Polygenic Risk Scores Distribution Research Articles

Genetic risk of prostate cancer in Ugandan men.

Men of African-ancestry have elevated prostate cancer (PCa) incidence and mortality compared to men of other racial groups. There is support for a genetic contribution to this disparity, with evidence of genetic heterogeneity in the underlying risk alleles between populations. Studies of PCa among African men may inform the contribution of genetic risk factors to the elevated disease burden in this population. We conducted an association study of >100 previously reported PCa risk alleles among 571 incidence cases and 485 controls among Uganda men. Unconditional logistic regression was used to test genetic associations and a polygenic risk score (PRS) was derived to assess the cumulative effect of the known risk alleles in association with PCa risk. In an exploratory analysis, we also tested associations of 17 125 421 genotyped and imputed markers genome-wide in association with PCa risk. Of the 111 known risk loci with a frequency >1%, 75 (68%) had effects that were directionally consistent with the initial discovery population,14 (13%) of which were nominally significantly associated with PCa risk at P < 0.05. Compared to men with average risk (25th -75th percentile in PRS distribution), Ugandan men in the top 10% of the PRS, constructed of alleles outside of 8q24, had a 2.9-fold (95%CI: 1.75, 4.97) risk of developing PCa; risk for the top 10% increased to 4.86 (95%CI: 2.70, 8.76) with the inclusion of risk alleles at 8q24. In genome-wide association testing, the strongest associations were noted with known risk alleles located in the 8q24 region, including rs72725854 (OR = 3.37, P = 2.14 × 10-11 ) that is limited to populations of African ancestry (6% frequency). The ∼100 known PCa risk variants were shown to effectively stratify PCa risk in Ugandan men, with 10% of men having a >4-fold increase in risk. The 8q24 risk region was also found to be a major contributor to PCa risk in Ugandan men, with the African ancestry-specific risk variant rs72725854 estimated to account for 12% of PCa in this population.

Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores.

PurposeBRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated—for the first time to our knowledge—associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/2 mutations and implications for cancer risk prediction.Materials and MethodsWe genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights.ResultsIn male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10−6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10−9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively.ConclusionPRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers.

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]–positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2×10−53). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2×10−20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

Prediction of breast cancer risk based on common genetic variants in women of East Asian ancestry.

BackgroundApproximately 100 common breast cancer susceptibility alleles have been identified in genome-wide association studies (GWAS). The utility of these variants in breast cancer risk prediction models has not been evaluated adequately in women of Asian ancestry.MethodsWe evaluated 88 breast cancer risk variants that were identified previously by GWAS in 11,760 cases and 11,612 controls of Asian ancestry. SNPs confirmed to be associated with breast cancer risk in Asian women were used to construct a polygenic risk score (PRS). The relative and absolute risks of breast cancer by the PRS percentiles were estimated based on the PRS distribution, and were used to stratify women into different levels of breast cancer risk.ResultsWe confirmed significant associations with breast cancer risk for SNPs in 44 of the 78 previously reported loci at P < 0.05. Compared with women in the middle quintile of the PRS, women in the top 1% group had a 2.70-fold elevated risk of breast cancer (95% CI: 2.15–3.40). The risk prediction model with the PRS had an area under the receiver operating characteristic curve of 0.606. The lifetime risk of breast cancer for Shanghai Chinese women in the lowest and highest 1% of the PRS was 1.35% and 10.06%, respectively.ConclusionApproximately one-half of GWAS-identified breast cancer risk variants can be directly replicated in East Asian women. Collectively, common genetic variants are important predictors for breast cancer risk. Using common genetic variants for breast cancer could help identify women at high risk of breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0786-1) contains supplementary material, which is available to authorized users.

