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

Batel Blechter¹, Xiaoyu Wang¹, Juncheng Dai^{2

3}, Christiana Karsonaki⁴, Jianxin Shi¹, Kouya Shiraishi⁵, Jiyeon Choi¹, Keitaro Matsuo⁶, Tzu-Yu Chen^{7

8}, Rayjean J Hung⁹, Kexin Chen¹⁰, Xiao-Ou Shu¹¹, Young Tae Kim¹², Parichoy Pal Choudhury¹³, Jacob Williams¹, Maria Teresa Landi¹, Dongxin Lin¹⁴, Wei Zheng¹¹, Zhihua Yin¹⁵, Baosen Zhou¹⁶, Jiucun Wang^{17

18}, Wei Jie Seow^{19

20}, Lei Song¹, I-Shou Chang²¹, Wei Hu¹, Li-Hsin Chien^{7

22}, Qiuyin Cai¹¹, Yun-Chul Hong²³, Hee Nam Kim²⁴, Yi-Long Wu²⁵, Maria Pik Wong²⁶, Brian Douglas Richardson^{1

27}, Shilan Li^{1

28}, Tongwu Zhang¹, Charles Breeze¹, Zhaoming Wang²⁹, Bryan A Bassig³⁰, Jin Hee Kim³¹, Demetrius Albanes¹, Jason Yy Wong Sm³², Min-Ho Shin²⁴, Lap Ping Chung²⁶, Yang Yang³³, Hong Zheng¹⁰, Hongji Dai¹⁰, Yasushi Yatabe³⁴, Xu-Chao Zhang²⁵, Young-Chul Kim^{35

36}, Neil E Caporaso¹, Jiang Chang³⁷, James Chung Man Ho³⁸, Yataro Daigo^{39

40}, Yukihide Momozawa⁴¹, Yoichiro Kamatani⁴², Masashi Kobayashi⁴³, Kenichi Okubo⁴³, Takayuki Honda⁴⁴, H Dean Hosgood⁴⁵, Hideo Kunitoh⁴⁶, Shun-Ichi Watanabe⁴⁷, Yohei Miyagi⁴⁸, Shingo Matsumoto⁴⁹, Hidehito Horinouchi⁴⁷, Masahiro Tsuboi⁵⁰, Ryuji Hamamoto⁵¹, Koichi Goto⁴⁹, Atsushi Takahashi⁵², Akiteru Goto⁵³, Yoshihiro Minamiya⁵⁴, Megumi Hara⁵⁵, Yuichiro Nishida⁵⁵, Kenji Takeuchi⁵⁶, Kenji Wakai⁵⁶, Koichi Matsuda⁵⁷, Yoshinori Murakami⁵⁸, Kimihiro Shimizu⁵⁹, Hiroyuki Suzuki⁶⁰, Motonobu Saito⁶¹, Yoichi Ohtaki⁶², Kazumi Tanaka⁶³, Tangchun Wu⁶⁴, Fusheng Wei⁶⁵, Mitchell J Machiela¹, Yeul Hong Kim⁶⁶, In-Jae Oh^{67

36}, Victor Ho Fun Lee⁶⁸, Gee-Chen Chang^{69

70

71

72

73}, Kuan-Yu Chen⁷⁴, Wu-Chou Su⁷⁵, Yuh-Min Chen⁷⁶, Adeline Seow¹⁹, Jae Yong Park⁷⁷, Sun-Seog Kweon^{24

78}, Yu-Tang Gao⁷⁹, Jianjun Liu^{80

81}, Ann G Schwartz⁸², Richard Houlston⁸³, Ivan P Gorlov⁸⁴, Xifeng Wu⁸⁵, Ping Yang⁸⁶, Stephen Lam⁸⁷, Adonina Tardon⁸⁸, Chu Chen⁸⁹, Stig E Bojesen^{90

