Polymorphisms in DNA repair gene XRCC1 and increased genetic susceptibility to breast cancer

Abstract

X-ray repair cross-complementing 1 (XRCC1) gene encodes for a scaffolding protein, which plays an important role in base excision DNA repair by bringing together DNA polymerase beta, DNA ligase III and poly(ADP-Ribose) polymerase (PARP) at the site of DNA damage. Three polymorphisms of the XRCC1 gene at codons 194, 280 and 399 leading to amino acid changes at evolutionary conserved regions are found to alter the efficiency of the resulting protein and may therefore constitute potential breast cancer risk. In the present study we sought to determine whether these genetic variants of the XRCC1 gene was associated with any increased risk of breast cancer among the South Indian women in a hospital based case control study using PCR-RFLP and DNA sequencing techniques. Our data showed a positive association between the polymorphisms of codons 194 (OR = 1.98, 95% CI = 1.13-3.48 for Trp allele) and 399 (OR = 2.14, 95% CI = 1.29-3.58 for Gln allele) and breast cancer risk. However, XRCC1 codon 280 genotype analysis showed no evidence for an association with increased risk of breast cancer. A combined analysis of the effect of XRCC1 codon 194 and 399 revealed the highest risk (OR = 3.64, 95% CI = 1.57-8.46) for carriers of the polymorphic alleles in both these codons. In conclusion, the present study suggested involvement of XRCC1 codon 194 and 399 polymorphisms in the genetic predisposition to breast cancer among South Indian women. Our preliminary results based on the analysis of functionally relevant polymorphisms in XRCC1 low penetrance gene may provide a better model that would exhibit additive effects on individual susceptibility to breast cancer.

Association of XRCC1 Gene Polymorphisms with Breast Cancer Susceptibility in Saudi Patients

“…Similar to this even European population didn't show any association with XRCC1 399 polymorphism in lung cancer patients (Lopez-Cima et al, 2007) and in bladder patients (Kelsey et al, 2004). Some studies have also demonstrated a strong association of the Arg399Gln XRCC1 polymorphism with an increased risk of breast cancer (Chacko, 2005;Dufloth et al, 2008;Sterpone et al, 2010). However in 2006, the Breast Cancer Association Consortium, as well as a large meta-analysis, reported no evidence of its association with breast cancer development (Breast Cancer Association Consortium, 2010).…”

“…Data from studies on the association of the XRCC1 polymorphisms with breast cancer risk are also inconsistent (Duell et al, 2001, Kim et al, 2002, Moullan et al, 2003, Figueiredo et al, 2004, Forsti et al, 2004, Chacko et al, 2005. Therefore the association between genetic polymorphism of XRCC1 at codon 194, codon 399 and susceptibility to breast cancer is still an open question (Saadat et al, 2008).…”

Polymorphisms of the NER pathway genes, ERCC1 and XPD are associated with esophageal adenocarcinoma risk

“…There is no commonly acceptable method for combining atrisk alleles in a pathway analysis. Some researchers have studied associations between DNA repair polymorphisms and lung cancer risk using combined analysis of at-risk alleles [24,[33][34][35], and this method has also been used in breast cancer [36]. We took a similar approach in the present study.…”

The XRCC1 Arg399Gln Genetic Polymorphism Contributes to Hepatocellular Carcinoma Susceptibility: An Updated Meta-analysis

“…XRCC1 acts as a nonenzymatic, scaffold protein by recruiting and interacting with a variety of proteins important to the BER pathway, such as DNA glycosylase MPG, OGG1 (Whitehouse et al, 2001). Polymorphisms of XRCC1 were found to have reduced recruitment of XRCC1 interacting proteins, deteriorated overall efficiency of DNA damage restoration, and increased exposure to hepatocarcinogenesis (Chacko et al, 2005). Currently, it is reported that there are eight validated single nucleotide polymorphisms (SNPs) of XRCC1 gene.…”