Polymorphisms in cancer susceptibility genes XRCC1, RAD51 and TP53 and the risk of breast cancer in Serbian women.

BACKGROUND: Thanks to immense improvements in technology over the past few decades, we have witnessed a major shift towards the idea that breast cancer results from a combined effect of multiple common alleles conferring low risk. This study investigates the role of 3 nonsynonymous SNPs in the DNA repair genes XRCC1 (R399Q), RAD51 (G135C) and TP53 (Arg72Pro) in breast cancer in Serbian women. PATIENTS AND METHODS: Cases of BRCA1/2-negative hereditary breast cancer (n = 52), sporadic breast cancer (n = 106) and age-matched cancer-free female controls (n = 104) were obtained from the Institute for Oncology and Radiology of Serbia's blood bank. Restriction fragment length polymorphism analysis was used for genotyping. Descriptive analyses included genotype and allelic frequencies; the odds ratio and 95% confidence interval were calculated as an estimate of the relative risk. RESULTS: A significant difference in QQ+RQ versus RR genotype distribution of XRCC1 was observed between hereditary breast cancer patients and cancer-free controls. The association was confirmed among young breast cancer patients from these high-risk families. The existence of 3 recessive alleles in the RAD51 and XRCC1 genotype combination showed an association with hereditary breast cancer. Odds ratio analysis indicated a strong protective role of the RAD51 GG + TP53 ArgArg + XRCC1 RR combined genotype against hereditary breast cancer negative for BRCA1/2 mutations. CONCLUSIONS: The XRCC1 R399Q polymorphism showed an association with increased breast cancer risk in Serbia, especially in the hereditary form of the disease and in young breast cancer patients. Dominant alleles of RAD51, TP53 and XRCC1 combined genotypes indicated a strong protective role against hereditary breast cancer.

Impact of RAD51 G135C and XRCC1 Arg399Gln polymorphisms on ovarian carcinoma risk in Serbian women.

OBJECTIVE: The polymorphic variations of DNA repair genes may contribute to functional deficiencies in DNA repair processes increasing susceptibility to cancer. We aimed to investigate the impact of 135G>C RAD51 and XRCC1 Arg399Gln polymorphisms on ovarian carcinoma risk in Serbian women. METHODS: The study included 50 ovarian carcinoma samples and 78 cervical swabs of gynecologically healthy age-matched controls. RAD51 G135C and XRCC1 Arg399Gln polymorphisms were determined by PCR-RFLP. Deviations of the genotype frequencies from Hardy-Weinberg equilibrium were assessed using the χ2 test. The allele- and genotype-specific risks were estimated as odds ratios with 95% confidence intervals. RESULTS: RAD51 135C and XRCC1 Arg allele are associated with ovarian carcinoma [OR (95% CI): 2.54 (1.22-5.29) for C vs. G; 2.64 (1.53-4.55) for Arg vs. Gln]. RAD51 C exerts its effect in dominant (CC plus GC vs. GG) [OR (95% CI): 2.83 (1.21-6.62], while XRCC1Arg in dominant (ArgArg plus ArgGln vs. GlnGln) [OR (95% CI): 4.76 (1.69-13.42)] and recessive model (ArgArg vs. ArgGln plus GlnGln) [OR (95% CI): 2.21 (1.07-4.56)]. CONCLUSION: The results suggest that the RAD51 G135C and XRCC1 Arg399Gln polymorphisms could be biomarkers of susceptibility for ovarian carcinoma development. Further larger case-control study is needed to confirm our findings.

RAD51 135G>C and TP53 Arg72Pro polymorphisms and susceptibility to breast cancer in Serbian women.

Breast cancer is a complex disease with both genetic and environmental factors involved in its etiology. An important role of polymorphisms in genes involved in DNA repair has been reported related to breast cancer risk. We conducted a case-control study in order to investigate the association of RAD51 135G>C and TP53 Arg72Pro polymorphisms with breast cancer in Serbian women.48 BRCA negative women with breast cancer and family history of breast/ovarian cancer (hereditary group), 107 women with breast cancer but without family history of the disease (sporadic group) and 114 healthy women without a history of the disease (control group) were included. Restriction fragment length polymorphism was used for genotyping. Genotype and allelic frequencies, the odds ratio (OR) and the 95 % confidence interval (CI) were calculated as an estimate of relative risk. The Hardy-Weinberg equilibrium was tested using χ(2) test. Significance was considered for p < 0.05. RAD51 135G>C showed statistically significant association of CC genotype and increased breast cancer risk (OR 10.28, 95 % CI 1.12-94.5) in hereditary group of patients compared to the control group. Regarding the TP53 Arg72Pro, we showed statistical significance for ProPro + ProArg comparing to ArgArg (OR 2.34, 95 %, CI 1.17-4.70) in hereditary compared to sporadic group. RAD51 135G>C contributes to hereditary breast cancer in Serbian population, with CC genotype as a risk factor. We also found that carriers of Pro allele of TP53 codon 72 is related to hereditary cancer comparing to sporadic one, which indicates it as a potential risk factor for hereditary form of disease.

Association of TP53 codon 72 polymorphism with susceptibility to ovarian carcinomas in Serbian women.

OBJECTIVES: Finding a potential genetic factor associated with a deadly disease, such as ovarian carcinoma, is of particular importance. The aim of this study was to examine the role of the TP53 codon 72 polymorphism in ovarian carcinoma development in Serbian women. STUDY DESIGN: 47 wild-type TP53 gene ovarian carcinoma samples and 70 cervical smears from gynecologically healthy women were analyzed. DNA was extracted by a salting-out procedure. Codon 72 polymorphism was assessed by PCR-RFLP method. χ(2), Fisher exact test and odds ratio were used for statistical analysis. RESULTS: The distribution of Arg/Arg, Arg/Pro and Pro/Pro genotypes of codon 72 of the TP53 gene was: 46.8%, 46.8% and 6.4%, respectively in the ovarian carcinomas and 64.3%, 31.4% and 4.3%, respectively in the control group. We observed an increased risk for the development of ovarian carcinoma for Pro homozygotes in relation to heterozygotes plus Arg homozygotes (OR=1.52; 95% CI 0.29-7.89) and a higher one for Pro/Pro plus Arg/Pro genotype in relation to Arg homozygotes (OR=2.04; 95% CI 0.96-4.34). CONCLUSION: The results showed no association between codon 72 TP53 gene polymorphism and risk for development of ovarian carcinoma in Serbian women. However, this observation requires further analysis of a larger case-control study group.