Genetic polymorphisms in double-strand break DNA repair genes associated with risk of oral premalignant lesions

Abstract

Oral premalignant lesions (OPLs) are early genetic events en route to oral cancer. To identify individuals susceptible to OPL is critical to the prevention of oral cancer. In a case-control study consisting of 147 patients with histologically confirmed OPL and 147 matched controls, we evaluated the associations of 10 genetic variants in nine genes of the double-strand break (DSB) DNA repair pathway with OPL risk. The most notable finding was an intronic polymorphism (A17893G) of the XRCC3 gene. Compared with the homozygous wild-type AA genotype, the odds ratios [OR] (95% confidence interval [CI]) for the heterozygous AG and homozygous variant GG genotype were 0.85 (0.49-1.48) and 0.18 (0.07-0.47), respectively (P for trend=0.002). In addition, compared with the most common A-C haplotype of XRCC3 (in the order of A17893G-T241M), the G-C haplotype was associated with a significantly decreased risk of OPL (OR=0.40, 95% CI 0.23-0.68). Moreover, compared with individuals without the G-C haplotype, the ORs were 1.04 (0.56-1.95) and 0.20 (0.08-0.51) for subjects with one copy and two copies of the G-C haplotype, respectively (P for trend=0.005). Classification and regression tree (CART) analysis further revealed potential highorder gene-gene and gene-environmental interactions and categorized subjects into different risk groups according to their specific polymorphic signatures. Overall, our study provides the first epidemiological evidence supporting a connection between DSB gene variants and OPL development. Our data also suggest that the effects of high-order interactions should be taken into consideration when evaluating OPL predisposition.

Genetic variability of Xrcc3 and Rad51 modulates the risk of head and neck cancer

“…The latter ones may include UV light, ionizing radiation or chemical agents contained for example in the tobacco smoke, all of which may lead to double-strand break (DSB) DNA damage. If not repaired by means of the homologic recombination (HR) by the non-homologous end joining (NHEJ) repair pathways, DSBs of DNA may induce precancerous lesions and cancer itself as well (Khanna and Jackson, 2001;Yang et al, 2008). The HR pathway repairs the DSBs with high fidelity using the intact sister DNA strand as the template in order to reconstruct the missing part of the other strand with Rad51 homolog protein and Rad51 paralogs playing a crucial role in this pathway.…”

Lack of Influence of an XRCC3 Gene Polymorphism on Oral Cancer Susceptibility: Meta-analysis

“…This change may influence their protein activity, resulting in differences of individual DNA repair capacity (DRC) that may affect the susceptibility of oral cancer. Growing number of studies have been done to examine the relationship between this SNP and the risks of oral cancer (Benhamou et al, 2004;Majumder et al, 2005;Matullo et al, 2006;Kietthubthew et al, 2006;Yang et al, 2008;Yen et al, 2008;Dos Reis et al, 2013). However, the results are inconclusive.…”

“…XRCC3 gene is involved in the repair of DNA double-strand breaks (DSB), which is important to prevent chromosomal fragmentation, translocations and deletions (Kanaar et al, 1998). To date, there are studies reporting the association between polymorphisms of XRCC3 codon 241 with oral cancer risk but these published data were contradictory (Benhamou et al, 2004;Majumder et al, 2005;Matullo et al, 2006;Kietthubthew et al, 2006;Yang et al, 2008;Yen et al, 2008;Dos Reis et al, 2013). Until now, there was no meta-analysis or systematic review on the risk of oral cancer with XRCC3 polymorphism.…”

Head and Neck Squamous Cell Carcinoma: Prognosis using molecular approach

“…From their study, it was found that the combination of the 722CT/135GC (OR 3.81; 95% CI 1.55-9.75) as well as the 722TT/135GC genotypes (OR 5.33; 95% CI 1.96-14.47) carried an increased risk of PHLL, with the same gene combinations showing a higher probability of HNSCC occurrence respectively (OR 2.42; 95% CI 1.22-4.79 for 722CT/135GC and OR 3.63; 95% CI 1.69-7.76 for 722TT/135GC) together with tobacco and alcohol exposure [56]. The study conducted by Yang et al [57] provides the first epidemiological evidence supporting a connection between DSB gene variants and oral premalignant lesion (OPL) development. The most notable finding was an intronic polymorphism (A17893G) in XRCC3.…”

“…Moreover, compared with individuals without the G-C haplotype, the ORs were 1.04 (0.56-1.95) and 0.20 (0.08-0.51) for subjects with one copy and two copies of the G-C haplotype, respectively (P for trend=0.005). [57]. Despite the large number of case control studies on XRCC3 polymorphism and HNSCC from different populations worldwide, the results are still not satisfactory, which may be due to various environmental factors, lifestyles, and other variables, and so further large scale population based research needs to be carried out on this subject.…”