Validation of a multi-ancestry polygenic risk score and age-specific risks of prostate cancer: A meta-analysis within diverse populations
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Evaluation Summary:
This paper is mainly for an audience of genetic epidemiologists interested in the evaluation and portability of polygenic scores. The authors show that a polygenic risk score to predict prostate cancer risk is very informative for individuals that are classified on three different ancestry categories. The authors show that the polygenic risk score can be used to predict the risk to develop prostate cancer as a function of age. This paper provides evidence that genetic information could be used to provide guidance to clinicians on when to perform screenings to detect prostate cancer in patients.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Abstract
We recently developed a multi-ancestry polygenic risk score (PRS) that effectively stratifies prostate cancer risk across populations. In this study, we validated the performance of the PRS in the multi-ancestry Million Veteran Program and additional independent studies.
Methods:
Within each ancestry population, the association of PRS with prostate cancer risk was evaluated separately in each case–control study and then combined in a fixed-effects inverse-variance-weighted meta-analysis. We further assessed the effect modification by age and estimated the age-specific absolute risk of prostate cancer for each ancestry population.
Results:
The PRS was evaluated in 31,925 cases and 490,507 controls, including men from European (22,049 cases, 414,249 controls), African (8794 cases, 55,657 controls), and Hispanic (1082 cases, 20,601 controls) populations. Comparing men in the top decile (90–100% of the PRS) to the average 40–60% PRS category, the prostate cancer odds ratio (OR) was 3.8-fold in European ancestry men (95% CI = 3.62–3.96), 2.8-fold in African ancestry men (95% CI = 2.59–3.03), and 3.2-fold in Hispanic men (95% CI = 2.64–3.92). The PRS did not discriminate risk of aggressive versus nonaggressive prostate cancer. However, the OR diminished with advancing age (European ancestry men in the top decile: ≤55 years, OR = 7.11; 55–60 years, OR = 4.26; >70 years, OR = 2.79). Men in the top PRS decile reached 5% absolute prostate cancer risk ~10 years younger than men in the 40–60% PRS category.
Conclusions:
Our findings validate the multi-ancestry PRS as an effective prostate cancer risk stratification tool across populations. A clinical study of PRS is warranted to determine whether the PRS could be used for risk-stratified screening and early detection.
Funding:
This work was supported by the National Cancer Institute at the National Institutes of Health (grant numbers U19 CA214253 to C.A.H., U01 CA257328 to C.A.H., U19 CA148537 to C.A.H., R01 CA165862 to C.A.H., K99 CA246063 to B.F.D, and T32CA229110 to F.C), the Prostate Cancer Foundation (grants 21YOUN11 to B.F.D. and 20CHAS03 to C.A.H.), the Achievement Rewards for College Scientists Foundation Los Angeles Founder Chapter to B.F.D, and the Million Veteran Program-MVP017. This research has been conducted using the UK Biobank Resource under application number 42195. This research is based on data from the Million Veteran Program, Office of Research and Development, and the Veterans Health Administration. This publication does not represent the views of the Department of Veteran Affairs or the United States Government.
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Evaluation Summary:
This paper is mainly for an audience of genetic epidemiologists interested in the evaluation and portability of polygenic scores. The authors show that a polygenic risk score to predict prostate cancer risk is very informative for individuals that are classified on three different ancestry categories. The authors show that the polygenic risk score can be used to predict the risk to develop prostate cancer as a function of age. This paper provides evidence that genetic information could be used to provide guidance to clinicians on when to perform screenings to detect prostate cancer in patients.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with …
Evaluation Summary:
This paper is mainly for an audience of genetic epidemiologists interested in the evaluation and portability of polygenic scores. The authors show that a polygenic risk score to predict prostate cancer risk is very informative for individuals that are classified on three different ancestry categories. The authors show that the polygenic risk score can be used to predict the risk to develop prostate cancer as a function of age. This paper provides evidence that genetic information could be used to provide guidance to clinicians on when to perform screenings to detect prostate cancer in patients.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
This manuscript presents a useful application of a multi-ancestry polygenic risk score to predict the risk of prostate cancer in approximately 500,000 individuals that are classified on three different ancestry categories. The authors show that the multi-ancestry polygenic risk score can be used to predict the risk of prostate cancer in individuals of different ages that were classified to have either European, African, or Hispanic ancestry. The authors show that the ages of individuals must be taken into account, along with the polygenic risk score, to predict the risk of having prostate cancer.
This paper is very well conceived and the authors do a great job showing that the multi-ancestry polygenic risk score, previously developed by the same group, is a useful predictor of the risk to develop prostate …
Reviewer #1 (Public Review):
This manuscript presents a useful application of a multi-ancestry polygenic risk score to predict the risk of prostate cancer in approximately 500,000 individuals that are classified on three different ancestry categories. The authors show that the multi-ancestry polygenic risk score can be used to predict the risk of prostate cancer in individuals of different ages that were classified to have either European, African, or Hispanic ancestry. The authors show that the ages of individuals must be taken into account, along with the polygenic risk score, to predict the risk of having prostate cancer.
This paper is very well conceived and the authors do a great job showing that the multi-ancestry polygenic risk score, previously developed by the same group, is a useful predictor of the risk to develop prostate cancer. The cohorts analyzed are very large and support the main conclusion made by the authors that the polygenic score is a useful tool to diagnose the risk for prostate cancer. The authors make a good case showing that taking into account the ancestral background of an individual along with the age and the polygenic score can be very useful in the clinic to make decisions about the frequency to perform prostate-specific antigen screenings on different patients.
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Reviewer #2 (Public Review):
Chen and Darst et al present a rigorous evaluation of a previously developed multi-ancestry polygenic risk score (PRS) for prostate cancer in multiple multi-ancestry datasets through meta-analysis. They found that their multi-ancestry PRS for prostate cancer shows strong risk stratification across European, African, and Hispanic populations (i.e., increased estimated associations with prostate cancer in increasing deciles of genetic risk). Consistent with previous literature, the authors showed that the PRS associations with prostate cancer risk attenuated in older men with higher genetic risks; the authors also show that this attenuation occurs in African ancestry men. Lastly, the authors show that men with higher genetic risk, across all three ancestry groups, reach a 5% absolute risk of prostate cancer …
Reviewer #2 (Public Review):
Chen and Darst et al present a rigorous evaluation of a previously developed multi-ancestry polygenic risk score (PRS) for prostate cancer in multiple multi-ancestry datasets through meta-analysis. They found that their multi-ancestry PRS for prostate cancer shows strong risk stratification across European, African, and Hispanic populations (i.e., increased estimated associations with prostate cancer in increasing deciles of genetic risk). Consistent with previous literature, the authors showed that the PRS associations with prostate cancer risk attenuated in older men with higher genetic risks; the authors also show that this attenuation occurs in African ancestry men. Lastly, the authors show that men with higher genetic risk, across all three ancestry groups, reach a 5% absolute risk of prostate cancer far earlier than those in the median risk group. Overall, the results of the paper support the conclusions and the main take-home message of increasing sample sizes in non-European populations to fully evaluate the capabilities of this PRS in risk-stratifying during screening is clear.
The main strength of the study is a clear statement of aims and demonstration of conclusions. Applying this multi-ancestry PRS to multiple multi-ancestry datasets shows that the PRS is effective in risk stratification. The methods are well-articulated and the figures are easy to understand. I also commend the authors for providing links to data and sample code.
The main weakness is the lack of some background on polygenic scores. The manuscript is written for a genetic epidemiology and/or clinical audience, where a background understanding of polygenic scores is assumed. Adding context about PRS for a wider audience of life sciences readers would be warranted.
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