Stratifying lung adenocarcinoma risk with multi-ancestry polygenic risk scores in East Asian never-smokers.
Journal
Journal of the National Cancer Institute
Journal Volume
118
Journal Issue
2
Start Page
231
End Page
249
ISSN
1460-2105
Date Issued
2025-10-01
Author(s)
Blechter, Batel
Wang, Xiaoyu
Dai, Juncheng
Karsonaki, Christiana
Shi, Jianxin
Shiraishi, Kouya
Choi, Jiyeon
Matsuo, Keitaro
Chen, Tzu-Yu
Hung, Rayjean J
Chen, Kexin
Shu, Xiao-Ou
Kim, Young Tae
Choudhury, Parichoy Pal
Williams, Jacob
Landi, Maria Teresa
Lin, Dongxin
Zheng, Wei
Yin, Zhihua
Zhou, Baosen
Wang, Jiucun
Seow, Wei Jie
Song, Lei
Chang, I-Shou
Hu, Wei
Chien, Li-Hsin
Cai, Qiuyin
Hong, Yun-Chul
Kim, Hee Nam
Wu, Yi-Long
Wong, Maria Pik
Richardson, Brian Douglas
Li, Shilan
Zhang, Tongwu
Breeze, Charles
Wang, Zhaoming
Bassig, Bryan A
Kim, Jin Hee
Albanes, Demetrius
Wong Sm, Jason Yy
Shin, Min-Ho
Chung, Lap Ping
Yang, Yang
Zheng, Hong
Dai, Hongji
Yatabe, Yasushi
Zhang, Xu-Chao
Kim, Young-Chul
Caporaso, Neil E
Chang, Jiang
Ho, James Chung Man
Daigo, Yataro
Momozawa, Yukihide
Kamatani, Yoichiro
Kobayashi, Masashi
Okubo, Kenichi
Honda, Takayuki
Hosgood, H Dean
Kunitoh, Hideo
Watanabe, Shun-Ichi
Miyagi, Yohei
Matsumoto, Shingo
Horinouchi, Hidehito
Tsuboi, Masahiro
Hamamoto, Ryuji
Goto, Koichi
Takahashi, Atsushi
Goto, Akiteru
Minamiya, Yoshihiro
Hara, Megumi
Nishida, Yuichiro
Takeuchi, Kenji
Wakai, Kenji
Matsuda, Koichi
Murakami, Yoshinori
Shimizu, Kimihiro
Suzuki, Hiroyuki
Saito, Motonobu
Ohtaki, Yoichi
Tanaka, Kazumi
Wu, Tangchun
Wei, Fusheng
Machiela, Mitchell J
Kim, Yeul Hong
Oh, In-Jae
Lee, Victor Ho Fun
Chang, Gee-Chen
Chen, Kuan-Yu
Su, Wu-Chou
Chen, Yuh-Min
Seow, Adeline
Park, Jae Yong
Kweon, Sun-Seog
Gao, Yu-Tang
Liu, Jianjun
Schwartz, Ann G
Houlston, Richard
Gorlov, Ivan P
Wu, Xifeng
Yang, Ping
Lam, Stephen
Tardon, Adonina
Chen, Chu
Bojesen, Stig E
Johansson, Mattias
Risch, Angela
Bickeböller, Heike
Ji, Bu-Tian
Wichmann, H-Erich
Christiani, David C
Rennert, Gad
Arnold, Susanne M
Brennan, Paul
McKay, James
Field, John K
Davies, Michael P A
Shete, Sanjay S
Le Marchand, Loïc
Liu, Geoffrey
Andrew, Angeline S
Kiemeney, Lambertus A
Zienolddiny-Narui, Shan
Grankvist, Kjell
Cox, Angela
Taylor, Fiona
Yuan, Jian-Min
Lazarus, Philip
Schabath, Matthew B
Aldrich, Melinda C
Jeon, Hyo-Sung
Jiang, Shih Sheng
Chen, Chung-Hsing
Hsiao, Chin-Fu
Hu, Zhibin
Burdett, Laura
Yeager, Meredith
Hutchinson, Amy
Hicks, Belynda
Liu, Jia
Berndt, Sonja I
Wu, Wei
Wang, Junwen
Li, Yuqing
Choi, Jin Eun
Park, Kyong Hwa
Sung, Sook Whan
Kang, Chang Hyun
Wang, Wen-Chang
Xu, Jun
Guan, Peng
Tan, Wen
Yang, Gong
Sihoe, Alan Dart Loon
Choi, Yi Young
Park, In Kyu
Hung, Hsiao-Han
Vermeulen, Roel C H
Cheng, Iona
Wu, Junjie
Tsai, Fang-Yu
Chan, John K C
Li, Jihua
Lin, Hsien-Chih
Liu, Jie
Song, Bao
Sawada, Norie
Yamaji, Taiki
Wyatt, Kathleen
Ma, Hongxia
Zhu, Meng
Wang, Yifan
Qi, Tianchen
Li, Xuelian
Ren, Yangwu
Chao, Ann
Iwasaki, Motoki
Zhu, Junjie
Wu, Guoping
ScD, Chien-Jen Chen
Stevens, Victoria L
Fraumeni, Joseph F
Lin, Kuang
Walters, Robin G
Chen, Zhengming
Chatterjee, Nilanjan
Gorlova, Olga Y
Amos, Christopher I
Shen, Hongbing
Hsiung, Chao Agnes
Chanock, Stephen J
Rothman, Nathaniel
Kohno, Takashi
Lan, Qing
Zhang, Haoyu
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.
Subjects
East Asian never smokers
Genome-wide association studies
Lifetime absolute risk
Lung adenocarcinoma
Polygenic risk scores
Type
journal article