Polygenic risk score for genetic evaluation of prostate cancer risk in Asian populations: A narrative review.
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ABSTRACT:
SUBMITTER: Song SH
PROVIDER: S-EPMC8100017 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Polygenic risk scores (PRSs) of common genetic variants have shown promise in prostate cancer risk stratification, but their validity across populations has yet to be confirmed. We evaluated a multiethnic PRS model based on 269 germline genetic risk variants (261 were available for analysis) using an independent population of 13 628 US men. The PRS was strongly associated with prostate cancer but not with any other disease. Comparing men in the top PRS decile with those at average risk (40%-60%), the odds ratio of prostate cancer was 3.89 (95% confidence interval = 3.24 to 4.68) for men of European ancestry and 3.81 (95% confidence interval = 1.48 to 10.19) for men of African ancestry. By age 85 years, the cumulative incidence of prostate cancer for European American men was 7.1% in the bottom decile and 54.1% in the top decile. This suggests that the PRS can be used to identify a substantial proportion of men at high risk for prostate cancer.
| S-EPMC9086757 | biostudies-literature
Project description:BackgroundPolygenic risk scores comprising established susceptibility variants have shown to be informative classifiers for several complex diseases including prostate cancer. For prostate cancer it is unknown if inclusion of genetic markers that have so far not been associated with prostate cancer risk at a genome-wide significant level will improve disease prediction.MethodsWe built polygenic risk scores in a large training set comprising over 25,000 individuals. Initially 65 established prostate cancer susceptibility variants were selected. After LD pruning additional variants were prioritized based on their association with prostate cancer. Six-fold cross validation was performed to assess genetic risk scores and optimize the number of additional variants to be included. The final model was evaluated in an independent study population including 1,370 cases and 1,239 controls.ResultsThe polygenic risk score with 65 established susceptibility variants provided an area under the curve (AUC) of 0.67. Adding an additional 68 novel variants significantly increased the AUC to 0.68 (P = 0.0012) and the net reclassification index with 0.21 (P = 8.5E-08). All novel variants were located in genomic regions established as associated with prostate cancer risk.ConclusionsInclusion of additional genetic variants from established prostate cancer susceptibility regions improves disease prediction.
| S-EPMC7745998 | biostudies-literature
Project description:Hereditary factors have a strong influence on prostate cancer (PC) risk and poorer outcomes, thus stratification by genetic factors addresses a critical need for targeted PC screening and risk-adapted follow-up. In this Finnish population-based retrospective study 2283 clinically diagnosed and 455 screen-detected patients from the Finnish Randomised Study of Screening for Prostate Cancer (FinRSPC), 2400 healthy individuals have been involved. Individual genetic risk through establishment of a polygenic risk score based on 55 PC risk SNPs identified through the Finnish subset of the Collaborative Oncological Gene-Environment Study was assessed. Men with PC had significantly higher median polygenic risk score compared to the controls (6.59 vs. 3.83, P < 0.0001). The polygenic risk score above the control median was a significant predictor of PC (OR 2.13, 95% CI 1.90-2.39). The polygenic risk score predicted the risk of PC with an AUC of 0.618 (95% CI 0.60-0.63). Men in the highest polygenic risk score quartile were 2.8-fold (95% CI 2.4-3.30) more likely to develop PC compared with men in the lowest quartile. In the FinRSPC cohort, a significantly higher percentage of men had a PSA level of ≥ 4 ng/mL in polygenic risk score quartile four compared to quartile one (18.7% vs 8.3%, P < 0.00001). Adding the PRS to a PSA-only model contributed additional information in predicting PC in the FinRSPC model. Results strongly suggest that use of the polygenic risk score would facilitate the identification of men at increased risk for PC.
| S-EPMC7553910 | biostudies-literature
Project description:Although prostate cancer is known to have a strong genetic basis and is influenced by both common and rare variants, the ability to investigate the combined effect of such genetic risk factors has been limited to date. We conducted an investigation of 81 094 men from the UK Biobank, including 3568 prostate cancer cases, to examine the combined effect of rare pathogenic/likely pathogenic/deleterious (P/LP/D) germline variants and common prostate cancer risk variants, measured using a polygenic risk score (PRS), on prostate cancer risk. The absolute risk of prostate cancer for HOXB13, BRCA2, ATM, and CHEK2 P/LP/D carriers ranged from 9% to 56%, and the absolute risk in noncarriers ranged from 2% to 31%, by age 85 yr, for men in the lowest and highest PRS decile, respectively. The high-penetrant HOXB13 G84E prostate cancer risk variant was most common in cases in the lowest PRS quintile (4.4%) and least common in cases in the highest PRS quintile (0.5%; p = 0.005), whereas there was no statistically significant difference in frequencies by PRS in controls. While rare and common variants strongly and distinctly influence prostate cancer onset, consideration of rare and common variants in conjunction will lead to more precise estimates of a man's lifetime risk of prostate cancer. PATIENT SUMMARY: We found that the risk of prostate cancer conveyed by rare variants could vary depending on an individual's genetic profile of common risk variants. This implies that in order to comprehensively assess genetic risk of prostate cancer, it is important to consider both rare and common variants.
