Blechter, B 
ORCID: 0000-0001-7610-2554, Wang, X, Dai, J ORCID: 0000-0002-3909-5671, Karsonaki, C ORCID: 0000-0002-3981-3418, Shi, J, Shiraishi, K ORCID: 0000-0002-5821-7400, Choi, J ORCID: 0000-0002-0955-2384, Matsuo, K ORCID: 0000-0003-1761-6314, Chen, TY ORCID: 0000-0002-0146-3782, Hung, RJ ORCID: 0000-0002-4486-7496 et al (show 90 more authors)
(2026)
Stratifying lung adenocarcinoma risk with multi-ancestry polygenic risk scores in East Asian never-smokers
Journal of the National Cancer Institute, 118 (2).
pp. 231-249.
ISSN 0027-8874, 1460-2105
|
PDF
Stratifying lung adenocarcinoma risk with multi-ancestry polygenic risk scores in East Asian never-smokers.pdf - Submitted version Download (1MB) | Preview |
Abstract
Background Lung adenocarcinoma in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve lung adenocarcinoma risk prediction. Methods PRSs were developed using genome-wide association study summary statistics from East Asian (8002 cases; 20 782 controls) and European (2058 cases; 5575 controls) populations. Single-ancestry models included a PRS with 25 single nucleotide variants (PRS-25), PRS clumping and thresholding (CT), and LDpred2; multi-ancestry models included LDpred2 plus European PRS-128, PRS-CSx, and clumping and thresholding, super learning, empirical Bayes (CT-SLEB). Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium and externally validated in the Nanjing Lung Cancer Cohort. We assessed predictive accuracy via area under the curve operating procedure (AUC), with 10-year and (ages 30-80 years) absolute risks estimates. Results The best multi-ancestry PRS, using East Asian and European data via CT-SLEB, outperformed the best East Asian-only (LDpred2; AUC = 0.629, 95% confidence interval [CI] = 0.618 to 0.641), achieving an AUC of 0.640 (95% CI = 0.629 to 0.653) and odds ratio of 1.71 (95% CI = 1.61 to 1.82) per standard deviation increase. Nanjing Lung Cancer Cohort validation confirmed robust performance (AUC = 0.649, 95% CI = 0.623 to 0.676). The top 20% PRS group had a 3.92-fold higher lung adenocarcinoma risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year lung adenocarcinoma risk at age 50 years (0.42%) by age 41 years, 9 years earlier. Conclusions Multi-ancestry PRS approaches enhance lung adenocarcinoma risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | East Asian never smokers, Genome-wide association studies, Lifetime absolute risk, Lung adenocarcinoma, Polygenic risk scores |
| Divisions: | Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Inst. Systems, Molec & Integrative Biology (T&R Staff) Faculty of Health & Life Sciences > Inst. Systems, Molec & Integrative Biology > Molecular & Clinical Cancer Medicine |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 02 Dec 2025 10:25 |
| Last Modified: | 11 Apr 2026 01:18 |
| DOI: | 10.1093/jnci/djaf272 |
| Related Websites: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3195760 |
| Disclaimer: | The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate. |
Altmetric
Altmetric