Single nucleotide polymorphisms in the DNA repair genes in HPV-positive cervical cancer

Abstract

Genetic variation in DNA repair genes can modulate DNA repair capacity and may be related to the risk of cancer. The human papillomavirus is considered to be a necessary but not sufficient cause for cervical cancer and, therefore, other factors contribute to the carcinogenesis. A hereditary component for this neoplasia has been reported. Evaluation of the association of six polymorphisms was carried out in the following DNA repair genes: XRCC1 (Arg194Trp, Arg280His, and Arg399Gln), ERCC1 (Asp118Asp), ERCC2 (Lys751Gln), and ERCC4 (Arg415Gln). The cases (n=110) included 65 squamous cell carcinomas (SCCs) and 45 squamous intraepithelial lesions (SIL). Controls (n=68) were recruited from among women without cervical abnormalities. Genotypes were determined by PCR-restriction fragment length polymorphism and DNA sequencing. A positive association was observed between the polymorphisms of XRCC1 genes, that is, in codons 194 [P=0.001, odds ratio (OR)=20.1, 95% confidence interval (CI)=5.9-68.8], 280 (P=0.001, OR=5.4, 95% CI=2.3-12.6), and 399 (P=0.008, OR=4.2, 95% CI=1.5-12.1) and cervical cancer. SIL patients also showed a significant association with codon 194 (P=0.012, OR=3.8, 95% CI=1.3-10.6), but not with 280 (P=0.35) and 399 (P=0.81). A positive correlation was also found in ERCC4 Gln415Gln in both SCCs and SILs (P=0.001, OR=21.3, 95% CI=7.1-64.0 and P=0.001, OR=7.8, 95% CI=2.9-20.9, respectively). For ERCC2 Gln751Gln, the association was significant for both SCCs (P=0.001, OR=10.1, 95% CI=2.6-37.9) and SILs (P=0.001, OR=8.9, 95% CI=2.8-28.3). However, the risk of SCC did not appear to differ significantly among individuals with the ERCC1 Asp118Asp genotype (P=0.404). For SILs, it appeared to be a protective genotype (95% CI=0.1-0.7). This study indicates that variant types of DNA repair genes play an important role in modifying individual susceptibility to SCC.

Association between XRCC1 polymorphisms and the risk of cervical cancer: a meta-analysis based on 4895 subjects

“…All studies were consistent with HWE except for three studies for Arg194Trp [17, 21, 22], one study for Arg280His [23], and one study for Arg 399Gln [24]. …”

“…However, the heterogeneity among studies droped to zero when excluding the study which didn't conform to HWE. Despite of this, the pooled results stayed stable when we eliminated the one [23]. (Table 4)…”

“…Consequently, a total of 11 articles involving 2092 cases and 2803 controls were recruited in the present meta-analysis [14–24] (Figure 1). Among these articles, 7 articles were about Arg194Trp (rs1799782) [14, 16, 17, 20–23], 4 articles were about Arg280His (rs25489) [14, 15, 20, 23], and 11 articles were about Arg399Gln (rs25487) [14–24]. However, we only recruited 10 studies when analyzing the association between Arg399Gln polymorphism and cervical cancer risk because an article offered data concerning CIN and cervical cancer as a whole [16].…”

“…However, the finding that the pooled OR still incorporated 1.0 showed that the Arg194Trp polymorphism had no association with the risk of cervical cancer. Then we excluded three studies which were not consistent with HWE [17, 22, 23] and reassessed the relationship between this locus and cervical cancer risk. The final results did not change substantially.…”

“…For example, Zhang et al found the XRCC1 Arg194Trp polymorphism showed no significant association with CIN and squamous cervical carcinomas (SCC), while the Arg280His polymorphism acted as a protective factor for SCC, and the Arg399Gln polymorphism increased CIN risk among women who first gave birth before 22 years old [14]. Bajpai et al suggested XRCC1 polymorphisms (Arg194Trp, Arg280His and Arg399Gln) increased cervical cancer risk greatly [23]. Barbisan et al convinced that XRCC1 polymorphisms (Arg194Trp and Arg399Gln) genotypes and haplotypes contributed to reducing the risk of cervical cancer development in Argentin women [22].…”