XPD / ERCC 2 polymorphisms and risk of head and neck cancer : a case-control analysis

carcinogenesis would greatly improve the efficiency of prevenDNA repair capacity is central in maintaining normal tion and eventually chemoprevention programs. cellular functions. Variants of several DNA repair genes,inGenetic differences in the ability to metabolize carcinogens, cluding the nucleotide excision repair gene XPD, have been repair DNA damage and induce apoptosis may contribute to described recently. Because we previously reported that the variation in cancer risk in the population at large. We have patients with squamous cell carcinoma of the head and previously reported an increased risk of SCCHN associated neck (SCCHN) had lower DNA repair capacity than healthy with variants of carcinogen detoxifying genes (GSTM1 and controls, we hypothesized that inherited polymorphisms of GSTT1) (3) and of the DNA repair gene XRCC1 (4). Recently, XPD may contribute to genetic susceptibility to SCCHN, a the entire coding region of the DNA repair gene XPD/ERCC2 tobacco-related cancer. To test this hypothesis, we conwas resequenced in 12 normal individuals; six polymorphic ducted a hospital-based case-control study of 189 SCCHN variants were described (5). The XPD protein is an evolupatients and 496 cancer-free controls who were frequencytionarily conserved helicase, a subunit of transcription factor matched on age, gender and smoking status. All subjects IIH (TFIIH) that is essential for transcription and nucleotide were non-Hispanic whites. Two XPD polymorphisms excision repair (6). Mutations in XPD prevent its protein (C22541A and A35931C) were typed using the restriction product from interacting with p44, another subunit of TFIIH enzymes TfiI and PstI, respectively. Multivariate logistic (7) and reduce its helicase activity, resulting in a defect in regression analysis was performed to calculate adjusted nucleotide excision repair. Mutations at different sites result odds ratios (ORs) and 95% confidence intervals (CIs). In in three distinct clinical phenotypes: xeroderma pigmentosum, the controls, the frequencies of the variant 22541A and trichothiodystrophy and xeroderma pigmentosum combined 35931C alleles were 44.7% and 33.8%, respectively. The with Cockayne sydrome (8). Studies have shown that XPD is frequency of the 22541A homozygous genotype (22541AA) involved in repairing genetic damage induced by tobacco was lower in cases (15.9%) than in controls (20.4%) but carcinogens and other carcinogens (9). was not associated with risk (adjusted OR 0.90; 95% Although we do not know the functional significance of the CI 0.52–1.56) for SCCHN. The frequency of the 35931C newly identified XPD variants, we hypothesized that genetic homozygous genotype (35931CC) was higher in cases variants in XPD may be markers for SCCHN susceptibility (16.4%) than in controls (11.5%) and associated with a and therefore would exist at different frequencies in individuals borderline increased risk (adjusted OR 1.55; 95% CI with and without cancer. To test this hypothesis, we performed 0.96–2.52) for SCCHN. The risk was higher in older a hospital based case control study using a polymerase chain subjects (OR 2.22; 95% CI 1.03–4.80), current reaction (PCR) restriction fragment length polymorphism smokers (OR 1.83; 95% CI 0.79–4.27) and current (RFLP) assay to genotype two variants of the XPD gene in drinkers (OR 2.59; 95% CI 1.25–5.34) in the strati189 patients with SCCHN and 496 cancer-free controls. The fication analysis. These results suggest a gene–environment two XPD variants, C22541A at codon 156 of exon 6 and interaction, but this did not reach statistical significance. A35931C at codon 751 of exon 23, were chosen because their The findings are limited due to the relatively small numbers allele frequencies are higher ( 25%) than those of other in the subgroups and need to be verified by further reported variants (5) and because it has been suggested that investigations. the C22541A and A35931C polymorphisms are associated with