Hsuan-Yu Chen1, Sung-Liang Yu1, Bing-Ching Ho1, Kang-Yi Su1, Yi-Chiung Hsu1, Chi-Sheng Chang1, Yu-Cheng Li1, Shi-Yi Yang1, Pin-Yen Hsu1, Hao Ho1, Ya-Hsuan Chang1, Chih-Yi Chen1, Hwai-I Yang1, Chung-Ping Hsu1, Tsung-Ying Yang1, Kun-Chieh Chen1, Kuo-Hsuan Hsu1, Jeng-Sen Tseng1, Jiun-Yi Hsia1, Cheng-Yen Chuang1, Shinsheng Yuan1, Mei-Hsuan Lee1, Chia-Hsin Liu1, Guan-I Wu1, Chao A Hsiung1, Yuh-Min Chen1, Chih-Liang Wang1, Ming-Shyan Huang1, Chong-Jen Yu1, Kuan-Yu Chen1, Ying-Huang Tsai1, Wu-Chou Su1, Huei-Wen Chen1, Jeremy J W Chen1, Chien-Jen Chen1, Gee-Chen Chang2, Pan-Chyr Yang1, Ker-Chau Li1. 1. Hsuan-Yu Chen, Yi-Chiung Hsu, Chi-Sheng Chang, Yu-Cheng Li, Hao Ho, Ya-Hsuan Chang, Shinsheng Yuan, Chia-Hsin Liu, Guan-I Wu, and Ker-Chau Li, Institute of Statistical Science, and Shi-Yi Yang, Hwai-I Yang, and Chien-Jen Chen, Genomics Research Center, Academia Sinica; Hsuan-Yu Chen, Sung-Liang Yu, Bing-Ching Ho, Kang-Yi Su, and Pin-Yen Hsu, College of Medicine; Hsuan-Yu Chen, College of Life Science; Sung-Liang Yu, Kang-Yi Su, and Pan-Chyr Yang, Center of Genomic Medicine; Huei-Wen Chen, Graduate Institute of Toxicology, National Taiwan University; Sung-Liang Yu, Chong-Jen Yu, Kuan-Yu Chen, and Pan-Chyr Yang, National Taiwan University Hospital; Yuh-Min Chen, Taipei Veterans General Hospital; Chung-Ping Hsu, Tsung-Ying Yang, and Gee-Chen Chang, School of Medicine, National Yang-Ming University; Mei-Hsuan Lee, Institute of Clinical Medicine, National Yang-Ming University, Taipei; Chih-Yi Chen, Chung Shan Medical University; Chung-Ping Hsu, Tsung-Ying Yang, Kun-Chieh Chen, Kuo-Hsuan Hsu, Jeng-Sen Tseng, Jiun-Yi Hsia, Cheng-Yen Chuang, and Gee-Chen Chang, Taichung Veterans General Hospital; Kun-Chieh Chen, Kuo-Hsuan Hsu, Jeng-Sen Tseng, and Jeremy J.W. Chen, Institute of Biomedical Sciences, National Chung-Hsing University; Gee-Chen Chang, Comprehensive Cancer Center, Taichung Veterans General Hospital, Taichung; Chao A. Hsiung, Institute of Population Health Sciences, National Health Research Institutes, Zhunan; Chih-Liang Wang, Chang Gung Memorial Hospital, Tao-Yuan; Ying-Huang Tsai, Chang-Gung Memorial Hospital, Chia-Yi; Ming-Shyan Huang, Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung; Wu-Chou Su, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; and Ker-Chau Li, University of California Los Angeles, Los Angeles, CA. 2. Hsuan-Yu Chen, Yi-Chiung Hsu, Chi-Sheng Chang, Yu-Cheng Li, Hao Ho, Ya-Hsuan Chang, Shinsheng Yuan, Chia-Hsin Liu, Guan-I Wu, and Ker-Chau Li, Institute of Statistical Science, and Shi-Yi Yang, Hwai-I Yang, and Chien-Jen Chen, Genomics Research Center, Academia Sinica; Hsuan-Yu Chen, Sung-Liang Yu, Bing-Ching Ho, Kang-Yi Su, and Pin-Yen Hsu, College of Medicine; Hsuan-Yu Chen, College of Life Science; Sung-Liang Yu, Kang-Yi Su, and Pan-Chyr Yang, Center of Genomic Medicine; Huei-Wen Chen, Graduate Institute of Toxicology, National Taiwan University; Sung-Liang Yu, Chong-Jen Yu, Kuan-Yu Chen, and Pan-Chyr Yang, National Taiwan University Hospital; Yuh-Min Chen, Taipei Veterans General Hospital; Chung-Ping Hsu, Tsung-Ying Yang, and Gee-Chen Chang, School of Medicine, National Yang-Ming University; Mei-Hsuan Lee, Institute of Clinical Medicine, National Yang-Ming University, Taipei; Chih-Yi Chen, Chung Shan Medical University; Chung-Ping Hsu, Tsung-Ying Yang, Kun-Chieh Chen, Kuo-Hsuan Hsu, Jeng-Sen Tseng, Jiun-Yi Hsia, Cheng-Yen Chuang, and Gee-Chen Chang, Taichung Veterans General Hospital; Kun-Chieh Chen, Kuo-Hsuan Hsu, Jeng-Sen Tseng, and Jeremy J.W. Chen, Institute of Biomedical Sciences, National Chung-Hsing University; Gee-Chen Chang, Comprehensive Cancer Center, Taichung Veterans General Hospital, Taichung; Chao A. Hsiung, Institute of Population Health Sciences, National Health Research Institutes, Zhunan; Chih-Liang Wang, Chang Gung Memorial Hospital, Tao-Yuan; Ying-Huang Tsai, Chang-Gung Memorial Hospital, Chia-Yi; Ming-Shyan Huang, Kaohsiung Medical University Hospital, College of Medicine, Kaohsiung Medical University, Kaohsiung; Wu-Chou Su, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; and Ker-Chau Li, University of California Los Angeles, Los Angeles, CA. august@vghtc.gov.tw.
