Background: Exposure to occupational carcinogens is an important preventable cause of lung cancer. Single nucleotide polymorphisms (SNPs) have been reported in association with lung cancer risk, in particular for tobacco smoking exposure. However, few studies have evaluated the interaction between genetic variants and occupational carcinogens in the etiology of lung cancer risk. Aim: The aim of this study is to investigate the interaction between exposures to selected known/suspected occupational carcinogens and phase II metabolic gene polymorphisms for lung cancer risk. Methods: In the Environment And Genetics in Lung cancer Etiology (EAGLE) population-based case-control study (Lombardy region, Italy, 2002-2005), lifetime work-histories were collected by personal interview and coded according to the International Standard Classification for Occupations (ISCO). A job-exposure matrix (JEM) was applied to translate the ISCO codes into never, low, and high exposure levels for six known/suspected occupational lung carcinogens. 293 SNPs tagging 23 phase II metabolic genes were selected to conduct a candidate gene association study based on SNP, gene, haplotype and pathway analyses. Gene expression data were used to evaluate the function of the selected genetic variants. An unconditional logistic regression model, adjusted for potential confounders including smoking, was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) among never and ever exposed to occupational carcinogens. Interactions between genetic variants and occupational carcinogens were tested on the multiplicative scale using 2-df likelihood ratio tests (LRT). The large sample size allowed subgroup analyses by gender and histology. All estimates were corrected for multiple testing using a False Discovery Rate (FDR) method. Results: Men showed an increased lung cancer risk even at low exposure to asbestos (OR: 1.76; 95%CI: 1.42-2.18), crystalline silica (OR: 1.31; 95%CI: 1.00-1.71), and nickel-chromium (OR: 1.18; 95%CI: 0.90-1.53); risk increased with exposure level. The population attributable fractions for any exposure to asbestos, silica and nickel-chromium were 18.1%, 5.7%, and 7.0%, respectively. Given the high impact of asbestos in our study, it was the only carcinogen tested for interactions with the selected candidate genes. Polymorphisms of the GSTM4 gene consistently showed, across different levels of analysis, a positive interaction with asbestos exposure for lung cancer risk. However, only at the gene level analysis did the interaction pass the FDR correction (LRT p-value <0.001). Discussion: In a large population-based case-control study, polymorphisms of the GSTM4 gene have been found in association with asbestos exposure for lung cancer risk. This finding is biologically plausible, has never previously been reported, and should be validated in further studies. Strengths of this study were its large sample size, the validity of its occupational exposure and genotype assessment, and its systematic and integrated analyses. Conclusion: The findings of this study suggest a possible role of GSTM4 polymorphisms in the etiology of asbestos-related lung cancer. Further studies are required to evaluate this gene as a target of future molecular diagnostic tests and genetic therapies, given the potential high impact at a public health level.
|Titolo:||INTERACTION BETWEEN GENETIC AND OCCUPATIONAL FACTORS IN LUNG CANCER ETIOLOGY.A POPULATION-BASED CASE-CONTROL STUDY.|
|Data di pubblicazione:||7-feb-2013|
|Parole Chiave:||lung neoplasms ; case-control study ; carcinogens ; occupational health ; genetic polymorphisms ; gene-environment interaction ; candidate gene approach|
|Settore Scientifico Disciplinare:||Settore MED/44 - Medicina del Lavoro|
|Citazione:||INTERACTION BETWEEN GENETIC AND OCCUPATIONAL FACTORS IN LUNG CANCER ETIOLOGY.A POPULATION-BASED CASE-CONTROL STUDY. / S. De Matteis ; tutor: M. Rotunno, P.A. Bertazzi ; correlatore: M.T. Landi. - Milano : Università degli studi di Milano. DIPARTIMENTO DI SCIENZE CLINICHE E DI COMUNITA', 2013 Feb 07. ((25. ciclo, Anno Accademico 2012.|
|Digital Object Identifier (DOI):||10.13130/de-matteis-sara_phd2013-02-07|
|Appare nelle tipologie:||Tesi di dottorato|