91}, Mattias Johansson⁹², Angela Risch^{93

94

95}, Heike Bickeböller⁹⁶, Bu-Tian Ji¹, H-Erich Wichmann^{97

98}, David C Christiani⁹⁹, Gad Rennert¹⁰⁰, Susanne M Arnold¹⁰¹, Paul Brennan⁹², James McKay⁹², John K Field¹⁰², Michael P A Davies¹⁰², Sanjay S Shete¹⁰³, Loïc Le Marchand¹⁰⁴, Geoffrey Liu¹⁰⁵, Angeline S Andrew¹⁰⁶, Lambertus A Kiemeney¹⁰⁷, Shan Zienolddiny-Narui¹⁰⁸, Kjell Grankvist¹⁰⁹, Angela Cox¹¹⁰, Fiona Taylor¹¹¹, Jian-Min Yuan¹¹², Philip Lazarus¹¹³, Matthew B Schabath¹¹⁴, Melinda C Aldrich¹¹⁵, Hyo-Sung Jeon¹¹⁶, Shih Sheng Jiang²¹, Chung-Hsing Chen^{21

117}, Chin-Fu Hsiao⁷, Zhibin Hu², Laura Burdett^{1

118}, Meredith Yeager^{1

118}, Amy Hutchinson^{1

118}, Belynda Hicks^{1

118}, Jia Liu^{1

118}, Sonja I Berndt¹, Wei Wu¹⁵, Junwen Wang^{119

120}, Yuqing Li¹²¹, Jin Eun Choi¹²², Kyong Hwa Park¹²³, Sook Whan Sung¹²⁴, Chang Hyun Kang¹²⁵, Wen-Chang Wang¹²⁶, Jun Xu¹²⁷, Peng Guan^{15

128}, Wen Tan¹⁴, Chong-Jen Yu¹²⁹, Gong Yang¹¹, Alan Dart Loon Sihoe¹³⁰, Yi Young Choi¹¹⁶, In Kyu Park¹²⁵, Hsiao-Han Hung²¹, Roel C H Vermeulen¹³¹, Iona Cheng¹²¹, Junjie Wu¹³², Fang-Yu Tsai²¹, John K C Chan¹³³, Jihua Li^{134

135}, Hsien-Chih Lin^{7

135}, Jie Liu¹³⁶, Bao Song¹³⁶, Norie Sawada¹³⁷, Taiki Yamaji¹³⁸, Kathleen Wyatt^{1

118}, Hongxia Ma^{2

3}, Meng Zhu^{2

3}, Yifan Wang^{2

3}, Tianchen Qi^{2

3}, Xuelian Li^{15

128}, Yangwu Ren^{15

128}, Ann Chao¹³⁹, Motoki Iwasaki^{137

138}, Junjie Zhu³³, Guoping Wu⁶⁵, Chih-Yi Chen^{140

141}, Chien-Jen Chen ScD¹⁴², Pan-Chyr Yang¹⁴³, Victoria L Stevens¹⁴⁴, Joseph F Fraumeni Jr¹, Kuang Lin⁴, Robin G Walters⁴, Zhengming Chen⁴, Nilanjan Chatterjee^{1

145

146}, Olga Y Gorlova^{147

148

149}, Christopher I Amos^{147

148

149

150}, Hongbing Shen^{2

3}, Chao Agnes Hsiung⁷, Stephen J Chanock¹, Nathaniel Rothman¹, Takashi Kohno⁵, Qing Lan¹, Haoyu Zhang¹

