XPD/ERCC2 polymorphisms and risk of head and neck cancer: a case-control analysis

Abstract

DNA repair capacity is central in maintaining normal cellular functions. Variants of several DNA repair genes,including the nucleotide excision repair gene XPD, have been described recently. Because we previously reported that patients with squamous cell carcinoma of the head and neck (SCCHN) had lower DNA repair capacity than healthy controls, we hypothesized that inherited polymorphisms of XPD may contribute to genetic susceptibility to SCCHN, a tobacco-related cancer. To test this hypothesis, we conducted a hospital-based case-control study of 189 SCCHN patients and 496 cancer-free controls who were frequency-matched on age, gender and smoking status. All subjects were non-Hispanic whites. Two XPD polymorphisms (C22541A and A35931C) were typed using the restriction enzymes TfiI and PstI, respectively. Multivariate logistic regression analysis was performed to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). In the controls, the frequencies of the variant 22541A and 35931C alleles were 44.7% and 33.8%, respectively. The frequency of the 22541A homozygous genotype (22541AA) was lower in cases (15.9%) than in controls (20.4%) but was not associated with risk (adjusted OR = 0.90; 95% CI = 0.52-1. 56) for SCCHN. The frequency of the 35931C homozygous genotype (35931CC) was higher in cases (16.4%) than in controls (11.5%) and associated with a borderline increased risk (adjusted OR = 1.55; 95% CI = 0.96-2.52) for SCCHN. The risk was higher in older subjects (OR = 2.22; 95% CI = 1.03-4.80), current smokers (OR = 1.83; 95% CI = 0.79-4.27) and current drinkers (OR = 2.59; 95% CI = 1.25-5.34) in the stratification analysis. These results suggest a gene-environment interaction, but this did not reach statistical significance. The findings are limited due to the relatively small numbers in the subgroups and need to be verified by further investigations.

Polymorphisms at XPD and XRCC1 DNA repair loci and increased risk of oral leukoplakia and cancer among NAT2 slow acetylators

“…The A > C (Arg > Arg) polymorphism at codon 156 of XPD was screened in all samples generating a 644-bp PCR product, digesting with TfiI and electrophoresing in 2% agarose gel. 14 In addition to the TfiI site at codon 156, one additional monomorphic TfiI site, producing a 57-bp DNA fragment, served as an internal control for restriction enzyme digestion. Genotypes were determined by banding patterns such as A/A (474, 113 and 57 bp); A/C (587, 474, 113 and 57 bp); and C/C (587, 57 bp).…”

“…Several synonymous and nonsynonymous SNPs including those at codons 156 (exon 6 C > A, Arg > Arg), 312 (exon 10 G > A, Asp > Asn) and 751 (exon 23 A > C, Lys > Gln) have been described in XPD locus and reported to be associated with tobacco related cancers. 14,15 The XRCC1 plays an important role in base excision repair (BER) pathway, and interacts with DNA polymerase b, poly ADP-ribose polymerase and DNA ligase III. It also contains a BRCT (BRCA1 COOH terminus) domain, which is characteristic of proteins involved in cell cycle checkpoint functions and this domain can be responsive to DNA damage.…”

A variant of the DNA repair gene XRCC3 and risk of squamous cell carcinoma of the head and neck: A case‐control analysis

“…8 Briefly, patients with newly diagnosed and histologically confirmed SCCHN (i.e., having primary tumors of the oral cavity, pharynx and larynx) were recruited from May 1995 to November 2001 at the Department of Head and Neck Surgery of M.D. Anderson Cancer Center.…”

“…5,6 Recent molecular epidemiological studies have demonstrated that polymorphisms in DNA repair genes contribute to genetic susceptibility to SCCHN. 7,8 Therefore, studies of biological relevance of newly identified genetic polymorphisms 9 should ultimately help identify those at high risk for carcinogenesis and eventually improve cancer prevention and chemoprevention programs.…”

“…15 Recently, we have demonstrated that polymorphisms of DNA repair genes contribute to DNA repair phenotype 16 that is associated with cancer risk. 17 For instance, polymorphisms of X-ray repair cross-complementing group 1 (XRCC1), 7 which is involved in repair of single-base damage 18 and xeroderma pigmentosum group D (XPD), 8 which is involved in repair of bulky DNA damage, 19 are both associated with risk of SCCHN. However, no reported studies have investigated the role of polymorphisms of genes involved in the repair of DNA double-strand breaks in the etiology of SCCHN.…”