R331W missense mutation of oncogene YAP1 is a germline risk allele for lung adenocarcinoma with medical actionability
Journal
Journal of Clinical Oncology
Journal Volume
33
Journal Issue
20
Pages
2303-2310
Date Issued
2015
Author(s)
Chen H.-Y.
Ho B.-C.
Hsu Y.-C.
Chang C.-S.
Li Y.-C.
Yang S.-Y.
Hsu P.-Y.
Ho H.
Chang Y.-H.
Chen C.-Y.
Yang H.-I.
Hsu C.-P.
Yang T.-Y.
Chen K.-C.
Hsu K.-H.
Tseng J.-S.
Hsia J.-Y.
Chuang C.-Y.
Yuan S.
Lee M.-H.
Liu C.-H.
Wu G.-I.
Hsiung C.A.
Chen Y.-M.
Wang C.-L.
Huang M.-S.
Tsai Y.-H.
Su W.-C.
Chen J.J.W.
Chen C.-J.
Chang G.-C.
Li K.-C.
Abstract
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. ? 2015 by American Society of Clinical Oncology.
SDGs
Other Subjects
transcription factor Yap1; phosphoprotein; signal transducing adaptor protein; tumor marker; YAP1 (Yes-associated) protein, human; adult; aged; allele; Article; bioinformatics; cancer cell; cancer growth; cancer risk; chromosome 11q; clinical article; colony formation; computer assisted tomography; controlled study; female; follow up; gene mutation; gene sequence; genetic screening; genotype; germline mutation; human; lung adenocarcinoma; male; matrix assisted laser desorption ionization time of flight mass spectrometry; missense mutation; penetrance; population; priority journal; single nucleotide polymorphism; adenocarcinoma; biology; case control study; gene frequency; genetic association; genetic predisposition; genetics; germline mutation; heredity; infant; lung tumor; mass spectrometry; middle aged; missense mutation; multivariate analysis; nucleotide sequence; pathology; pedigree; personalized medicine; phenotype; procedures; radiography; risk; risk factor; statistical model; Taiwan; very elderly; Adaptor Proteins, Signal Transducing; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Case-Control Studies; Computational Biology; DNA Mutational Analysis; Female; Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Germ-Line Mutation; Heredity; Humans; Individualized Medicine; Infant; Logistic Models; Lung Neoplasms; Male; Middle Aged; Multivariate Analysis; Mutation, Missense; Odds Ratio; Pedigree; Penetrance; Phenotype; Phosphoproteins; Risk Factors; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Taiwan; Tomography, X-Ray Computed; Tumor Markers, Biological
Type
journal article