Stratifying lung adenocarcinoma risk with multi-ancestry polygenic risk scores in East Asian never-smokers

作者：Batel Blechter, Xiaoyu Wang, Juncheng Dai, Christiana Karsonaki, Jianxin Shi, Kouya Shiraishi, Jiyeon Choi, Keitaro Matsuo, Tzu‐Yu Chen, Rayjean J. Hung, Kexin Chen, Xiao-Ou Shu, Young Tae Kim, Parichoy Pal Choudhury, Jacob Williams, Maria Teresa Landi, Dongxin Lin, Wei Zheng, Zhihua Yin, Baosen Zhou, Jiucun Wang, Wei Jie Seow, Lei Song, I‐Shou Chang, Wei Hu, Li-Hsin Chien, Qiuyin Cai, Yun-Chul Hong, Hee Nam Kim, Yi‐Long Wu, Maria Pik Wong, Brian Douglas Richardson, Shilan Li, Tongwu Zhang, Charles E. Breeze, Zhaoming Wang, Bryan A. Bassig, Jin Hee Kim, Demetrius Albanes, Jason Yy Wong Sm, Min‐Ho Shin, Lap Ping Chung, Yang Yang, Hong Zheng, Hong Dai, Yasushi Yatabe, Xu‐Chao Zhang, Young‐Chul Kim, Neil E. Caporaso, Jiang Chang, Jcm Ho, Yataro Daigo, Yukihide Momozawa, Yoichiro Kamatani, Masashi Kobayashi, Kenichi Okubo, Takayuki Honda, H. Dean Hosgood, Hideo Kunitoh, Shun-ichi Watanabe, Yohei Miyagi, Shingo Matsumoto, Hidehito Horinouchi, Masahiro Tsuboi, Ryuji Hamamoto, Kōichi Goto, Atsushi Takahashi, Akiteru Goto, Yoshihiro Minamiya, Megumi Hara, Yuichiro Nishida, Kenji Takeuchi, Kenji Wakai, Koichi Matsuda, Yoshinori Murakami, Kimihiro Shimizu, Hiroyuki Suzuki, Motonobu Saito, Yoichi Ohtaki, Kazumi Tanaka, Tangchun Wu, Fusheng Wei, Mitchell J. Machiela, Yeul Hong Kim, In‐Jae Oh, Victor Lee, Gee-Chen Chang, Kuan‐Yu Chen, Wu‐Chou Su, Yuh-Min Chen, Adeline Seow, Jae Yong Park, Sun-Seog Kweon, Yu‐Tang Gao, Jianjun Liu, Ann G. Schwartz, Richard S. Houlston, Ivan Gorlov, Xifeng Wu, Ping Yang, Stephen Lam, Adonina Tardón, Chen Chu, Stig E. Bojesen, Mattias Johansson, Angela Risch, Heike Bickeböller, Bu‐Tian Ji, H. E. Wichmann, D.C. Christiani, Gad Rennert, Susanne M. Arnold, Paul Brennan, James McKay, John K. Field, Michael P.A. Davies, Sanjay Shete, Loı̈c Le Marchand, Geoffrey Liu, Angeline S. Andrew, Lambertus A. Kiemeney, Shan Zienolddiny-Narui, Kjell Grankvist, Angela Cox, Fiona Taylor, Jian-Min Yuan, Philip Lazarus, Matthew B. Schabath, Melinda C. Aldrich, Hyo‐Sung Jeon, Shih Sheng Jiang, Chung–Hsing Chen, Chin‐Fu Hsiao, Zhibin Hu, Laura Burdett, Meredith Yeager, Amy Hutchinson, Belynda Hicks, Jia Liu, Sonja I Berndt, Wei Wu, Junwen Wang, Yuqing Li, Jin Eun Choi, Kyong Hwa Park, Sook Whan Sung, Chang Hyun Kang, Wen‐Chang Wang, Jun Xu, Peng Guan, Wen Tan, Chong‐Jen Yu, Gong Yang, Alan Sihoe, Yi Young Choi, In Kyu Park, Hsiao-Han Hung, Roel Vermeulen, Iona Cheng, Junjie Wu, Fang-Yu Tsai, John K. C. Chan, Jihua Li, Hsien-Chih Lin, Jie Liu, Bao‐Liang Song, Norie Sawada, Taiki Yamaji, Kathleen Wyatt, Hongxia Ma, Meng Zhu, Yifan Wang, T. Y. Qi, Xuelian Li, Yangwu Ren, Ann Chao, Motoki Iwasaki, Junjie Zhu, Guoping Wu, Chih‐Yi Chen, Chien-Jen Chen ScD, Pan‐Chyr Yang, Victoria L. Stevens, Joseph F. Fraumeni, Kuang Lin, Robin G. Walters, Zhengming Chen, Nilanjan Chatterjee, Olga Y. Gorlova, Christopher I. Amos, Hongbing Shen, Chao A. Hsiung, Stephen J Chanock, Nathaniel Rothman, Takashi Kohno, Qing Lan, Haoyu Zhang · 发表于：JNCI Journal of the National Cancer Institute · 年份：2025 · DOI：10.1093/jnci/djaf272 · 被引用次数：1 · 研究领域：Genetic Associations and Epidemiology、Ferroptosis and cancer prognosis、Lung Cancer Treatments and Mutations

BACKGROUND: 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. METHODS: 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. RESULTS: 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 ...