A YAP1 mutation is a germline risk allele for lung adenocarcinoma According to statistics from the Ministry of Health and Welfare in Taiwan, lung cancer is the leading cause of death among malignancies. In non-smokers, lung adenocarcinoma is the predominant histologic type. However, early diagnosis of lung adenocarcinoma is difficult because there are no obvious symptoms and no history of smoking. Because early symptoms of lung adenocarcinoma are vague, genetic factors may be useful for screening. Compared with hereditary factors in many other human neoplastic diseases, the role of hereditary factors in lung cancer is still poorly understood. Genome-wide association studies (GWASs) have identified some common genetic variants, including 15q25, 6p21, and 5p15, that confer susceptibility to lung adenocarcinoma. However, these variants are common alleles, with allelic frequencies higher than 20%. In addition, the penetrance is also low, which means that only a few people with these genetic variants will develop lung adenocarcinoma. Taken together, these genetic variants are of limited clinical utility . Therefore, it is important to identify potential actionable alleles to identify patients with lung adenocarcinoma. In July 2015, Professor Yang and colleagues published their study in the Journal of Clinical Oncology concerning the identification of genes associated with lung adenocarcinoma using whole-genome sequencing. Previously, whole-genome sequencing was a time-consuming process; the Human Genome Project took nearly 13 years to complete. However, technological advances have decreased the processing time of whole-genome sequencing to only 1 week. To determine target genes in lung cancer, whole-genome sequencing was performed in a family with an unusually high incidence of lung adenocarcinoma using available DNA from the affected mother, four affected daughters and one unaffected son. After screening and comparison, one allele located on chromosome 11q of the oncogene YAP1 was associated with lung adenocarcinoma development. The allele had an R to W mutation at position 331.. Next, a cohort of 1135 participants without cancer and 1312 patients with lung carcinoma was used for YAP1 genotyping. The results revealed that the allele carriers had an increased risk for lung adenocarcinoma, with an adjusted odds ratio of 5.9. Furthermore, only a few people in the control group (0.18%) carried the allele. Finally, a family follow-up study of the relatives of YAP1 mutation carriers was performed using genotyping. In this study, 13 YAP1 allele carriers were genotyped; four were diagnosed with lung adenocarcinoma and six developed ground glass opacity lung lesions that were identified using CT imaging. Based on the results, YAP1 mutation carriers have a higher frequency of developing lung lesions. This study revealed that the YAP1 R331W mutation plays an important role in lung adenocarcinoma and has high penetrance. Allele carriers should receive regular low-dose CT screening 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