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


OBJECTIVE
We tested whether polymorphisms in the NER genes XPA (A23G) and XPD (Asp312Asn and Lys751Gln) modify the association between arsenic and NMSC.


METHODS
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.


RESULTS
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).


CONCLUSIONS
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.
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
Katie M
KM
Applebaum
Margaret R
MR
Karagas
David J
DJ
Hunter
Paul J
PJ
Catalano
Steven H
SH
Byler
Steve
S
Morris
Heather H
HH
Nelson
D000328:Adult; D000368:Aged; D001151:Arsenic / Q000032:analysis / Q000633:toxicity*; D002273:Carcinogens / Q000032:analysis / Q000633:toxicity; D002280:Basal Cell Carcinoma / Q000453:epidemiology / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000453:epidemiology / Q000235:genetics*; D004781:Environmental Exposure / Q000009:adverse effects / Q000032:analysis; D004785:Environmental Pollutants / Q000032:analysis / Q000633:toxicity; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009262:Nails / Q000737:chemistry; D009513:New Hampshire / Q000453:epidemiology; D011110:Polymorphism, Genetic; D012878:Skin Neoplasms / Q000453:epidemiology / Q000235:genetics*; D051760:Xeroderma Pigmentosum Group A Protein / Q000235:genetics*; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics*
D002273:Carcinogens; D004785:Environmental Pollutants; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D001151:Arsenic