Polygenic risk scores for the prediction of common cancers in East Asians: A population-based prospective cohort study
- Genome Institute of Singapore, Singapore
- National Cancer Centre Singapore, Singapore
- UPMC Hillman Cancer Center, United States
- National University of Singapore, Singapore
Abstract
Background: To evaluate the utility of polygenic risk scores (PRS) in identifying high-risk individuals, different publicly available PRS 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) and 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 hazard ratios 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).
Data availability
All polygenic risk scores used in this study are publicly available in the PGS Catalog (https://www.pgscatalog.org).The data that support the findings of our study are available from the corresponding authors of the study upon reasonable request (Dr Rajkumar s/o Dorajoo, dorajoor@gis.a-star.edu.sg and Dr Jingmei Li, lijm1@gis.a-star.edu.sg). More information regarding the data access to SCHS can be found at: https://sph.nus.edu.sg/research/cohort-schs/. The data are not publicly available due to Singapore laws.Source Data 1 contain the numerical data used to generate the figure 1.The code for the study is uploaded as Source Code 1.
Article and author information
Author details
Funding
National Research Foundation Singapore (PRECISE)
- Jingmei Li
National Medical Research Council (NMRC/CSA/0055/2013)
- Woon-Puay Koh
National Research Foundation Singapore (NRF-NRFI2018-01)
- Chiea Chuen Khor
Ministry of Health -Singapore (HLCA20Jan-0022)
- Rajkumar Dorajoo
National Institutes of Health (R01 CA144034 and UM1 CA182876)
- Jian-Min Yuan
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The study was approved by the Institutional Review Boards of the National University of Singapore, University of Pittsburgh, and the Agency for Science, Technology and Research (A*STAR, reference number 2022-042). Written, informed consent was obtained from all study participants.
Copyright
© 2023, Ho et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Polygenic risk scores for the prediction of common cancers in East Asians: A population-based prospective cohort study
eLife 12:e82608.
https://doi.org/10.7554/eLife.82608
Further reading
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- Cancer Biology
- Epidemiology and Global Health
Cancer is considered a risk factor for COVID-19 mortality, yet several countries have reported that deaths with a primary code of cancer remained within historic levels during the COVID-19 pandemic. Here, we further elucidate the relationship between cancer mortality and COVID-19 on a population level in the US. We compared pandemic-related mortality patterns from underlying and multiple cause (MC) death data for six types of cancer, diabetes, and Alzheimer’s. Any pandemic-related changes in coding practices should be eliminated by study of MC data. Nationally in 2020, MC cancer mortality rose by only 3% over a pre-pandemic baseline, corresponding to ~13,600 excess deaths. Mortality elevation was measurably higher for less deadly cancers (breast, colorectal, and hematological, 2–7%) than cancers with a poor survival rate (lung and pancreatic, 0–1%). In comparison, there was substantial elevation in MC deaths from diabetes (37%) and Alzheimer’s (19%). To understand these differences, we simulated the expected excess mortality for each condition using COVID-19 attack rates, life expectancy, population size, and mean age of individuals living with each condition. We find that the observed mortality differences are primarily explained by differences in life expectancy, with the risk of death from deadly cancers outcompeting the risk of death from COVID-19.
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- Epidemiology and Global Health
Background:
The associations of age at diagnosis of breast cancer with incident myocardial infarction (MI) and heart failure (HF) remain unexamined. Addressing this problem could promote understanding of the cardiovascular impact of breast cancer.
Methods:
Data were obtained from the UK Biobank. Information on the diagnosis of breast cancer, MI, and HF was collected at baseline and follow-ups (median = 12.8 years). The propensity score matching method and Cox proportional hazards models were employed.
Results:
A total of 251,277 female participants (mean age: 56.8 ± 8.0 years), of whom 16,241 had breast cancer, were included. Among breast cancer participants, younger age at diagnosis (per 10-year decrease) was significantly associated with elevated risks of MI (hazard ratio [HR] = 1.36, 95% confidence interval [CI] 1.19–1.56, p<0.001) and HF (HR = 1.31, 95% CI 1.18–1.46, p<0.001). After propensity score matching, breast cancer patients with younger diagnosis age had significantly higher risks of MI and HF than controls without breast cancer.
Conclusions:
Younger age at diagnosis of breast cancer was associated with higher risks of incident MI and HF, underscoring the necessity to pay additional attention to the cardiovascular health of breast cancer patients diagnosed at younger age to conduct timely interventions to attenuate the subsequent risks of incident cardiovascular diseases.
Funding:
This study was supported by grants from the National Natural Science Foundation of China (82373665 and 81974490), the Nonprofit Central Research Institute Fund of Chinese Academy of Medical Sciences (2021-RC330-001), and the 2022 China Medical Board-open competition research grant (22-466).
