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

Abstract

Polymorphisms at N-acetyl transferase 2 locus (NAT2) lead to slow, intermediate and rapid acetylation properties of the enzyme. Improper acetylation of heterocyclic and aromatic amines, present in tobacco, might cause DNA adduct formation. Generally, DNA repair enzymes remove these adduct to escape malignancy. But, tobacco users carrying susceptible NAT2 and DNA repair loci might be at risk of oral leukoplakia and cancer. In this study, 389 controls, 224 leukoplakia and 310 cancer patients were genotyped at 5 polymorphic sites on NAT2 and 3 polymorphic sites on each of XRCC1 and XPD loci by PCR-RFLP method to determine the risk of the diseases. None of the SNPs on these loci independently could modify the risk of the diseases in overall population but variant genotype (Gln/Gln) at codon 399 on XRCC1 and major genotype (Lys/Lys) at codon 751 on XPD were associated with increased risk of leukoplakia and cancer among slow acetylators, respectively (OR 5 4.2, 95% CI 5 1.2-15.0; OR 5 1.6, 95% CI 5 1.1-2.3, respectively). Variant genotype (Asn/Asn) at codon 312 on XPD was also associated with increased risk of cancer among rapid and intermediate acetylators (OR 5 1.9, 95% CI 5 1.2-2.9). Variant C-G-A haplotype at XRCC1 was associated with increased risk of leukoplakia (OR 5 1.7, 95% CI 5 1.2-2.4) but leukoplakia and cancer in mixed tobacco users (OR 5 3.1, 95% CI 5 1.4-7.1, OR 5 2.4, 95% CI 5 1.1-5.4, respectively) among slow acetylators. Although none of the 3 loci could modulate the risk of the diseases independently but 2 loci in combination, working in 2 different biochemical pathways, could do so in these patient populations. ' 2007 Wiley-Liss, Inc.Key words: tobacco use; oral cancer; leukoplakia, NAT2; XPD; XRCC1; polymorphism As an early sign of damage to oral mucosa, tobacco smokers and chewers often develop different precancerous lesions, such as leukoplakia, erythroplakia, submucous fibrosis, etc., and these lesions are easily accessible to diagnosis. Annual incidence of oral leukoplakia has been reported as 0.2-11.7% in different populations of India 1-3 and about 2-12% of leukoplakia becomes malignant within several years. 2 Since leukoplakia is one of the good predictors of oral cancer so diagnosis and treatment of leukoplakia will be a useful strategy to control oral cancer incidence. Annually about 270,000 cases of oral cancer are reported worldwide but about 82,000 of them are diagnosed in India. 4 Major procarcinogens present in the tobacco smoke are polycyclic aromatic hydrocarbons, aromatic and heterocyclic amines and nitroso-compounds whereas nitrosamines and aromatic and heterocyclic amines are major components present in smokeless tobacco. Most of the tobacco carcinogens generally undergo bioactivation and inactivation by phase I and phase II enzymes respectively. Human N-acetylation transferase 2 (NAT2) is one of the phase II enzymes that participate in the bioconversion of aromatic and heterocyclic amines and variation in NAT2 enzyme activity is defined as polymorphism in N-acetylation capacit...

Genetic polymorphisms in key DNA repair genes and risk of head and neck cancer in a Chinese population

“…There have been several studies showing associations between this SNP and risk of multiple cancers, including HNC, but the results from different populations were confusing rather than conclusive (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39). Recently, a meta-analysis with a total of 12 studies claimed that the XPD Lys751Gln polymorphism was not associated with HNC risk (17); however, no genotyping data from the Chinese population was included, with the exception of a Taiwan study with a small sample size of 154 cases and 105 controls (30).…”

The Arg194Trp Polymorphism in the X-ray Repair Cross-Complementing Group 1 Gene as a Potential Risk Factor of Oral Cancer: A Meta-Analysis

“…XRCC1 polymorphisms were first reported as a risk factor for oral cancer (Sturgis et al 1999). Since then, a number of studies have confirmed or refuted this phenomenon (Majumder et al 2005(Majumder et al , 2007Matullo et al 2006;Ramachandran et al 2006;Kietthubthew et al 2006;Ho et al 2007;Yen et al 2008). These disparate findings may be due to insufficient power in some studies, differences between cancer types, type of study populations and study design.…”

DNA Repair Gene Polymorphisms at XRCC1, XRCC3, XPD, and OGG1 Loci in the Hyderabad Population of India

“…In conclusion, our study could provide a preliminary basis for cancer risks assessment that are associated with polymorphisms among these DNA repair genes by (Harithy and Ghazzawi et al 2011); GIH-Gujarati Indians in Houston, Texas; SInd-South Indian population in India (Vettriselvi et al, 2007); NInd-North Indian population in India (Gangwar et al, 2009); EInd-Eastern Indian population from Calcutta, India (Majumder et al, 2007) performing genetic epidemiological studies in the Deccan region population of India. Furthermore, our results indicate a distinct molecular profile of polymorphisms for the DNA repair genes XRCC1, XRCC3, OGG1 and XPD loci for HYB compared to other populations.…”

“…The CHB, JPT, YRI, MKK, and GIH populations differed significantly with HYB population based on Pairwise Chi-square (χ 2 ) ( Table 4). (Harithy and Ghazzawi et al 2011); GIH-Gujarati Indians in Houston, Texas; SInd-South Indian population in India (Vettriselvi et al, 2007); NInd-North Indian population in India (Gangwar et al, 2009); EInd-Eastern Indian population from Calcutta, India (Majumder et al, 2007); MAH-Maharashtrian population residing in Vidarbha region of central India; HYB-Hyderabad population residing in Deccan region of South India; a Chi-square test statistic value less than 3.841 at 5% significance level, so populations are not significantly different from HYB (92) 0.66 (188) 0.021 (6) …”