Combined effect of polymorphisms in Rad51 and Xrcc3 on breast cancer risk and chromosomal radiosensitivity

Abstract

Abstract. Enhanced in vitro chromosomal radiosensitivity (CRS) has been proposed as a marker for low-penetrance gene mutations predisposing to breast cancer (BC). Since the double strand break (DSB) is the most detrimental form of DNA damage induced by ionizing radiation, it is possible that mutations in genes encoding proteins involved in DSB repair affect breast cancer risk. The purpose of the present study was to examine whether five single nucleotide polymorphisms (SNPs) in Rad51 and Xrcc3 (rs1801320, rs1801321, rs1799796, rs861539 and rs1799794) exhibited an association with breast cancer susceptibility in a Belgian population of BC patients with a known or putative genetic predisposition. We also ascertained whether a relationship exists between the occurrence of the 'variant' alleles of these variations and in vitro CRS. Blood samples were obtained from BC patients and from healthy female individuals. Variations in the 5' UTR of Rad51 and Xrcc3 were genotyped, and statistical analysis was performed. The results showed that low-penetrant variations in Rad51 and Xrcc3, two proteins belonging to the homologous recombination DSB repair pathway, may modify BC risk in patients already carrying a pathological mutation in the highly penetrant BC genes BRCA1 and BRCA2. Combined risk genotype analysis revealed that Rad51 SNPs enhance BC risk in BRCA2 patients, whereas Xrcc3 SNPs significantly enhance BC risk in carriers of BRCA1 mutations and in patients with hereditary BC. When four putative risk genotypes of Rad51 and Xrcc3 were combined, positive significant odds ratios were obtained in the entire patient population and in patients with a hereditary history of disease. Although obtained from a limited number of patients, our data are supportive of a polygenic model whereby combinations of weak variations are responsible for an enhanced BC risk by acting jointly with high-penetrant mutations in BRCA1 or BRCA2.

Polymorphisms in DNA Repair GeneXRCC3and Susceptibility to Breast Cancer in Saudi Females

“…Several other studies and meta-analyses have confirmed an association between the XRCC3 Thr241Met polymorphism and it is suggested that this may be involved in modifying the risk of cancer [ 40 ]. Interestingly some studies show that it may have a protective effect [ 4 , 41 ], while still others failed to show any association with lung cancer in the Danish [ 42 ], breast cancer in the Polish [ 3 ], Belgian [ 43 ], and Jordanian populations [ 37 ], and ovarian cancer in a meta-analysis including Caucasian, Asian, and African populations [ 44 ]. During our analysis, no differences were found in the frequency of this SNPs when the patients were separated into groups on the basis of the age of diagnosis, tumor grade, and receptor (ER, PR, and HER2) status.…”

“…Several studies have investigated this mutation in different cancers and the results are contradictory even in patients suffering from the same type of cancer in different populations, as shown in Table 7 . A study from the British population showed that rs1799796 decreases the risk of breast cancer [ 2 ] while another study from Belgium reported an increased risk associated with this SNP in BRCA1 and BRCA2 carriers [ 43 ]. More recently, a significant association with ovarian cancer was confirmed in a meta-analysis involving Caucasian, Asian, and African populations [ 44 ].…”

Ionizing radiation-induced DNA injury and damage detection in patients with breast cancer

“…Mechanisms of hypersensitivity to ionizing radiation are still unclear, but is estimated that 70% of hypersensitivity cases are due to genetic variants ( Turesson et al , 1996 ). As mentioned above, mutations in the ATM gene are associated with extreme hypersensitivity to ionizing radiation ( Masuda and Kamiya, 2012 ), and polymorphisms in genes like XRCC3 and RAD51 increase the risk of radiosensitivity ( Vral et al , 2011 ). These genes are also implicated in breast cancer.…”

The study of radiosensitivity in left handed compared to right handed healthy women

“…MSH2 is one of the genes involved in DNA mismatch repair and located on chromosome 2 at 2p21. It has also been shown that polymorphism in Rad51 a gene located on chromosome 15 at 15q15.1 and involved in double strand break repair, can enhance cancer risk and in vitro chromosomal radiosensitivity [4,5]. It has also been postulated that genetic polymorphism of androgen receptor may act as a risk-modifier for BRCA2-associated breast cancers [36].…”