Polygenic risk scores for the prediction of common cancers in East Asians: A population-based prospective cohort study
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eLife assessment
This important study reveals the role of polygenic scores for four commonly diagnosed cancers with high genetic predisposition (breast, prostate, colorectal, and lung) in East Asian populations, which is developed in participants of European descent. The data is convincing that is derived from a prospective cohort including 21,694 Singaporean participants of East Asian descent. The work will be of interest and provide great help to disease specialists in the field.
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Abstract
To evaluate the utility of polygenic risk scores (PRSs) in identifying high-risk individuals, different publicly available PRSs for breast (n=85), prostate (n=37), colorectal (n=22), and lung cancers (n=11) were examined in a prospective study of 21,694 Chinese adults.
Methods:
We constructed PRS using weights curated in the online PGS Catalog. PRS performance was evaluated by distribution, discrimination, predictive ability, and calibration. Hazard ratios (HR) and corresponding confidence intervals (CI) of the common cancers after 20 years of follow-up were estimated using Cox proportional hazard models for different levels of PRS.
Results:
A total of 495 breast, 308 prostate, 332 female-colorectal, 409 male-colorectal, 181 female-lung, and 381 male-lung incident cancers were identified. The area under receiver operating characteristic curve for the best-performing site-specific PRS were 0.61 (PGS000873, breast), 0.70 (PGS00662, prostate), 0.65 (PGS000055, female-colorectal), 0.60 (PGS000734, male-colorectal), 0.56 (PGS000721, female-lung), and 0.58 (PGS000070, male-lung), respectively. Compared to the middle quintile, individuals in the highest cancer-specific PRS quintile were 64% more likely to develop cancers of the breast, prostate, and colorectal. For lung cancer, the lowest cancer-specific PRS quintile was associated with 28–34% decreased risk compared to the middle quintile. In contrast, the HR observed for quintiles 4 (female-lung: 0.95 [0.61–1.47]; male-lung: 1.14 [0.82–1.57]) and 5 (female-lung: 0.95 [0.61–1.47]) were not significantly different from that for the middle quintile.
Conclusions:
Site-specific PRSs can stratify the risk of developing breast, prostate, and colorectal cancers in this East Asian population. Appropriate correction factors may be required to improve calibration.
Funding:
This work is supported by the National Research Foundation Singapore (NRF-NRFF2017-02), PRECISION Health Research, Singapore (PRECISE) and the Agency for Science, Technology and Research (A*STAR). WP Koh was supported by National Medical Research Council, Singapore (NMRC/CSA/0055/2013). CC Khor was supported by National Research Foundation Singapore (NRF-NRFI2018-01). Rajkumar Dorajoo received a grant from the Agency for Science, Technology and Research Career Development Award (A*STAR CDA - 202D8090), and from Ministry of Health Healthy Longevity Catalyst Award (HLCA20Jan-0022).
The Singapore Chinese Health Study was supported by grants from the National Medical Research Council, Singapore (NMRC/CIRG/1456/2016) and the U.S. National Institutes of Health (NIH) (R01 CA144034 and UM1 CA182876).
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eLife assessment
This important study reveals the role of polygenic scores for four commonly diagnosed cancers with high genetic predisposition (breast, prostate, colorectal, and lung) in East Asian populations, which is developed in participants of European descent. The data is convincing that is derived from a prospective cohort including 21,694 Singaporean participants of East Asian descent. The work will be of interest and provide great help to disease specialists in the field.
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Reviewer #1 (Public Review):
The majority of polygenic scores have been developed in individuals of European descent and the analysis of the generalisability and applicability of these PRSes in diverse populations has hitherto been limited. In this study, the authors make an important contribution to addressing this gap by evaluating utility of common PRS, curated in the Polygenic Score (PGS) Catalog, in predicting the risk of the commonly diagnosed cancers with high genetic predisposition (breast, prostate, colorectal, and lung) in a prospective cohort comprising 21,694 participants of East Asian descent in Singapore.