| S-EPMC8286329 | biostudies-literature
Project description:BackgroundGenome-wide association studies have identified over 100 single-nucleotide polymorphisms (SNPs) associated with prostate cancer (PrCa), and polygenic risk scores (PRS) based on their combined genotypes have been developed for risk stratification. We aimed to assess the contribution of PRS to PrCa risk in a large multisite study.MethodsThe sample included 1972 PrCa cases and 1919 unaffected controls. Next-generation sequencing was used to assess pathogenic variants in 14 PrCa-susceptibility genes and 72 validated PrCa-associated SNPs. We constructed a population-standardized PRS and tested its association with PrCa using logistic regression adjusted for age and family history of PrCa.ResultsThe mean age of PrCa cases at diagnosis and age of controls at testing/last clinic visit was 59.5 ± 7.2 and 57.2 ± 13.0 years, respectively. Among 1740 cases with pathology data, 57.4% had Gleason score ≤ 6, while 42.6% had Gleason score ≥ 8. In addition, 39.6% cases and 20.1% controls had a family history of PrCa. The PRS was significantly higher in cases than controls (mean ± SD: 1.42 ± 1.11 vs 1.02 ± 0.76; P < .0001). Compared with men in the 1st quartile of age-adjusted PRS, those in the 2nd, 3rd, and 4th quartile were 1.58 (95% confidence interval [CI]: 1.31-1.90), 2.36 (95% CI: 1.96-2.84), and 3.98 (95% CI: 3.29-4.82) times as likely to have PrCa (all P < .0001). Adjustment for family history yielded similar results. PRS predictive performance was consistent with prior literature (area under the receiver operating curve = 0.64; 95% CI: 0.62-0.66).ConclusionsThese data suggest that a 72-SNP PRS is predictive of PrCa, supporting its potential use in clinical risk assessment.
| S-EPMC7590110 | biostudies-literature
Project description:PurposeNon-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups.MethodsThe development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases).ResultsThe best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk.ConclusionPRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.
| S-EPMC7612481 | biostudies-literature
Project description:Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10-180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
| S-EPMC7902617 | biostudies-literature
Project description:It is difficult to identify people with nonalcoholic fatty liver disease (NAFLD) who are at high risk for developing hepatocellular carcinoma (HCC). A polygenic risk score (PRS) for hepatic fat (HFC-PRS) derived from non-Asians has been reported to be associated with HCC risk in European populations. However, population-level data of this risk in Asian populations are lacking. Utilizing resources from 24,333 participants of the Singapore Chinese Health Study (SCHS), we examined the relationship between the HFC-PRS and HCC risk. In addition, we constructed and evaluated a NAFLD-related PRS (NAFLD-PRS) with HCC risk in the SCHS. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of HCC incidence with both HFC-PRS and NAFLD-PRS. The HFC-PRS and NAFLD-PRS were highly correlated (Spearman r = 0.79, p < 0.001). The highest quartiles of both the HFC-PRS and the NAFLD-PRS were associated with significantly increased risk of HCC with HR of 2.39 (95% CI 1.51, 3.78) and 1.77 (95% CI 1.15, 2.73), respectively, compared with their respective lowest quartile. Conclusion: The PRS for hepatic fat content or NAFLD may be useful for assessing HCC risk in both Asian and European populations. The findings of this and prior studies support a potential causal role of genetically determined NAFLD in HCC development.
| S-EPMC9426386 | biostudies-literature
Project description:The development of new screening methods and diagnostic tests for traits, common diseases, and cancer is linked to the advent of precision genomic medicine, in which health care is individually adjusted based on a person's lifestyle, environmental influences, and genetic variants. Based on genome-wide association study (GWAS) analysis, rapid and continuing progress in the discovery of relevant single nucleotide polymorphisms (SNPs) for traits or complex diseases has increased interest in the potential application of genetic risk models for routine health practice. The polygenic risk score (PRS) estimates an individual's genetic risk of a trait or disease, calculated by employing a weighted sum of allele counts combined with non-genetic variables. However, 98.38% of PRS records held in public databases relate to the European population. Therefore, PRSs for multiethnic populations are urgently needed. We performed a systematic review to discuss the role of polygenic risk scores in advancing precision medicine for different cancer types in multiethnic non-European populations.
| S-EPMC9406904 | biostudies-literature
Project description:BackgroundPolygenic risk scores (PRS) derived from European individuals have reduced portability across global populations, limiting their clinical implementation at worldwide scale. Here, we investigate the performance of a wide range of PRS models across four ancestry groups (Africans, Europeans, East Asians, and South Asians) for 14 conditions of high-medical interest.MethodsTo select the best-performing model per trait, we first compared PRS performances for publicly available scores, and constructed new models using different methods (LDpred2, PRS-CSx and SNPnet). We used 285 K European individuals from the UK Biobank (UKBB) for training and 18 K, including diverse ancestries, for testing. We then evaluated PRS portability for the best models in Europeans and compared their accuracies with respect to the best PRS per ancestry. Finally, we validated the selected PRS models using an independent set of 8,417 individuals from Biobank of the Americas-Genomelink (BbofA-GL); and performed a PRS-Phewas.ResultsWe confirmed a decay in PRS performances relative to Europeans when the evaluation was conducted using the best-PRS model for Europeans (51.3% for South Asians, 46.6% for East Asians and 39.4% for Africans). We observed an improvement in the PRS performances when specifically selecting ancestry specific PRS models (phenotype variance increase: 1.62 for Africans, 1.40 for South Asians and 0.96 for East Asians). Additionally, when we selected the optimal model conditional on ancestry for CAD, HDL-C and LDL-C, hypertension, hypothyroidism and T2D, PRS performance for studied populations was more comparable to what was observed in Europeans. Finally, we were able to independently validate tested models for Europeans, and conducted a PRS-Phewas, identifying cross-trait interplay between cardiometabolic conditions, and between immune-mediated components.ConclusionOur work comprehensively evaluated PRS accuracy across a wide range of phenotypes, reducing the uncertainty with respect to which PRS model to choose and in which ancestry group. This evaluation has let us identify specific conditions where implementing risk-prioritization strategies could have practical utility across diverse ancestral groups, contributing to democratizing the implementation of PRS.
| S-EPMC11367857 | biostudies-literature