ABSTRACT
Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.
Subject(s)
Humans , Adenocarcinoma of Lung/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Squamous Cell/genetics , Genetic Heterogeneity , Genetic Predisposition to Disease , Genome-Wide Association Study , Lung Neoplasms/genetics , Polymorphism, Single NucleotideABSTRACT
ImportanceOur study helps fill the knowledge gap related to work-related transmission in the emerging coronaviral pandemic. ObjectiveTo demonstrate high-risk occupations for early coronavirus disease 2019 (Covid-19) local transmission. MethodsIn this observational study, we extracted confirmed Covid-19 cases from governmental investigation reports in Hong Kong, Japan, Singapore, Taiwan, Thailand, and Vietnam. We followed each country/area for 40 days after its first locally transmitted case, and excluded all imported cases. We defined a possible work-related case as a worker with evidence of close contact with another confirmed case due to work, or an unknown contact history but likely to be infected in the working environment (e.g. an airport taxi driver). We calculated the case number for each occupation, and illustrated the temporal distribution of all possible work-related cases and healthcare worker (HCW) cases. The temporal distribution was further defined as early outbreak (the earliest 10 days of the following period) and late outbreak (11th to 40th days of the following period). ResultsWe identified 103 possible work-related cases (14.9%) among a total of 690 local transmissions. The five occupation groups with the most cases were healthcare workers (HCWs) (22%), drivers and transport workers (18%), services and sales workers (18%), cleaning and domestic workers (9%) and public safety workers (7%). Possible work-related transmission played a substantial role in early outbreak (47.7% of early cases). Occupations at risk varied from early outbreak (predominantly services and sales workers, drivers, construction laborers, and religious professionals) to late outbreak (predominantly HCWs, drivers, cleaning and domestic workers, police officers, and religious professionals). ConclusionsWork-related transmission is considerable in early Covid-19 outbreaks, and the elevated risk of infection was not limited to HCW. Implementing preventive/surveillance strategies for high-risk working populations is warranted.
ABSTRACT
Lung cancer is the leading cause of cancer death worldwide, with large variation of the incidence and mortality across regions. Although the mortality of lung cancer has been decreasing, or steady in the US, it has been increasing in Asia for the past two decades. Smoking is the leading cause of lung cancer, and other risk factors such as indoor coal burning, cooking fumes, and infections may play important roles in the development of lung cancer among Asian never smoking women. The median age of diagnosis in Asian patients with lung cancer is generally younger than Caucasian patients, particularly among never-smokers. Asians and Caucasians may have different genetic susceptibilities to lung cancer, as evidenced from candidate polymorphisms and genome-wide association studies. Recent epidemiologic studies and clinical trials have shown consistently that Asian ethnicity is a favorable prognostic factor for overall survival in non-small cell lung cancer (NSCLC), independent of smoking status. Compared with Caucasian patients with NSCLC, East Asian patients have a much higher prevalence of epidermal growth factor receptor (EGFR) mutation (approximately 30% vs. 7%, predominantly among patients with adenocarcinoma and never-smokers), a lower prevalence of K-Ras mutation (less than 10% vs. 18%, predominantly among patients with adenocarcinoma and smokers), and higher proportion of patients who are responsive to EGFR tyrosine kinase inhibitors. The ethnic differences in epidemiology and clinical behaviors should be taken into account when conducting global clinical trials that include different ethnic populations.
Subject(s)
Female , Humans , Adenocarcinoma , Ethnology , Genetics , Metabolism , Asian People , Genetics , Carcinoma, Non-Small-Cell Lung , Ethnology , Genetics , Metabolism , White People , Genetics , Asia, Eastern , Epidemiology , Genetic Predisposition to Disease , Lung Neoplasms , Ethnology , Genetics , Metabolism , Mutation , Oncogene Proteins, Fusion , Metabolism , ErbB Receptors , Genetics , Metabolism , Risk Factors , Smoking , United States , Epidemiology , ras Proteins , Genetics , MetabolismABSTRACT
<p><b>BACKGROUND</b>Cigarette smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). However, only 10% - 20% of chronic heavy cigarette smokers develop symptomatic disease. COPD is most likely the result of complex interactions between environmental and genetic factors. Genetic susceptibility to COPD might depend on the variations in enzyme activities that detoxify cigarette smoke products, such as microsomal epoxide hydrolase (mEH) and glutathione S-transferase (GST). In this study, we investigated the relationship between polymorphisms in the genes encoding mEH and glutathione S-transferase P1 (GSTP1) and COPD in a Chinese population.</p><p><b>METHODS</b>Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was performed to find mEH polymorphism in exon 3 (Tyr113-->His), exon 4 (His139-->Arg) and GSTP1 polymorphism in exon 5 (Ile105-->Val) in 100 COPD patients and 100 age- and sex-matched healthy controls.</p><p><b>RESULTS</b>The proportion of mEH exon 3 heterozygotes was significantly higher in patients with COPD than that in the control subjects (42% vs 32%). The odds ratio (OR) adjusted by age, sex, body mass index (BMI) and cigarette years was 2.96 (95% CI 1.24 - 7.09). There was no marked difference in very slow activity genotype versus other genotypes between COPD patients and the controls. When COPD patients were non-smokers, the OR of very slow activity genotype versus other genotypes was more than 1.00; and when COPD patients were smokers (current smokers and ex-smokers), the OR was less than 1.00. There was no significant difference in GSTP1 polymorphism adjusted by age, sex, BMI and smoking between COPD patients and the controls.</p><p><b>CONCLUSIONS</b>mEH exon 3 heterozygotes might be associated with susceptibility to COPD in China. The interaction might exist between mEH genotype and smoke. The gene polymorphism for GSTP1 might not be associated with susceptibility to COPD in the Chinese population.</p>
