ATM missense variant P1054R predisposes to prostate cancer

Abstract

Background: Prostate cancer is associated with defective DNA strand break repair after DNA damage leading to genetic instability and prostate cancer progression. The ATM (ataxia-telangiectasia mutated) gene product is known to play an important role in cell cycle regulation and maintenance of genomic integrity. We investigated whether the prevalence of the ATM missense substitution P1054R is increased in a hospital-based series of prostate cancer patients and whether carriers are at increased risk for treatment-related side effects.

Materials and methods: A consecutive series of 261 patients treated for early-stage prostate cancer with I-125 brachytherapy (permanent seed implantation) between 10/2000 and 04/2006 at our institution and a comparison group of 460 male control individuals were screened for the presence of the P1054R variant. Outcome of therapy regarding morbidity was assessed prospectively and compared between carriers vs. non-carriers with the International Prostate Symptom Score (IPSS), a Quality-of-Life-index (QoL) and the International Index of Erectile Function (IIEF-15) with its subgroups (IIEF-5 and EF).

Results: The proportion of carriers of the P1054R variant was significantly higher among prostate cancer patients than in the general population (25 out of 261 vs. 22 out of 460; OR 2.1; 95% CI 1.2-3.8, p<0.01). A subgroup of the carriers additionally harboured the ATM missense variant F858L that was associated with a similar risk (OR=2.2; 95% CI 1.1-4.6; p=0.03). After a mean follow-up of 18 months there were no statistically significant differences regarding IPSS (p=0.48), QoL (p=0.61), IIEF-15 score (p=0.78), IIEF-5 score (p=0.83), and EF score (p=0.80), respectively.

Conclusions: The ATM missense variant P1054R confers an about twofold increased risk for prostate cancer in our series. The subgroup of patients with the second-site variant F858L is not at significantly higher risk. After 18 months, there was no evidence for an increased adverse radiotherapy response in P1054R carriers.