Dataset Information

Polymorphisms in nucleotide excision repair genes, arsenic exposure, and non-melanoma skin cancer in New Hampshire.

ABSTRACT: Arsenic exposure may alter the efficiency of DNA repair. UV damage is specifically repaired by nucleotide excision repair (NER), and common genetic variants in NER may increase risk for non-melanoma skin cancer (NMSC).We tested whether polymorphisms in the NER genes XPA (A23G) and XPD (Asp312Asn and Lys751Gln) modify the association between arsenic and NMSC.Incident cases of basal and squamous cell carcinoma (BCC and SCC, respectively) were identified through a network of dermatologists and pathology laboratories across New Hampshire. Population-based controls were frequency matched to cases on age and sex. Arsenic exposure was assessed in toenail clippings. The analysis included 880 cases of BCC, 666 cases of SCC, and 780 controls.There was an increased BCC risk associated with high arsenic exposure among those homozygous variant for XPA [odds ratio (OR) = 1.8; 95% confidence interval (CI), 0.9-3.7]. For XPD, having variation at both loci (312Asn and 751Gln) occurred less frequently among BCC and SCC cases compared with controls (OR = 0.8; 95% CI, 0.6-1.0) for both case groups. In the stratum of subjects who have variant for both XPD polymorphisms, there was a 2-fold increased risk of SCC associated with elevated arsenic (OR = 2.2; 95% CI, 1.0-5.0). The test for interaction between XPD and arsenic in SCC was of borderline significance (p < 0.07, 3 degrees of freedom).Our findings indicate a reduced NMSC risk in relation to XPD Asp312Asn and Lys751Gln variants. Further, these data support the hypothesis that NER polymorphisms may modify the association between NMSC and arsenic.

SUBMITTER: Applebaum KM

PROVIDER: S-EPMC1940098 | biostudies-literature | 2007 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Polymorphisms in nucleotide excision repair genes, arsenic exposure, and non-melanoma skin cancer in New Hampshire.

Applebaum Katie M KM Karagas Margaret R MR Hunter David J DJ Catalano Paul J PJ Byler Steven H SH Morris Steve S Nelson Heather H HH

Environmental health perspectives 20070801 8

<h4>Background</h4>Arsenic exposure may alter the efficiency of DNA repair. UV damage is specifically repaired by nucleotide excision repair (NER), and common genetic variants in NER may increase risk for non-melanoma skin cancer (NMSC).<h4>Objective</h4>We tested whether polymorphisms in the NER genes XPA (A23G) and XPD (Asp312Asn and Lys751Gln) modify the association between arsenic and NMSC.<h4>Methods</h4>Incident cases of basal and squamous cell carcinoma (BCC and SCC, respectively) were id ...[more]

PMID: 17687452

Similar Datasets

Project description:BACKGROUND:The causative link between UV exposure and melanoma development is well known, however the mechanistic relationship remains incompletely characterised. UVA and UVB components of sunlight are implicated in melanomagenesis; however the majority of studies have focused on the effects of UVB and UVC light. Interestingly, melanoma tumour sequencing has revealed an overrepresentation of mutations signature of unrepaired UV-induced DNA damage. Repair of UVA-induced DNA damage is thought to occur primarily through the Nucleotide Excision Repair (NER) pathway, which recognises and repairs damage either coupled to transcription (Transcription Coupled Repair; TCR), or through global genome scanning (Global Genome Repair; GGR). Current literature suggests NER is deficient in melanoma, however the cause of this remains unknown; and whether reduced NER activity in response to UVA may be involved in melanoma development remains uncharacterised. In this study we aimed to determine if melanoma cells exhibit reduced levels of NER activity in response to UVA. METHODS:Melanocyte and melanoma cell lines were UVA-irradiated, and DNA damage levels assessed by immunodetection of Cyclobutane Pyrimidine Dimer (CPD) and (6-4) Photoproduct [(6-4)PP] lesions. Expression of NER pathway components and p53 following UVA treatment was quantified by qPCR and western blot. RESULTS:UVA did not induce detectable induction of (6-4)PP lesions, consistent with previous studies. Repair of CPDs induced by UVA was initiated at 4 h and complete within 48 h in normal melanocytes, whereas repair initiation was delayed to 24 h and >40 % of lesions remained in melanoma cell lines at 48 h. This was coupled with a delayed and reduced induction of GGR component XPC in melanoma cells, independent of p53. CONCLUSION:These findings support that NER activity is reduced in melanoma cells due to deficient GGR. Further investigation into the role of NER in UVA-induced melanomagenesis is warranted and may have implications for melanoma treatment.

Dataset Information

Polymorphisms in nucleotide excision repair genes, arsenic exposure, and non-melanoma skin cancer in New Hampshire.

Publications

Polymorphisms in nucleotide excision repair genes, arsenic exposure, and non-melanoma skin cancer in New Hampshire.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets