Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2015
R331W Missense Mutation of Oncogene YAP1 Is a Germline Risk Allele for Lung Adenocarcinoma With Medical Actionability.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Chen Hsuan-Yu, Yu Sung-Liang, Ho Bing-Ching, Su Kang-Yi, Hsu Yi-Chiung, Chang Chi-Sheng, Li Yu-Cheng, Yang Shi-Yi, Hsu Pin-Yen, Ho Hao, Chang Ya-Hsuan, Chen Chih-Yi, Yang Hwai-I, Hsu Chung-Ping, Yang Tsung-Ying, Chen Kun-Chieh, Hsu Kuo-Hsuan, Tseng Jeng-Sen, Hsia Jiun-Yi, Chuang Cheng-Yen, Yuan Shinsheng, Lee Mei-Hsuan, Liu Chia-Hsin, Wu Guan-I, Hsiung Chao A, Chen Yuh-Min, Wang Chih-Liang, Huang Ming-Shyan, Yu Chong-Jen, Chen Kuan-Yu, Tsai Ying-Huang, Su Wu-Chou, Chen Huei-Wen, Chen Jeremy J W, Chen Chien-Jen, Chang Gee-Chen, Yang Pan-Chyr, Li Ker-Chau
Аннотация
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.
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.
Предметные рубрики MeSH
Adaptor Proteins, Signal TransducingAdenocarcinomaAdenocarcinoma of LungAdultAgedAged, 80 and overBiomarkers, TumorCase-Control StudiesComputational BiologyDNA Mutational AnalysisFemaleGene FrequencyGenetic Predisposition to DiseaseGenome-Wide Association StudyGerm-Line MutationHeredityHumansInfantLogistic ModelsLung NeoplasmsMaleMiddle AgedMultivariate AnalysisMutation, MissenseOdds RatioPedigreePenetrancePhenotypePhosphoproteinsPrecision MedicineRisk FactorsSpectrometry, Mass, Matrix-Assisted Laser Desorption-IonizationTaiwanTomography, X-Ray ComputedTranscription FactorsYAP-Signaling Proteins