Polymorphism in the ERCC2 codon 751 is associated with arsenic-induced premalignant hyperkeratosis and significant chromosome aberrations

Abstract

In West Bengal, India more than 6 million people are exposed to high levels of arsenic through drinking water. Since, only 15-20% of the exposed individuals show arsenic-induced skin lesions, it is assumed that genetic variation might play an important role in arsenic toxicity and carcinogenicity. Arsenic exposure often leads to the development of hyperkeratosis, the precursor of arsenic-induced skin cancer. ERCC2 (excision repair cross-complementing rodent repair deficiency, complementation group 2) is a nucleotide excision repair pathway gene, and its SNPs have been implicated in several types of epithelial cancers. We investigated the possible association of ERCC2 codon 751 A-->C polymorphism (lysine to glutamine) with arsenic-induced hyperkeratosis and correlated ERCC2 genotypes with increased frequencies of chromosomal aberration to ascertain whether any genotype leads to sub-optimal DNA repair. For this association study, 318 unrelated arsenic exposed subjects (165 with hyperkeratosis and 153 without any arsenic-induced skin lesions), drinking water contaminated with arsenic to a similar extent, were recruited. Genotyping was done through PCR-RFLP procedure. Lys/Lys genotype was significantly over-represented in the arsenic-induced hyperkeratosis-exhibiting group [odds ratio (OR) = 4.77, 95% confidence interval (CI) = 2.75-8.23]. A statistically significant increase in both CA/cell and percentage of aberrant cells was observed in the individuals with AA genotype compared to those with AC or CC genotype combined (P < 0.01) in each of the two study groups, as also, in the total study population. This study indicates that ERCC2 codon 751 Lys/Lys genotype is significantly associated with arsenic-induced premalignant hyperkeratosis and is possibly due to sub-optimal DNA repair capacity of the ERCC2 codon 751 Lys/Lys genotype.

Genetic Determinants of Mitochondrial Response to Arsenic in YeastSaccharomyces cerevisiae

“…The information on the biological functions for each of these genes was obtained from Saccharomyces Genome Database (SGD) 1 and Comprehensive Yeast Genome Database (CYGD). 2 Interaction analysis of the genes using PathwayAssist software. The deletion mutants were analyzed using PathwayAssist software (version 3.0; Stratagene Corp.) at the Gene Expression Facility of Roswell Park Cancer Institute.…”

“…Arsenic is considered a ''paradoxical'' carcinogen as it can induce tumors in humans but not in any other animal model (2). The mechanism of human carcinogenicity remains unclear.…”

“…Human exposure to arsenic poses a global health problem affecting millions of people worldwide (1,2). The situation has been described as ''humanity's biggest mass poisoning'' (3).…”

“…Exposure to arsenic is associated with lung, skin, liver, bladder, kidney, and prostate cancer (6). Although arsenic is shown to be human carcinogen, studies have failed to produce tumors in laboratory animals and data for animal carcinogenicity have proven to be inconclusive (2). Despite its carcinogenic effects in humans, arsenic-containing drugs are used for therapy of cancer.…”

Polymorphism of genes encoding proteins of DNA repair vs. occupational and environmental exposure to lead, arsenic and pesticides

“…[38] zbadali znaczenie polimorfizmu genu ERCC2 (excision repair cross-complementing -białko biorące udział w naprawie DNA przez wycinanie nukleotydów) (rs13181) na ryzyko narażenia na arsen. Gen ten koduje białko ERCC2, które uczestniczy w naprawie DNA typu NER.…”