Abstract
PURPOSE: Adenocarcinoma is the most dominant type of lung cancer in never-smoker patients. The risk alleles from genome-wide association studies have small odds ratios and unclear biologic roles. Here we have taken an approach featuring suitable medical actionability to identify alleles with low population frequency but high disease-causing potential. PATIENTS AND METHODS: Whole-genome sequencing was performed for a family with an unusually high density of lung adenocarcinoma with available DNA from the affected mother, four affected daughters, and one nonaffected son. Candidate risk alleles were confirmed by matrix-assisted laser desorption ionization time of flight mass spectroscopy. Validation was conducted in an external cohort of 1,135 participants without cancer and 1,312 patients with lung adenocarcinoma. Family follow-ups were performed by genotyping the relatives of the original proband and the relatives of the identified risk-allele carriers. Low-dose computed tomography scans of the chest were evaluated for lung abnormalities. RESULTS: YAP1 R331W missense mutation from the original family was identified and validated in the external controls and the cohort with lung adenocarcinoma. The YAP1 mutant-allele carrier frequency was 1.1% in patients with lung adenocarcinoma compared with 0.18% in controls (P = .0095), yielding an odds ratio (adjusted for age, sex, and smoking status) of 5.9. Among the relatives, YAP1-mutant carriers have overwhelmingly higher frequencies of developing lung adenocarcinoma or ground-glass opacity lung lesions than those who do not carry the mutation (10:0 v 1:7; P < .001). YAP1 mutation was shown to increase the colony formation ability and invasion potential of lung cancer cells. CONCLUSION: These results implicated YAP1 R331W as an allele predisposed for lung adenocarcinoma with high familial penetrance. Low-dose computed tomography scans may be recommended to this subpopulation, which is at high risk for lung cancer, for personalized prevention and health management.
PURPOSE:Adenocarcinoma is the most dominant type of lung cancer in never-smoker patients. The risk alleles from genome-wide association studies have small odds ratios and unclear biologic roles. Here we have taken an approach featuring suitable medical actionability to identify alleles with low population frequency but high disease-causing potential. PATIENTS AND METHODS: Whole-genome sequencing was performed for a family with an unusually high density of lung adenocarcinoma with available DNA from the affected mother, four affected daughters, and one nonaffected son. Candidate risk alleles were confirmed by matrix-assisted laser desorption ionization time of flight mass spectroscopy. Validation was conducted in an external cohort of 1,135 participants without cancer and 1,312 patients with lung adenocarcinoma. Family follow-ups were performed by genotyping the relatives of the original proband and the relatives of the identified risk-allele carriers. Low-dose computed tomography scans of the chest were evaluated for lung abnormalities. RESULTS:YAP1R331W missense mutation from the original family was identified and validated in the external controls and the cohort with lung adenocarcinoma. The YAP1 mutant-allele carrier frequency was 1.1% in patients with lung adenocarcinoma compared with 0.18% in controls (P = .0095), yielding an odds ratio (adjusted for age, sex, and smoking status) of 5.9. Among the relatives, YAP1-mutant carriers have overwhelmingly higher frequencies of developing lung adenocarcinoma or ground-glass opacity lung lesions than those who do not carry the mutation (10:0 v 1:7; P < .001). YAP1 mutation was shown to increase the colony formation ability and invasion potential of lung cancer cells. CONCLUSION: These results implicated YAP1R331W as an allele predisposed for lung adenocarcinoma with high familial penetrance. Low-dose computed tomography scans may be recommended to this subpopulation, which is at high risk for lung cancer, for personalized prevention and health management.
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