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
² Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.
³ Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China.
⁴ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁵ Division of Genome Biology, National Cancer Research Institute, Tokyo, Japan.
⁶ Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
⁷ Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.
⁸ Department of Smart Computing and Applied Mathematics, Tunghai University, Taichung, Taiwan.
⁹ Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada.
¹⁰ Department of Epidemiology and Biostatistics, Key Laboratory of Prevention and Control of Human Major Diseases of the Ministry of Education, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
¹¹ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
¹² Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
¹³ American Cancer Society, Atlanta, GA, USA.
¹⁴ Department of Etiology & Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹⁵ Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.
¹⁶ Department of Clinical Epidemiology and Center of Evidence Based Medicine, The First Hospital of China Medical University, Shenyang, China.
¹⁷ Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
¹⁸ State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Fudan University, Shanghai, China.
¹⁹ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
²⁰ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore.
²¹ National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.
²² Department of Applied Mathematics, National Dong Hwa University, Hualien, Taiwan.
²³ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
²⁴ Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
²⁵ Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
²⁶ Department of Pathology, Queen Mary Hospital, Hong Kong, China.
²⁷ Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
²⁸ Department of Biostatistics, Bioinformatics & Biomathematics, Georgetown University Medical Center, Washington DC, DC, USA.
²⁹ Department of Epidemiology and Cancer Control (Primary) & Department of Computational Biology (Secondary), St Jude Children's Research Hospital, Memphis, TN, USA.
³⁰ Saville Cancer Screening and Prevention Center, Inova Schar Cancer Institute, Inova Health System, Fairfax, VA, USA.
³¹ Department of Integrative Bioscience & Biotechnology, Institute of Bioscience, Sejong University, Seoul, 05006, Republic of Korea.
³² Epidemiology and Community Health Branch, National Heart Lung and Blood Institute, Bethesda, MD, USA.
³³ Shanghai Pulmonary Hospital, Shanghai, China.
³⁴ Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
³⁵ Lung Cancer Clinic, Pulmonary Medicine, Chonnam National University Medical School, Hwasun Hospital, Hwasun, Republic of Korea.
³⁶ Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
³⁷ School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³⁸ Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
³⁹ Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁴⁰ Department of Medical Oncology and Cancer Center, and Center for Advanced Medicine against Cancer, Shiga University of Medical Science, Japan, Shiga.
⁴¹ Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁴² Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
⁴³ Department of Thoracic Surgery, Tokyo Medical and Dental University, Tokyo, Japan.
⁴⁴ Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
⁴⁵ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, USA.
⁴⁶ Department of Medical Oncology, Japanese Red Cross Medical Center, Tokyo, Japan.
⁴⁷ Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.
⁴⁸ Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan.
⁴⁹ Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
⁵⁰ Department of Thoracic Oncology, Division of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan.
⁵¹ Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan.
⁵² RIKEN Center for Integrative Medical Sciences, Laboratory for Statistical Analysis, Japan, Yokohama.
⁵³ Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, Akita, Japan.
⁵⁴ Department of Thoracic Surgery, Graduate School of Medicine, Akita University, Akita, Japan.
⁵⁵ Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan.
⁵⁶ Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁵⁷ Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Science, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
⁵⁸ Department of Molecular Biology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan.
⁵⁹ Division of General Thoracic Surgery, Department of Surgery, Shinshu University School of Medicine Asahi, Nagano, Japan.
⁶⁰ Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan.
⁶¹ Department of Cancer Genome Medicine, Fukushima Medical University Hospital, Fukushima, Japan.
⁶² Department of Integrative center of General Surgery, Gunma University Hospital, Gunma, Japan.
⁶³ Department of Healthcare Quality and Safety, Gunma University Graduate School of Medicine, Gunma, Japan.
⁶⁴ Dept of Occupational and Environmental Health, Key Laboratory for Environment and Health, Ministry of Education and State Key Laboratory of Environmental Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁶⁵ China National Environmental Monitoring Center, Beijing, China.
⁶⁶ Korea University College of Medicine Anam Hospital, Seoul, Republic of Korea.
⁶⁷ Lung Cancer Center, Chonnam National University Hwasun Hospital, Hwasuneup, Republic of Korea.
⁶⁸ Department of Clinical Oncology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
⁶⁹ School of Medicine and Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
⁷⁰ Lung Cancer Diagnosis & Treatment Research Center, Chung Shan Medical University Hospital, Taichung, Taiwan.
⁷¹ Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
