Abstract
Background: Arsenic is a potent human carcinogen. It is estimated that over 100 million people worldwide are exposed to toxic levels of arsenic, mainly through drinking water. Skin, bladder, and lung are key target organs for arsenic-induced carcinogenesis. Lung cancer is the main cause of deaths due to arsenic toxicity, with this metalloid acting as the major etiological agent in cancers that occur in never smokers. Lung squamous cell carcinomas (SqCCs) occur at higher rates than other subtypes following arsenic exposure. The mechanisms for arsenic carcinogenesis are not fully understood, but it has been proposed that neoplastic effects as a result of arsenic biotransformation can occur at both the genetic and epigenetic levels. In this study, a rare panel of lung tumors from a population with chronic arsenic exposure, including SqCC tumors from patients with no smoking history, was analyzed to identify arsenic-associated copy-number alterations (CNAs) and DNA methylation changes.
Methods: 52 lung SqCCs were analyzed by whole-genome tiling path comparative genomic hybridization. Twenty-two were derived from arsenic-exposed patients from Northern Chile (10 never smokers and 12 smokers), and 30 additional cases were obtained for comparison from smokers without arsenic exposure from North America. In addition, 22 blood samples from healthy individuals from Northern Chile were examined to identify naturally occurring germline DNA copy-number variations that could be excluded from analysis. DNA methylation analysis was performed using Illumina's Infinium Human Methylation 450K array.
Results: We identified several DNA copy number alterations and DNA methylation changes associated with chronic arsenic exposure. These alterations were not accountable to either natural copy-number variations or smoking status. The most recurrent events were represented by DNA losses at chromosomes 1q21.1, 7p22.3, 9q12, and 19q13.31. The only arsenic-associated DNA gain occurred at 19q13.33, which contains genes previously recognized as oncogenes.
Conclusions: Our study has provided insights into the molecular mechanisms of arsenic-induced lung neoplasia. The unique and recurrent arsenic-associated genetic and epigenetic alterations suggest that this group of tumors may be considered as a distinct disease subclass.
Citation Information: Cancer Prev Res 2011;4(10 Suppl):A32.
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