YAP1 mutation is a germline risk allele for lung adenocarcinoma According to the statistics from Ministry of Health and Welfare in Taiwan, lung cancer is the leading cause of death among malignancies. Among non-smokers, lung adenocarcinoma is the predominant histologic type. However, lacking obvious symptoms and smoking history, early diagnosis is of great difficulty. As early symptoms are vague, genetic factors may be another guide for screening. Compared with heredity factors in many other human neoplastic disease, the role of genetic factors in lung cancer is still poorly understood. Genome-wide association studies (GWAS) have helped identify some common genetic variants, including 15q25, 6p21, and 5p15, that indicate susceptibility to lung adenocarcinoma. However, these variants are quite common alleles, with frequencies higher than 20%. Besides, the penetrance is also low, which means only few people with these genes develop lung adenocarcinoma. Taken these into consideration, further clinical action was hindered. Thus, identifying alleles with potential medical actionability is of great importance. On 2015 July, Professor Yang and colleagues published their study, mainly about the identification of genes associated with lung adenocarcinoma via the whole genome sequencing analysis, on Journal of Clinical Oncology. Whole genome sequencing used to be a time-consuming process, and it took almost 13 years in the Human Genome Project. However, as technology advances, it takes only 1 week to sequence the whole genome. In pursuing the target gene, 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 unaffected son. After series of screening and comparison, one allele located in chromosome 11q of the oncogene YAP1, causing the R to W mutation at position 331 was identified. Next, a cohort of 1135 participants without cancer and 1312 patients with lung carcinoma was obtained for YAP1 genotyping. The results revealed the allele carriers had an increased risk for lung adenocarcinoma and the adjusted odds ratio was 5.9. Furthermore, only few people (0.18%) carried the allele in the control group. At last, a family follow-up study by genotyping the relatives of YAP1 mutation carriers was performed. A total thirteen YAP1 allele carriers were obtained, with four diagnosed with lung adenocarcinoma and six developed ground glass opacity lung lesions on CT image. Based on the results, YAP1 mutation was shown to have higher frequencies of developing lung lesions. This study revealed that YAP1 R331W mutation played an important role in lung adenocarcinoma with high penetrance. Allele carriers should receive low dose CT screening regularly for early detection and treatment. Reference 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 Chuang, Shinsheng 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 and Ker-Chau Li. 2015a. R331W missense mutation of oncogene YAP1 is a germline risk allele for lung adenocarcinoma with medical actionability. J Clin. Oncol. 33:2303–2310. DOI:10.1200/ JCO.2014.59.3590. Professor Pan-Chyr Yang Center of Genomic Medicine, National Taiwan University Hospital pcyang@ntu.edu.tw