ATM role in prostate cancer (PrCa) progression and survival

Abstract

Background: Germline and/or somatic aberrations in ATM gene have been recently identified in up to 5% of PrCa cases. It has been also described that mutations in DNA repair genes predispose individuals to more aggressive and lethal phenotypes. For these reasons, our goal is to investigate the role of ATM in PrCa progression. Methods: To study the cooperation of Atmin prostate cancer progression in vivo, we crossed the transgenic mousemodel TRAMP with Atmnull mice inC57BL/6 background. This model allows us to elucidate the progression of prostate cancer in wild-type (+/+), heterozygous (+/-), and homozygous (-/-) Atmloss in mice. PIN, invasive and metastatic prostate cancer as well as survival curves were compared for the three arms. In addition, in a large cohort ofmCRPC (n=419) fromthe prospective PROREPAIR-B study (NCT03075735), in which a large panel of germlineDNA repair genes were studied, we compared the clinico-pathological characteristics at baseline andm CRPC diagnosis between germline ATMmutation carriers and non-ATMcarriers. Chi-Square and Exact Fisher test, the Kaplan-Meier method and Long-rank test were used for statistical analyses. Results: Twenty eight TRAMP(T/+); Atm(+/+) and 45 TRAMP(T/+); Atm(+/-) mice were follow-up until sacrifice-endpoint. Heterozygous Atm loss mice presented higher frequency of metastasis in the necropsy compared to Atm wild-type (44% vs. 21%, p=0,045) and shorter median survival (26 vs. 32 weeks, p=0,008). There were not significant different observed in PIN or invasive tumour prevalence. TRAMP(T/+); Atm(-/- ) mice were excluded from analyses due to the early development of lethal thymomas requiring sacrifice before week 16. On the other hand, 8 patients out of 419 were found to harbour germline pathogenic ATM mutations (1.9%), and compared with non- ATM carriers presented higher frequency stage IV at diagnosis (63% vs. 34%, p=0.2), bone metastasis (100% vs. 82%, p=0.4) without other relevant differences found in these preliminary analyses. Conclusions: Aberration in the ATM gene may favour metastatic progression in PrCa in prostate cancer preclinical models, although its clinical implication will require further clarification in the future.