Germline mutations in the ataxia telangiectasia mutated (ATM) gene occur in 0.5-1% of the overall population and are associated with tumour predisposition. The clinical and pathologic features of ATM-mutated prostate cancer (PC) have not been well defined. Data suggest that they are associated with poor prognosis PC. Herein, we examine our cohort of sequenced mCRPC for germline ATM mutations in patients with advanced PC, and report on associated clinical features.
We studied PC biopsies using validated immunohistochemical and next-generation sequencing assays on patients sequenced between Jan/14 and Dec/21. Demographic and clinical data were collected retrospectively.
Seven patients (n=7/1217; 0.6%) were found to carry germline ATM mutations in this cohort. All were adenocarcinomas, without neuroendocrine features at biopsy, with all having high-risk Gleason scores in keeping with the screened population. Five patients had a strong family history of cancer, while 2 did not. Overall, of the 7 cases, 2 had concomitant somatic mutations in tumour biopsies in genes other than ATM with 1 patient having more than one ATM pathogenic mutation. Interestingly, 2 patients did not have ATM loss on IHC. Median overall survival (OS) from diagnosis was 7.1 years (range 2.9-14 years) and median OS from CRPC was 4.8 years (range 2.2-7.3 years). When comparing these data with PC patients sequenced by The Cancer Genome Atlas (TCGA), we found that the spatial localization of mutations was surprisingly similar, with distribution of alterations occurring on the same positions or very close to these in the ATM gene. Interestingly, these include a mutation within the FAT domain, suggesting that this represents a mutational hotspot for ATM.
PC harbouring germline ATM mutations are rare but may occur at mutational hotspots; further research is warranted to better characterise their impact on PC clinical course.
Institute of Cancer Research.
Prostate Cancer Targeted Therapy Group.
A. Sharp: Non-Financial Interests, Personal, Principal Investigator, Clinical trial in progress: AstraZeneca, Amgen, Nurix; Non-Financial Interests, Personal, Principal Investigator, Clinical trial in set up: Exelixis; Non-Financial Interests, Institutional, Product Samples, Access to IMP as a gift for research: AstraZeneca; Other, Personal, Other, Paid consultancy: D.E Research. J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi Sankyo, Genentech-Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Sanofi Aventis, Sierra Oncology, Taiho, Vertex Pharmaceuticals, Crescendo Biologics; Non-Financial Interests, Personal, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech Roche, Genmab, GlaxoSmithKline, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Non-Financial Interests, Institutional, Product Samples: Daiichi Sankyo, Bayer, Merck Serono, AstraZeneca, Harpoon, Pfizer, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GlaxoSmithKline. All other authors have declared no conflicts of interest.