Two major strengths in this paper are that this is one of the largest prospective Asian cohorts with long term follow up data, and the authors have completed the evaluation of a large number of PRSes (although it should …
Reviewer #1 (Public Review):
The majority of polygenic scores have been developed in individuals of European descent and the analysis of the generalisability and applicability of these PRSes in diverse populations has hitherto been limited. In this study, the authors make an important contribution to addressing this gap by evaluating utility of common PRS, curated in the Polygenic Score (PGS) Catalog, in predicting the risk of the commonly diagnosed cancers with high genetic predisposition (breast, prostate, colorectal, and lung) in a prospective cohort comprising 21,694 participants of East Asian descent in Singapore.
Two major strengths in this paper are that this is one of the largest prospective Asian cohorts with long term follow up data, and the authors have completed the evaluation of a large number of PRSes (although it should be pointed out that not all of which are independent of each other).
However, the authors have only described the results of the best performing PRS and attempted to describe PRSes across 4 major common cancers as a group. In so doing, there is a missed opportunity to describe what lessons we might learn in the applicability of PRSes discovered in one population in another diverse population. In addition, it is not clear what benefits may be gleaned from the analysis of the PRSes as a group, rather than individually.
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Reviewer #2 (Public Review):
In this work, Li, Dorajoo, and colleagues use national Singaporean data to demonstrate the associations of previously published polygenic risk scores (PRS) for 4 cancers (breast, prostate, colorectal, and lung) with incident cases over 20 years of follow-up. Using available PRS for the four cancers from the Polygenic Score Catalog, they used recommended metrics to evaluate the distribution, discrimination, risk association, and calibration of the PRS. Although the PRS were derived from predominantly European populations, the authors confirmed all PRS-disease associations in this ethnic Chinese population, with per-standard deviation effect sizes ranging from hazard ratio 1.17 for lung cancer to 1.73 for prostate cancer.
The strengths of this work include the use of an apparently unbiased national population …
Reviewer #2 (Public Review):
In this work, Li, Dorajoo, and colleagues use national Singaporean data to demonstrate the associations of previously published polygenic risk scores (PRS) for 4 cancers (breast, prostate, colorectal, and lung) with incident cases over 20 years of follow-up. Using available PRS for the four cancers from the Polygenic Score Catalog, they used recommended metrics to evaluate the distribution, discrimination, risk association, and calibration of the PRS. Although the PRS were derived from predominantly European populations, the authors confirmed all PRS-disease associations in this ethnic Chinese population, with per-standard deviation effect sizes ranging from hazard ratio 1.17 for lung cancer to 1.73 for prostate cancer.
The strengths of this work include the use of an apparently unbiased national population with 20 years of follow-up and near-complete outcomes ascertainment. The authors use state-of-the-art methods for genotyping, imputation, and PRS construction, and they use recently published PRS reporting standards to evaluate the PRS and organize the presentation of their work. Although the authors used an unbiased approach to their initial selection of PRS to evaluate (all 1,706 entries with <10,000 predictors in the PGS Catalog at the time), a significant weakness is the lack of detail in how the final 110 cancer PRS were selected for evaluation. Notable absences from these 110 are the PRS from the largest prostate cancer GWAS to date (PGS000662) and a Chinese-specific lung cancer GWAS (PGS000070). The latter absence is particularly notable as the authors report poorest performance of the lung cancer PRS they did evaluate.
Nonetheless, this work confirms prior observations of imperfect portability of PRS derived in one population to another, particularly of different genetic ancestry. The practical consequences of this performance differential will depend on the proposed use of the PRS. One important distinction the authors rightly point out is whether a PRS is intended for individual- or population-level application. The authors do not quantify the potential consequences of applying these PRS to the Singaporean population in different use cases (e.g., screening programs based on PRS), but interested readers will be able to use these findings to make such projections on their own.
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