⁷² Department of Internal Medicine, Division of Chest Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
⁷³ Department of Pulmonary and Critical Care, Xiamen Chang Gung Hospital, Xiamen, China.
⁷⁴ Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
⁷⁵ Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁷⁶ Department of Chest Medicine, Taipei Veterans General Hospital, and School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁷⁷ Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea.
⁷⁸ Jeonnam Regional Cancer Center, Chonnam National University, Hwasun, Republic of Korea.
⁷⁹ Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China.
⁸⁰ Lab of Human Genomics, Genome Institute of Singapore, A*STAR, Singapore, Singapore.
⁸¹ Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore, Singapore.
⁸² Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
⁸³ Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
⁸⁴ Department of Medicine, Section of Epidemiology and Population Science, Institute for Clinical and Translational Research, Houston, TX, USA.
⁸⁵ School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
⁸⁶ Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, AZ, USA.
⁸⁷ Department of Integrative Oncology, BC Cancer, Vancouver, BC, Canada.
⁸⁸ Health Research Institute of Asturias (ISPA), IUOPA University of Oviedo and University Nebrija, Spain.
⁸⁹ Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁹⁰ Department Of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁹¹ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
⁹² International Agency for Research on Cancer (IARC/WHO), Lyon, France.
⁹³ German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁹⁴ Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
⁹⁵ Department of Biosciences and Medical Biology and Center for Tumorbiology and Immunology (CTBI), University of Salzburg and Cancer Cluster Salzburg, Salzburg, Austria.
⁹⁶ University Medical Center Goettingen, Goettingen, Germany.
⁹⁷ Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University, Munich, Germany.
⁹⁸ Helmholtz Center Munich, Institute of Epidemiology, Munich, Germany.
⁹⁹ Harvard TH Chan School of Public Health, Boston, MA, USA.
¹⁰⁰ Technion-Israel Institute of Technology and APRPM, Haifa, Israel.
¹⁰¹ Markey Cancer Center, Lexington, KY, USA.
¹⁰² University of Liverpool, Liverpool, UK.
¹⁰³ The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
¹⁰⁴ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
¹⁰⁵ Princess Margaret Cancer Center, Toronto, ON, Canada.
¹⁰⁶ Norris Cotton Cancer Center, Lebanon, NH, USA.
¹⁰⁷ Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁰⁸ National Institute of Occupational Health, Oslo, Norway.
¹⁰⁹ Department of Medical Biosciences, Umeå University, Umeå, Sweden.
¹¹⁰ Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK.
¹¹¹ University of Sheffield, Sheffield, UK.
¹¹² UPMC Hillman Cancer Center and Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
¹¹³ Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, SUNY University at Buffalo, NY, USA.
¹¹⁴ Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
¹¹⁵ Department of Medicine, Division of Genetic Medicine and Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹¹⁶ Cancer Research Center, Kyungpook National University Medical Center, Daegu, Republic of Korea.
¹¹⁷ Department of Mathematics, University of Taipei, Taipei, Taiwan.
¹¹⁸ Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc, Rockville, MD, USA.
¹¹⁹ Division of Applied Oral Sciences & Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China.
¹²⁰ State Key LaState Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.
¹²¹ Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA, San Francisco.
¹²² Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
¹²³ Department of Internal Medicine, Division of Oncology/Hematology, College of Medicine, Korea University Anam Hospital, Seoul, Republic of Korea.
¹²⁴ Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
¹²⁵ Department of Thoracic and Cardiovascular Surgery, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
¹²⁶ The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
¹²⁷ School of Public Health, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
¹²⁸ Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, China.
¹²⁹ Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan.
¹³⁰ Gleneagles Hong Kong Hospital, Hong Kong, China.
¹³¹ Division of Environmental Epidemiology, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, The Netherlands.
¹³² Department of Pulmonary and Critical Care Medicine Zhongshan Hospital, Fudan University Shanghai Geriatric Medical Center, Shanghai, China.
¹³³ Department of Pathology, Queen Elizabeth Hospital, Hong Kong, China.
¹³⁴ Qujing Center for Diseases Control and Prevention, Qujing, China.
¹³⁵ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
¹³⁶ Department of Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, China.
¹³⁷ Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
¹³⁸ Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
¹³⁹ Center for Global Health, National Cancer Institute, Bethesda, MD, USA.
¹⁴⁰ Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
¹⁴¹ Department of Surgery, Division of Thoracic Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan.
¹⁴² Genomic Research Center, Academia Sinica, Taipei, Taiwan.
¹⁴³ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
¹⁴⁴ Laboratory Services, American Cancer Society, Georgia, USA.
¹⁴⁵ Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹⁴⁶ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁴⁷ Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA.
¹⁴⁸ Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
¹⁴⁹ Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
¹⁵⁰ University of New Mexico, Comprehensive Cancer Center, Albuquerque, NM, USA.

