R331W missense mutation of oncogene YAP1 is a germline risk allele for lung adenocarcinoma with medical actionability

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

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


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.

Original languageEnglish
Pages (from-to)2303-2310
Number of pages8
JournalJournal of Clinical Oncology
Issue number20
StatePublished - 10 Jul 2015


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