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<65 years and 0.91 (95% CI 0.62-1.33) at age≥65 years for BRCA1 carriers.

Using genotypic and family history data on 16,633 PCa patients, I developed a risk prediction model that incorporates the explicit effects of rare PVs in HOXB13, BRCA1 and BRCA2, and a polygenic risk score that summarises the effects of 174 common low-risk variants identified through genome-wide association studies. The residual familial risk is modelled by a hypothetical recessively inherited high-risk variant associated with a RR for homozygotes of 104 (95% CI 21.4-502) and a risk allele frequency of 4.44% (95% CI 2.14%-8.97%), and an age-dependent normally distributed polygenic component with a SD of 2.11 (95% CI 1.98-2.24) at age 70 that decreases at a rate of 0.985 (95% CI 0.981-0.990) per year of age. The predicted familial relative risks are consistent with those reported in large observational studies.

Limitations include potential biases related to screening of relatives of affected men and known PV carriers, and use of self-reported family history information. The model has not been externally validated.

This is the first risk prediction model that can be used to provide future PCa risk based on age, family history and all known genetic factors. The risk estimates for HOXB13, BRCA1 and BRCA2 carriers and those given by the comprehensive model will facilitate the genetic counselling of men seen in family clinics and may enable future risk-stratified screening approaches.