Chih Liang Wang

R331W Missense Mutation of Oncogene YAP1 Is a Germline Risk Allele for Lung Adenocarcinoma With Medical Actionability

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.

Characteristics of young lung cancer: Analysis of Taiwan's nationwide lung cancer registry focusing on epidermal growth factor receptor mutation and smoking status

Lung cancer is relatively rare in young patients as the median age at diagnosis is 65–70 years. The main objective of this nationwide study was to investigate the characteristics of young lung cancer in Taiwan, especially the relationships among smoking behavior, epidermal growth factor receptor (EGFR) mutation, and age. The National Taiwan Lung Cancer Registry, a database contain detailed cancer statistics, was analyzed in this study for the period 2011–2012. Young lung cancer was defined as age ≦ 45 years. There were 21,536 lung cancer patients (13,187 men and 8349 women). Among these patients, 1074 (5.0%) were in the younger group, and 20,462 patients (95.0%) were in the older group. Female gender (48.8% versus 38.2%, P < 0.001), never-smokers (47.3% versus 43.8%, P = 0.015), and adenocarcinoma (70.4% versus 58.1%, P < 0.001) were more frequent in the younger group. While the EGFR mutation rate was lower in the younger group (52.5% versus 60.6%, P = 0.001), the primary site of lung cancer and stage distribution were not significantly different. If only adenocarcinoma patients were included in the analysis, female gender, older age, and never-smokers were more likely to have EGFR mutation. In conclusion, lung cancer in young patients (≦ 45 year-old) was associated with unique characteristics, with greater percentages of female patients, adenocarcinoma, and never-smokers and a lower EGFR mutation rate compared with older patients.

Consensus on dignosis for ALK positive non-small cell lung cancer in China, the 2013 version

随着分子医学进展和靶向药物的不断涌现,晚期非小细胞肺癌(NSCLC)的治疗已进入到个体化治疗的时代.目前临床应用的个体化靶向治疗主要针对表皮生长因子受体(EGFR)基因突变性和间变性淋巴瘤激酶(ALK)融合基因阳性肺癌,这两种基因变异型肺癌均具有明确的分子靶点、靶点检测技术及上市的靶向药物,临床疗效得到明显提高。

EGFR mutation, smoking, and gender in advanced lung adenocarcinoma

Purpose In the current targeted therapy era, information on the effect of smoking in epidermal growth factor receptor (EGFR)-mutant lung cancer patients is scarce. Results In total, 11,678 adenocarcinoma patients were enrolled. Of these, 33.3% and 91.8% of male and female patients were non-smokers, respectively. An increased amount of smoking (P < 0.001 for trend), fewer smoke-free years (P < 0.001 for trend), and younger age of smoking initiation (P = 0.034 for trend) were all associated with significantly lower EGFR mutation rates. Smokers had a shorter median overall survival (OS) among both EGFR-mutant and EGFR-wild type patients (17.8 vs. 21.1 months, and 7.9 vs. 11.4 months respectively; both P < 0.001). Among patients with EGFR-mutant adenocarcinoma, younger smokers were associated with shorter OS (P = 0.047). In multivariate analysis, female gender was an independent prognostic factor for OS (hazard ratio: 0.86 [95% confidence interval {CI}: 0.80–0.93]; P < 0.001 in the EGFR-mutant group and 0.88 [95% CI: 0.81–0.96]; P = 0.004 in the EGFR-wild type group). Materials and Methods We reviewed the National Lung Cancer database (Taiwan) to assess the impact of smoking on the EGFR mutation rate and survival in advanced lung adenocarcinoma patients during 2011 and 2014 retrospectively. Conclusions Smoking was associated with lower incidence of EGFR mutation rate and reduced OS of advanced lung adenocarcinoma patients in a dose-dependent manner. In addition to EGFR mutation and smoking, gender also plays an important role in survival among these patients.

Higher frequency but random distribution of EGFR mutation subtypes in familial lung cancer patients

Despite the advancement of epidermal growth factor receptor (EGFR) inhibitors in lung cancer therapy, it remains unclear whether EGFR mutation status in familial lung cancers is different from that of sporadic cases. In this multicenter retrospective study, we compared both the EGFR mutation frequency and patterns between familial and sporadic cases. The results explored that family history of lung cancer is an independent predictor for higher EGFR mutation rate in 1713 lung adenocarcinoma patients (Odd ratio 1.68, 95% CI 1.06–2.67, P = 0.028). However, the distribution of EGFR mutation subtypes was similar to that of sporadic cases. Part of our study involved 40 lung cancer families with at least 2 tumor tissues available within each single family (n = 88) and there was no familial aggregation pattern in EGFR mutation subtypes. There were two families harboring the YAP1 R331W germline risk allele and EGFR mutation statuses among YAP1 family members also varied. These phenomena may hint at the direction of future research into lung carcinogenesis and EGFR mutagenesis.