Implications of polygenic risk for personalised colorectal cancer screening

We modelled the utility of applying a personalised screening approach for colorectal cancer (CRC) when compared with standard age-based screening. In this personalised screening approach, eligibility is determined by absolute risk which is calculated from age and polygenic risk score (PRS), where the PRS is relative risk attributable to common genetic variation. In contrast, eligibility in age-based screening is determined only by age. We calculated absolute risks of CRC from UK population age structure, incidence and mortality rate data, and a PRS distribution which we derived for the 37 known CRC susceptibility variants. We compared the number of CRC cases potentially detectable by personalised and age-based screening. Using Genome-Wide Complex Trait Analysis to calculate the heritability attributable to common variation, we repeated the analysis assuming all common CRC risk variants were known. Based on the known CRC variants, individuals with a PRS in the top 1% have a 2.9-fold increased CRC risk over the population median. Compared with age-based screening (aged 60: 10-year absolute risk 1.96% in men, 1.19% in women, as per the UK NHS National Bowel Screening Programme), personalised screening of individuals aged 55-69 at the same risk would lead to 16% fewer men and 17% fewer women being eligible for screening with 10% and 8%, respectively, fewer screen-detected cases. If all susceptibility variants were known, individuals with a PRS in the top 1% would have an estimated 7.7-fold increased risk. Personalised screening would then result in 26% fewer men and women being eligible for screening with 7% and 5% fewer screen-detected cases. Personalised screening using PRS has the potential to optimise population screening for CRC and to define those likely to maximally benefit from chemoprevention. There are however significant technical and operational details to be addressed before any such programme is introduced.

Risk Analysis of Prostate Cancer in PRACTICAL, a Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci.

Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4-57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2-5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs.

Abstract 261: Implications of polygenic risk-stratified screening for prostate cancer on overdiagnosis

Abstract Purpose Personalized screening for prostate cancer with eligibility for screening based on an absolute risk that is dependent on age and polygenic risk-profile would improve the efficiency of the screening program. However, yet there is no evidence from empirical data that such personalized screening strategy would reduce harms of screening, by reducing overdiagnosis and subsequent overtreatment. This study aims at quantifying the probabilities of overdiagnosis by polygenic risk profile. Methods We calculated polygenic risk score based on 66 known prostate cancer susceptibility variants for 17,729 men aged 50-69 years (9,404 men identified with prostate cancer and 8,325 with no cancer) derived from three UK-based ongoing studies: Prostate Testing for Cancer and Treatment (ProtecT), Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH), and UK Genetic Prostate Cancer Study (UKGPCS). We estimated absolute risk of developing prostate cancer dependent on age and polygenic profile for each man. For each quartile of polygenic risk score distribution among the population, we calculated the observed prevalence of screen-detected prostate cancer within ProtecT and the mean absolute risk for clinically detected cancers within SEARCH and UKGPCS. We derived the probabilities of overdiagnosis by quartiles of polygenic risk considering that the observed prevalence is a combination of underlying incidence, the duration of the preclinical detectable period (sojourn time), test sensitivity, and overdiagnosis. Results The polygenic risk score among the population had log-normal distribution with variance of 0.40, with polygenic risk score of -0.63, -0.20, and 0.23 at 25th, 50th and 75th percentile respectively. Quartiles 1 to 4 had 17%, 21%, 25% and 37% of the cases respectively. From the lowest to highest quartile of risk, 42%, 29%, 25% and 19% of the prevalent screen-detected cancers were likely to be overdiagnosed cancers. The proportion of overdiagnosed cases decreased with increasing polygenic risk, with 50% drop in overdiagnosis between the lowest and the highest polygenic risk quartiles. Conclusion Targeting screening to men at higher polygenic risk would reduce the problem of overdiagnosis in prostate cancer. Citation Format: Nora Pashayan, Stephen W. Duffy, David E. Neal, Freddie Hamdy, Jenny Donovan, Richard M. Martin, Patricia Harrington, Sara Benlloch, Ali A. Al Olama, Mitul Shah, Zsofia Kote-Jarai, Douglas F. Easton, Rosalind Eeles, Paul D. Pharoah. Implications of polygenic risk-stratified screening for prostate cancer on overdiagnosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 261. doi:10.1158/1538-7445.AM2014-261