PMID: 41032288
DOI: 10.1093/jnci/djaf272

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

Batel Blechter et al. J Natl Cancer Inst. 2025.

. 2025 Oct 1:djaf272.

doi: 10.1093/jnci/djaf272. Online ahead of print.

Authors

Affiliations

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
² Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.
³ Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China.
⁴ Nuffield Department of Population Health, University of Oxford, Oxford, UK.
⁵ Division of Genome Biology, National Cancer Research Institute, Tokyo, Japan.
⁶ Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan.
⁷ Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan.
⁸ Department of Smart Computing and Applied Mathematics, Tunghai University, Taichung, Taiwan.
⁹ Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, Canada.
¹⁰ Department of Epidemiology and Biostatistics, Key Laboratory of Prevention and Control of Human Major Diseases of the Ministry of Education, Key Laboratory of Molecular Cancer Epidemiology of Tianjin, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China.
¹¹ Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center and Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
¹² Department of Thoracic and Cardiovascular Surgery, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea.
¹³ American Cancer Society, Atlanta, GA, USA.
¹⁴ Department of Etiology & Carcinogenesis and State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
¹⁵ Department of Epidemiology, School of Public Health, China Medical University, Shenyang, China.
¹⁶ Department of Clinical Epidemiology and Center of Evidence Based Medicine, The First Hospital of China Medical University, Shenyang, China.
¹⁷ Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China.
¹⁸ State Key Laboratory of Genetics and Development of Complex Phenotypes, School of Life Sciences, Fudan University, Shanghai, China.
¹⁹ Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore.
²⁰ Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore.
²¹ National Institute of Cancer Research, National Health Research Institutes, Zhunan, Taiwan.
²² Department of Applied Mathematics, National Dong Hwa University, Hualien, Taiwan.
²³ Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
²⁴ Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
²⁵ Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital & Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China.
²⁶ Department of Pathology, Queen Mary Hospital, Hong Kong, China.
²⁷ Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
²⁸ Department of Biostatistics, Bioinformatics & Biomathematics, Georgetown University Medical Center, Washington DC, DC, USA.
²⁹ Department of Epidemiology and Cancer Control (Primary) & Department of Computational Biology (Secondary), St Jude Children's Research Hospital, Memphis, TN, USA.
³⁰ Saville Cancer Screening and Prevention Center, Inova Schar Cancer Institute, Inova Health System, Fairfax, VA, USA.
³¹ Department of Integrative Bioscience & Biotechnology, Institute of Bioscience, Sejong University, Seoul, 05006, Republic of Korea.
³² Epidemiology and Community Health Branch, National Heart Lung and Blood Institute, Bethesda, MD, USA.
³³ Shanghai Pulmonary Hospital, Shanghai, China.
³⁴ Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.
³⁵ Lung Cancer Clinic, Pulmonary Medicine, Chonnam National University Medical School, Hwasun Hospital, Hwasun, Republic of Korea.
³⁶ Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea.
³⁷ School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³⁸ Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
³⁹ Center for Antibody and Vaccine Therapy, Research Hospital, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁴⁰ Department of Medical Oncology and Cancer Center, and Center for Advanced Medicine against Cancer, Shiga University of Medical Science, Japan, Shiga.
⁴¹ Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
⁴² Laboratory of Complex Trait Genomics, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
⁴³ Department of Thoracic Surgery, Tokyo Medical and Dental University, Tokyo, Japan.
⁴⁴ Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
⁴⁵ Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, USA.
⁴⁶ Department of Medical Oncology, Japanese Red Cross Medical Center, Tokyo, Japan.
⁴⁷ Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.
⁴⁸ Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan.
⁴⁹ Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
