rare in patients with lethal PC but occur at mutational hotspots; further research is warranted to better characterise the family histories of these men and PC clinical course.

Patient Summary: In this report, we studied the clinical and pathological features of advanced prostate cancers associated with germline mutations in the gene. We found that most patients had a strong family history of cancer and that this mutation might predict the course of these prostate cancers, as well as response to specific treatments.