Journal Article

DKFZ-2025-02022

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Stratifying lung adenocarcinoma risk with multi-ancestry polygenic risk scores in East Asian never-smokers.

Blechter, B. ; Wang, X. ; Dai, J. ; Karsonaki, C. ; Shi, J. ; Shiraishi, K. ; Choi, J. ; Matsuo, K. ; Chen, T.-Y. ; Hung, R. J. ; Chen, K. ; Shu, X.-O. ; Kim, Y. T. ; Choudhury, P. P. ; Williams, J. ; Landi, M. T. ; Lin, D. ; Zheng, W. ; Yin, Z. ; Zhou, B. ; Wang, J. ; Seow, W. J. ; Song, L. ; Chang, I.-S. ; Hu, W. ; Chien, L.-H. ; Cai, Q. ; Hong, Y.-C. ; Kim, H. N. ; Wu, Y.-L. ; Wong, M. P. ; Richardson, B. D. ; Li, S. ; Zhang, T. ; Breeze, C. ; Wang, Z. ; Bassig, B. A. ; Kim, J. H. ; Albanes, D. ; Wong Sm, J. Y. ; Shin, M.-H. ; Chung, L. P. ; Yang, Y. ; Zheng, H. ; Dai, H. ; Yatabe, Y. ; Zhang, X.-C. ; Kim, Y.-C. ; Caporaso, N. E. ; Chang, J. ; Ho, J. C. M. ; Daigo, Y. ; Momozawa, Y. ; Kamatani, Y. ; Kobayashi, M. ; Okubo, K. ; Honda, T. ; Hosgood, H. D. ; Kunitoh, H. ; Watanabe, S.-I. ; Miyagi, Y. ; Matsumoto, S. ; Horinouchi, H. ; Tsuboi, M. ; Hamamoto, R. ; Goto, K. ; Takahashi, A. ; Goto, A. ; Minamiya, Y. ; Hara, M. ; Nishida, Y. ; Takeuchi, K. ; Wakai, K. ; Matsuda, K. ; Murakami, Y. ; Shimizu, K. ; Suzuki, H. ; Saito, M. ; Ohtaki, Y. ; Tanaka, K. ; Wu, T. ; Wei, F. ; Machiela, M. J. ; Kim, Y. H. ; Oh, I.-J. ; Lee, V. H. F. ; Chang, G.-C. ; Chen, K.-Y. ; Su, W.-C. ; Chen, Y.-M. ; Seow, A. ; Park, J. Y. ; Kweon, S.-S. ; Gao, Y.-T. ; Liu, J. ; Schwartz, A. G. ; Houlston, R. ; Gorlov, I. P. ; Wu, X. ; Yang, P. ; Lam, S. ; Tardon, A. ; Chen, C. ; Bojesen, S. E. ; Johansson, M. ; Risch, A.DKFZ* ; Bickeböller, H. ; Ji, B.-T. ; Wichmann, H.-E. ; Christiani, D. C. ; Rennert, G. ; Arnold, S. M. ; Brennan, P. ; McKay, J. ; Field, J. K. ; Davies, M. P. A. ; Shete, S. S. ; Le Marchand, L. ; Liu, G. ; Andrew, A. S. ; Kiemeney, L. A. ; Zienolddiny-Narui, S. ; Grankvist, K. ; Cox, A. ; Taylor, F. ; Yuan, J.-M. ; Lazarus, P. ; Schabath, M. B. ; Aldrich, M. C. ; Jeon, H.-S. ; Jiang, S. S. ; Chen, C.-H. ; Hsiao, C.-F. ; Hu, Z. ; Burdett, L. ; Yeager, M. ; Hutchinson, A. ; Hicks, B. ; Liu, J. ; Berndt, S. I. ; Wu, W. ; Wang, J. ; Li, Y. ; Choi, J. E. ; Park, K. H. ; Sung, S. W. ; Kang, C. H. ; Wang, W.-C. ; Xu, J. ; Guan, P. ; Tan, W. ; Yu, C.-J. ; Yang, G. ; Sihoe, A. D. L. ; Choi, Y. Y. ; Park, I. K. ; Hung, H.-H. ; Vermeulen, R. C. H. ; Cheng, I. ; Wu, J. ; Tsai, F.-Y. ; Chan, J. K. C. ; Li, J. ; Lin, H.-C. ; Liu, J. ; Song, B. ; Sawada, N. ; Yamaji, T. ; Wyatt, K. ; Ma, H. ; Zhu, M. ; Wang, Y. ; Qi, T. ; Li, X. ; Ren, Y. ; Chao, A. ; Iwasaki, M. ; Zhu, J. ; Wu, G. ; Chen, C.-Y. ; ScD, C. C. ; Yang, P.-C. ; Stevens, V. L. ; Fraumeni, J. F. ; Lin, K. ; Walters, R. G. ; Chen, Z. ; Chatterjee, N. ; Gorlova, O. Y. ; Amos, C. I. ; Shen, H. ; Hsiung, C. A. ; Chanock, S. J. ; Rothman, N. ; Kohno, T. ; Lan, Q. ; Zhang, H.

2026
Oxford Univ. Press Oxford

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Please use a persistent id in citations: doi:10.1093/jnci/djaf272

Abstract: Lung adenocarcinoma (LUAD) 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 LUAD risk prediction.PRSs were developed using genome-wide association study summary statistics from East Asian (8,002 cases; 20,782 controls) and European (2,058 cases; 5,575 controls) populations. Single-ancestry models included PRS-25, PRS-CT, and LDpred2; multi-ancestry models included LDpred2+PRS-EUR128, PRS-CSx, and CT-SLEB. Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium (FLCCA) and externally validated in the Nanjing Lung Cancer Cohort (NJLCC). We assessed predictive accuracy via AUC, with 10-year and (age 30-80) absolute risks estimates.The best multi-ancestry PRS, using East Asian and European data via CT-SLEB (clumping and thresholding, super learning, empirical Bayes), outperformed the best East Asian-only PRS (LDpred2; AUC = 0.629, 95% CI:0.618,0.641), achieving an AUC of 0.640 (95% CI : 0.629,0.653) and odds ratio of 1.71 (95% CI : 1.61,1.82) per SD increase. NJLCC Validation confirmed robust performance (AUC =0.649, 95% CI: 0.623, 0.676). The top 20% PRS group had a 3.92-fold higher LUAD 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 LUAD risk at age 50 (0.42%) by age 41, nine years earlier.Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

Keyword(s): East Asian never smokers ; Genome-wide association studies ; Lifetime absolute risk ; Lung adenocarcinoma ; Polygenic risk scores

Note: ISSN 1460-2105 / Volume 118, Issue 2, February 2026, Pages 231–249

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Contributing Institute(s):

1. Epigenomik (B370)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

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; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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