⁵⁰ Department of Thoracic Oncology, Division of Thoracic Surgery, National Cancer Center Hospital East, Kashiwa, Japan.
⁵¹ Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan.
⁵² RIKEN Center for Integrative Medical Sciences, Laboratory for Statistical Analysis, Japan, Yokohama.
⁵³ Department of Cellular and Organ Pathology, Graduate School of Medicine, Akita University, Akita, Japan.
⁵⁴ Department of Thoracic Surgery, Graduate School of Medicine, Akita University, Akita, Japan.
⁵⁵ Department of Preventive Medicine, Faculty of Medicine, Saga University, Saga, Japan.
⁵⁶ Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁵⁷ Laboratory of Clinical Genome Sequencing, Department of Computational Biology and Medical Science, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
⁵⁸ Department of Molecular Biology, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan.
⁵⁹ Division of General Thoracic Surgery, Department of Surgery, Shinshu University School of Medicine Asahi, Nagano, Japan.
⁶⁰ Department of Chest Surgery, Fukushima Medical University, Fukushima, Japan.
⁶¹ Department of Cancer Genome Medicine, Fukushima Medical University Hospital, Fukushima, Japan.
⁶² Department of Integrative center of General Surgery, Gunma University Hospital, Gunma, Japan.
⁶³ Department of Healthcare Quality and Safety, Gunma University Graduate School of Medicine, Gunma, Japan.
⁶⁴ Dept of Occupational and Environmental Health, Key Laboratory for Environment and Health, Ministry of Education and State Key Laboratory of Environmental Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁶⁵ China National Environmental Monitoring Center, Beijing, China.
⁶⁶ Korea University College of Medicine Anam Hospital, Seoul, Republic of Korea.
⁶⁷ Lung Cancer Center, Chonnam National University Hwasun Hospital, Hwasuneup, Republic of Korea.
⁶⁸ Department of Clinical Oncology, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
⁶⁹ School of Medicine and Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
⁷⁰ Lung Cancer Diagnosis & Treatment Research Center, Chung Shan Medical University Hospital, Taichung, Taiwan.
⁷¹ Institute of Biomedical Sciences, National Chung Hsing University, Taichung, Taiwan.
⁷² Department of Internal Medicine, Division of Chest Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
⁷³ Department of Pulmonary and Critical Care, Xiamen Chang Gung Hospital, Xiamen, China.
⁷⁴ Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
⁷⁵ Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁷⁶ Department of Chest Medicine, Taipei Veterans General Hospital, and School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.
⁷⁷ Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea.
⁷⁸ Jeonnam Regional Cancer Center, Chonnam National University, Hwasun, Republic of Korea.
⁷⁹ Department of Epidemiology, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China.
⁸⁰ Lab of Human Genomics, Genome Institute of Singapore, A*STAR, Singapore, Singapore.
⁸¹ Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore, Singapore.
⁸² Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA.
⁸³ Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
⁸⁴ Department of Medicine, Section of Epidemiology and Population Science, Institute for Clinical and Translational Research, Houston, TX, USA.
⁸⁵ School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
⁸⁶ Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, AZ, USA.
⁸⁷ Department of Integrative Oncology, BC Cancer, Vancouver, BC, Canada.
⁸⁸ Health Research Institute of Asturias (ISPA), IUOPA University of Oviedo and University Nebrija, Spain.
⁸⁹ Program in Epidemiology, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
⁹⁰ Department Of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
⁹¹ Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
⁹² International Agency for Research on Cancer (IARC/WHO), Lyon, France.
⁹³ German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁹⁴ Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
⁹⁵ Department of Biosciences and Medical Biology and Center for Tumorbiology and Immunology (CTBI), University of Salzburg and Cancer Cluster Salzburg, Salzburg, Austria.
⁹⁶ University Medical Center Goettingen, Goettingen, Germany.
⁹⁷ Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University, Munich, Germany.
⁹⁸ Helmholtz Center Munich, Institute of Epidemiology, Munich, Germany.
⁹⁹ Harvard TH Chan School of Public Health, Boston, MA, USA.
¹⁰⁰ Technion-Israel Institute of Technology and APRPM, Haifa, Israel.
¹⁰¹ Markey Cancer Center, Lexington, KY, USA.
