Inherited TP53 Variants and Risk of Prostate Cancer

Abstract Background Inherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53. Objective To determine whether gTP53 predisposes to prostate cancer. Design, setting, and participants This multi-institutional retrospective study characterizes prostate cancer incidence in a cohort of LFS males and gTP53 prevalence in a prostate cancer cohort. Outcome measurements and statistical analysis We evaluated the spectrum of gTP53 variants and clinical features associated with prostate cancer. Results and limitations We identified 31 prostate cancer cases among 163 adult LFS males, including 26 of 54 aged ≥50 yr. Among 117 LFS males without prostate cancer at the time of genetic testing, six were diagnosed with prostate cancer over a median (interquartile range [IQR]) of 3.0 (1.3–7.2) yr of follow-up, a 25-fold increased risk (95% confidence interval [CI] 9.2–55; p  Conclusions Complementary analyses of prostate cancer incidence in LFS males and gTP53 prevalence in prostate cancer cohorts suggest that gTP53 predisposes to aggressive prostate cancer. Prostate cancer should be considered as part of LFS screening protocols and TP53 considered in germline prostate cancer susceptibility testing. Patient summary Inherited pathogenic variants in the TP53 gene are likely to predispose men to aggressive prostate cancer.