R331W Missense Mutation of Oncogene YAP1 Is a Germline Risk Allele for Lung Adenocarcinoma With Medical Actionability.

Authors: Chen, Hsuan-Yu and Yu, Sung-Liang and Ho, Bing-Ching and Su, Kang-Yi and Hsu, Yi-Chiung and Chang, Chi-Sheng and Li, Yu-Cheng and Yang, Shi-Yi and Hsu, Pin-Yen and Ho, Hao and Chang, Ya-Hsuan and Chen, Chih-Yi and Yang, Hwai-I and Hsu, Chung-Ping and Yang, Tsung-Ying and Chen, Kun-Chieh and Hsu, Kuo-Hsuan and Tseng, Jeng-Sen and Hsia, Jiun-Yi and Chuang, Cheng-Yen and Yuan, Shinsheng and Lee, Mei-Hsuan and Liu, Chia-Hsin and Wu, Guan-I and Hsiung, Chao A and Chen, Yuh-Min and Wang, Chih-Liang and Huang, Ming-Shyan and Yu, Chong-Jen and Chen, Kuan-Yu and Tsai, Ying-Huang and Su, Wu-Chou and Chen, Huei-Wen and Chen, Jeremy J W and Chen, Chien-Jen and Chang, Gee-Chen and Yang, Pan-Chyr and Li, Ker-Chau

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.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.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.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. © 2015 by American Society of Clinical Oncology.

Journal: Journal of clinical oncology
DOI: 10.1200/JCO.2014.59.3590
Year: 2015

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