Purpose: The ATM (ataxia telangiectasia mutated) gene is mutated in a subset of prostate cancers, and ATM mutation may confer specific therapeutic vulnerabilities, although ATM-deficient prostate cancers have not been well-characterized. Experimental Design: We genetically validated a clinical grade IHC assay to detect ATM protein loss and examined the frequency of ATM loss among tumors with pathogenic germline ATM mutations and genetically unselected primary prostate carcinomas using tissue microarrays (TMAs). Immunostaining results were correlated with targeted somatic genomic sequencing and clinical outcomes. Results: ATM protein loss was found in 13% (7/52) of primary Gleason pattern 5 cancers with available sequencing data and was 100% sensitive for biallelic ATM inactivation. In a separate cohort with pathogenic germline ATM mutations, 74% (14/19) had ATM protein loss of which 70% (7/10) of evaluable cases had genomic evidence of biallelic inactivation, compared with zero of four of cases with intact ATM expression. By TMA screening, ATM loss was identified in 3% (25/831) of evaluable primary tumors, more commonly in grade group 5 (17/181; 9%) compared with all other grades (8/650; 1%; P < 0.0001). Of those with available sequencing, 80% (4/5) with homogeneous ATM protein loss and 50% (6/12) with heterogeneous ATM protein loss had detectable pathogenic ATM alterations. In surgically treated patients, ATM loss was not significantly associated with clinical outcomes in random-effects Cox models after adjusting for clinicopathologic variables. Conclusions: ATM loss is enriched among high-grade prostate cancers. Optimal evaluation of ATM status requires both genomic and IHC studies and will guide development of molecularly targeted therapies.
Bibliographical noteFunding Information:
D.C. Salles reports non-financial support from Myriad Genetics during the conduct of the study. C.C. Pritchard reports personal fees from AstraZeneca outside the submitted work. A.M. De Marzo reports grants from NIH, NCI and The Department of Defense during the conduct of the study, Janssen Research and Development (sponsored research project unrelated to this manuscript) and Myriad Genetics (sponsored research project unrelated to this manuscript), and personal fees from Cepheid Inc (consulting fees, for project unrelated to this manuscript) outside the submitted work. J.S. Lanchbury reports personal fees from Myriad Genetics, Inc. (employee and stockholder) during the conduct of the study. K.M. Timms reports personal fees from Myriad Genetics, Inc. (employee and stockholder) during the conduct of the study and outside the submitted work. E.S. Antonarakis reports grants and personal fees from Janssen, and Sanofi, Dendreon, Merck, Bristol Myers Squibb, and AstraZeneca outside the submitted work, personal fees from Pfizer and Clovis, Eli Lilly, and Amgen outside the submitted work, grants from Johnson & Johnson, Genentech, Novartis, and Constellation outside the submitted work, and has a patent for AR-V7 liquid biopsy technology issued, licensed, and with royalties paid from Qiagen. T.L. Lotan reports non-financial support from Myriad Genetics (provided sequencing assays used) during the conduct of the study and grants from Roche/ Ventana outside the submitted work. No potential conflicts of interest were disclosed by the other authors.
This work was supported by the Patrick Walsh Prostate Cancer Research Fund (to E.S. Antonarakis), the Prostate Cancer Foundation (to E.S. Antonarakis), NIH/NCI Prostate SPORE P50CA58236 (to A.M. De Marzo), and the NCI Cancer Center Support Grant 5P30CA006973-52 (to T.L. Lotan and E.S. Antonarakis) as well as the NIH/NCI U01 CA196390 (to A.M. De Marzo) and the U.S. Department of Defense Prostate Cancer Research Program Prostate Cancer Biospecimen Network Site (W81XWH-18-2-0015 to A.M. De Marzo).
© 2020 American Association for Cancer Research.