A Comprehensive Genetic Risk Model for the Prediction of Future Prostate Cancer

The only established prostate cancer (PCa) risk factors are age, ethnic ancestry and family history. Several PCa genetic susceptibility variants have been identified, including rare moderate-to-high risk pathogenic variants (PVs) and common low-risk variants which jointly explain 40% of the excess familial risk. No risk prediction model exists that reflects the current knowledge on PCa susceptibility. The main objective of this thesis was to develop a comprehensive prediction model of future PCa risk in unaffected European ancestry men, that includes the effects of known genetic risk variants and explicitly modelled residual family history. Sub-objectives included characterisation of the PCa risks associated with rare HOXB13, BRCA1 and BRCA2 PVs. Through systematic review and meta-analysis of 20 publications, I estimated a pooled PCa relative risk (RR) of 3.42 (95% confidence interval [CI] 2.81-4.17) for HOXB13 G84E carriers. Based on complex segregation analysis of family history data on 11,983 genotyped PCa patients, the most parsimonious model was a multiplicative model for the effect of each HOXB13 G84E copy that assumed separate RRs by birth cohort. The estimated per-allele RRs were 3.09 (95% CI 2.03-4.71) for carriers born ≤1929 and 5.96 (95% CI 4.01-8.88) for carriers born ≥1930. The PCa risks varied by family history. Using a prospective cohort of 823 male BRCA1/2 carriers, I estimated age-specific RRs of 3.99 (95% CI 1.88-8.49) at age<65 years and 4.64 (95% CI 2.91-7.41) at age≥65 years for BRCA2 carriers, and 3.57 (95% CI 1.68-7.58) at age<65 years and 1.86 (95% CI 0.96-3.59) at age≥65 years for BRCA1 carriers. The risks varied by age, family history, and PV location within BRCA2. BRCA2 PVs were associated with moderate-to-high-grade PCa. Combining these and previous estimates in a systematic review and meta-analysis of 25 publications yielded pooled RR estimates of 7.04 (95% CI 5.30-9.35) at age<65 years and 3.84 (95% CI 2.84-5.18) at age≥65 years for non-Ashkenazi Jewish European ancestry BRCA2 carriers and 1.95 (95% CI 1.23-3.09) at age