¹⁰² University of Liverpool, Liverpool, UK.
¹⁰³ The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
¹⁰⁴ Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
¹⁰⁵ Princess Margaret Cancer Center, Toronto, ON, Canada.
¹⁰⁶ Norris Cotton Cancer Center, Lebanon, NH, USA.
¹⁰⁷ Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁰⁸ National Institute of Occupational Health, Oslo, Norway.
¹⁰⁹ Department of Medical Biosciences, Umeå University, Umeå, Sweden.
¹¹⁰ Division of Clinical Medicine, School of Medicine and Population Health, University of Sheffield, Sheffield, UK.
¹¹¹ University of Sheffield, Sheffield, UK.
¹¹² UPMC Hillman Cancer Center and Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.
¹¹³ Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, SUNY University at Buffalo, NY, USA.
¹¹⁴ Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
¹¹⁵ Department of Medicine, Division of Genetic Medicine and Clinical Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
¹¹⁶ Cancer Research Center, Kyungpook National University Medical Center, Daegu, Republic of Korea.
¹¹⁷ Department of Mathematics, University of Taipei, Taipei, Taiwan.
¹¹⁸ Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc, Rockville, MD, USA.
¹¹⁹ Division of Applied Oral Sciences & Community Dental Care, Faculty of Dentistry, The University of Hong Kong, Hong Kong, China.
¹²⁰ State Key LaState Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, China.
¹²¹ Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, USA, San Francisco.
¹²² Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
¹²³ Department of Internal Medicine, Division of Oncology/Hematology, College of Medicine, Korea University Anam Hospital, Seoul, Republic of Korea.
¹²⁴ Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
¹²⁵ Department of Thoracic and Cardiovascular Surgery, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
¹²⁶ The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
¹²⁷ School of Public Health, Li Ka Shing (LKS) Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
¹²⁸ Key Laboratory of Cancer Etiology and Intervention, University of Liaoning Province, Shenyang, China.
¹²⁹ Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan.
¹³⁰ Gleneagles Hong Kong Hospital, Hong Kong, China.
¹³¹ Division of Environmental Epidemiology, Institute for Risk Assessment Sciences (IRAS), Utrecht University, Utrecht, The Netherlands.
¹³² Department of Pulmonary and Critical Care Medicine Zhongshan Hospital, Fudan University Shanghai Geriatric Medical Center, Shanghai, China.
¹³³ Department of Pathology, Queen Elizabeth Hospital, Hong Kong, China.
¹³⁴ Qujing Center for Diseases Control and Prevention, Qujing, China.
¹³⁵ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
¹³⁶ Department of Oncology, Shandong Cancer Hospital and Institute, Shandong Academy of Medical Sciences, Jinan, China.
¹³⁷ Division of Cohort Research, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
¹³⁸ Division of Epidemiology, National Cancer Center Institute for Cancer Control, Tokyo, Japan.
¹³⁹ Center for Global Health, National Cancer Institute, Bethesda, MD, USA.
¹⁴⁰ Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
¹⁴¹ Department of Surgery, Division of Thoracic Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan.
¹⁴² Genomic Research Center, Academia Sinica, Taipei, Taiwan.
¹⁴³ Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
¹⁴⁴ Laboratory Services, American Cancer Society, Georgia, USA.
¹⁴⁵ Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
¹⁴⁶ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
¹⁴⁷ Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, TX, USA.
¹⁴⁸ Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
¹⁴⁹ Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA.
¹⁵⁰ University of New Mexico, Comprehensive Cancer Center, Albuquerque, NM, USA.

PMID: 41032288
DOI: 10.1093/jnci/djaf272

Abstract

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 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.

Conclusions: Multi-ancestry PRS approaches enhance LUAD risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

Keywords: East Asian never smokers; Genome-wide association studies; Lifetime absolute risk; Lung adenocarcinoma; Polygenic risk scores.

Published by Oxford University Press 2025.

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

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

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Abstract

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