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Evaluation of Polygenic Risk Scores for Prediction of Prostate Cancer in Korean Men.

ABSTRACT: Aims:The purpose of this study is to evaluate an aggregate influence of prostate cancer (PCa) susceptibility variants on the development of PCa in Korean men by using the polygenic risk score (PRS) approach. Methods:An analysis of 1,001 cases of PCa and 2,641 controls was performed to: (i) identify potential PCa-related risk loci in Koreans and (ii) validate the cumulative association between these loci and PCa using the PRS. Subgroup analyses based on risk stratification were conducted to better characterize the potential correlation to key PCa-related clinical outcomes (e.g., Gleason score, prostate-specific antigen levels). The results were replicated using 514 cases of PCa and 548 controls from an independent cohort. Results:Genome-wide association analysis from our discovery cohort revealed 11 candidate single-nucleotide polymorphisms (SNPs) associated with PCa showing statistical significance of p < 5.0 × 10-5. Seven variants were located at 8q24.21 (rs1016343, rs16901979, and rs13252298 in PRNCR1; rs4242384, rs7837688, and rs1447295 in CASC8; and rs1512268 in NKX3). Two variants located within HNF1B (rs7501939 and rs4430796) had a significant negative association with PCa risk [odds ratio (OR) = 0.717 and 0.747, p = 6.42 × 10-7 and 3.67 × 10-6, respectively]. Of the six independent SNPs that remained after linkage disequilibrium (LD) pruning, the top four SNPs best predicted PCa risk with an area under the receiver operating characteristic curve (AUC) of 0.637 (95% CI: 0.582-0.692). Those with top 25% polygenic risk had a 4.2-fold increased risk of developing PCa compared with those with low risk. Conclusion:Eleven PCa risk variants in Korean men were identified; PRSs of a subset of these variants could help predict PCa susceptibility.

SUBMITTER: Oh JJ

PROVIDER: S-EPMC7643004 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Evaluation of Polygenic Risk Scores for Prediction of Prostate Cancer in Korean Men.

Oh Jong Jin JJ Kim Eunae E Woo Eunjin E Song Sang Hun SH Kim Jung Kwon JK Lee Hakmin H Lee Sangchul S Hong Sung Kyu SK Byun Seok-Soo SS

Frontiers in oncology 20201022

<h4>Aims</h4>The purpose of this study is to evaluate an aggregate influence of prostate cancer (PCa) susceptibility variants on the development of PCa in Korean men by using the polygenic risk score (PRS) approach.<h4>Methods</h4>An analysis of 1,001 cases of PCa and 2,641 controls was performed to: (i) identify potential PCa-related risk loci in Koreans and (ii) validate the cumulative association between these loci and PCa using the PRS. Subgroup analyses based on risk stratification were con ...[more]

PMID: 33194723

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Project description:BackgroundGenome-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.MethodsWe 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.ResultsThe 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.ConclusionsBC 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.

Dataset Information

Evaluation of Polygenic Risk Scores for Prediction of Prostate Cancer in Korean Men.

Publications

Evaluation of Polygenic Risk Scores for Prediction of Prostate Cancer in Korean Men.

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