Abstract 5368: Genetic susceptibility to cervical cancer: Role of XRCC1

Abstract

Abstract Background: X-ray repair cross-complementation group 1 (XRCC1) is a scaffold protein involved in the early and late stages of Base Excision Repair (BER). Three single nucleotide polymorphisms occur in XRCC1, resulting in non-synonymous amino acid changes, which could change the binding or regulatory activities of XRCC1. Human papillomavirus (HPV) is considered to be a necessary but not sufficient cause for cervical cancer and, therefore, other factors contribute to the carcinogenic process. A hereditary component for this neoplasia has been reported and several studies indicate that genetic background of the host is important for cervical cancer susceptibility. Previous studies investigating the association of (XRCC1) polymorphisms with squamous intraepithelial lesions (SIL) and cervical cancer (CC) risk has provided inconsistent results. The aim of our study was to assess the association between the XRCC1 gene Arg194Trp, Arg399Gln, Arg280His polymorphisms as well as its expression and risk of SIL and CC. Methods: A case control study consisting of 178 samples (65 CC cases, 45 SIL cases and 68 controls) was carried out. HPV DNA detection was performed by consensus PCR and genotyping of positive samples by type specific primers. XRCC1 polymorphisms were determined by Restriction Fragment Length Polymorphism (RFLP). Expression at mRNA level was checked by Real Time PCR and at protein level by Western blotting. Results: The SNPs in XRCC1 gene was associated with increased risk of SIL and CC. The TT genotype of XRCC1 codon 194 and AA genotype of XRCC1 codon 280 presented 12 fold (p=0.001; OR=12.2; 95%CI=4.9-30.9) and 7.5 fold (p=0.001; OR=7.5; 95%CI=2.9-18.7) higher risk of cervical cancer, respectively. The variant genotype of XRCC1 codon 399 was associated with 4.2 fold (p=0.008; OR=4.2; 95%CI=1.5-12.1) higher risk of cervical cancer. The heterozygous genotype of all the three exons did not present any significant risk. In XRCC1 C194T, and XRCC1 G280A combining the heterozygous and variant genotype there was higher risk for CC (p=0.001; OR=7.01 95%CI=3.1-15.7 and p=0.001, OR=3.2, 95%CI=1.6-6.6, respectively). In SIL cases, the homozygous variant TT of Exon 6 presented 3.5 fold (p=0.012; OR=3.5; 95%CI=1.3-9.8) higher risk. The combined variant genotype (CT+TT) also showed an elevated risk of SIL (p=0.003, OR=3.3). The invasive cancer and SIL subjects demonstrated lower relative expression of the XRCC1 (p<0.001). Reduction was also found on the protein level. Conclusions: The present study suggested that XRCC1 as a predisposing factor in cervical precancer and increased risk of invasive cervical cancer. Low mRNA transcript of XRCC1 showed an increased risk of cervical cancer irrespective of HPV status, as majority of cervical cancer and SIL samples were HPV positive. This implies that polymorphism and reduction in expression of XRCC1 gene is associated with an early event in the progression to cervical cancer. Note: This abstract was not presented at the meeting. Citation Format: Deepti Bajpai, Ayan Banerjee, Sujata Pathak, Sunesh Jain, Neeta Singh. Genetic susceptibility to cervical cancer: Role of XRCC1. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5368. doi:10.1158/1538-7445.AM2014-5368