Genetic epidemiology of breast cancer in CYPRUS: A case -control study of DNA repair genes

Abstract

The occurrence of early-onset breast cancer (EOBC) has been associated with germline mutations in the BRCA1 and BRCA2 genes. The first aim of this thesis was to evaluate the frequency and distribution of mutations in these genes, in a group of Cypriot women diagnosed with EOBC. Pathogenic mutations were identified in 6 of the 26 unrelated patients. This study supports a strong correlation between the early onset breast cancer phenotype and the presence of pathogenic BRCA1/2 mutations. It is of interest that pathogenic mutations were detected in patients without a family history of the disease. Based on these results, we recommend that BRCA1/2 screening should be offered to patients with a diagnosis of EOBC irrespective of their family history. The known breast cancer susceptibility genes explain only about 5% of breast cancer cases. Thus, it is likely that other breast cancer susceptibility genes exist. The second aim of the present thesis was to assess whether alterations in DNA repair genes modify breast cancer risk in the Cypriot population. Towards this objective, blood samples were collected and genomic DNA isolated from 1109 Cypriot female breast cancer patients diagnosed between 40-70 years old, and from 1177 age-matched healthy female controls. A total of 79 single nucleotide polymorphisms (SNPs) were genotyped in all samples. Significant associations with breast cancer risk were observed for eight of the SNPs studied. Five SNPs in the BRCA2, MRE11A, MUS81, PBOV1 and XRCC1 genes, were associated with an increased risk for breast cancer, while two SNPs in the NBS1 gene and one SNP in the MRE11A gene appeared to be associated with reduced risk for the disease. The data from this study support the hypothesis that genetic variants in DNA repair genes influence breast cancer risk and provides further evidence for the existence of a polygenic model for breast cancer.