GENE'S POLYMORPHISM OF DNA DOUBLE-STRAND BREAKS REPAIR IN BREAST CANCER

Breast cancer is one of the most often female cancers. From the last few years in Poland morbidity increased about 4-5%. This cancer is also cause of the major part of deaths caused by malignant tumors. Etiology of most cases of breast cancer is not possible to determine. The most important risk factors are age and breast cancer occurrence in first and/or second step relatives. Germinal mutations in two major high penetrance genes, BRCA1 and BRCA2 are responsible for high risk of cancer development but they constitute less than 5% of all cases of this cancer. Breast cancer can be a result of genomic instability resulted from presence of DNA double strand breaks. DNA double strand breaks are one of the most dangerous DNA damage. Unrepaired can cause amplification or lost of genetic material, which in turn can cause neoplastic transformation by oncogene activation, inactivation of suppressor genes or loss of heterozygosity. Epithelial cells of mammary gland, in consideration of estrogen exposition are remarkable exposed to induction of different DNA damage, including also double strand breaks. These breaks are usually repaired with high fidelity by homologous recombination repair (HRR) or non-homologous end joining (NHEJ). Disorders of double strand DNA repair increase the breast cancer risk, in familiar as well as sporadic one. Differences in efficacy of DNA repair processes resulting from naturally occurred polymorphisms can also affect of breast cancer risk. Polymorphic genes of DNA repair are in great part included to low penetrance genes, with means that single gene product most often slightly affects the disease occurrence risk, but accumulation of changed alleles can have essential significance for it development. There are about 3 millions of single nucleotide polymorphisms (SNP) in human genome, which consist about 90% of all differences in the sequence. In the article were displayed information of significance of single nucleotide polymorphic variants of genes coding for proteins participating in DNA double strand breaks repair for breast cancer risk. In relatively small numbers of accessible articles, small number of SNPs for selected genes, coding for proteins of both DNA repair pathways, HRR as well as NHEJ were examined. The statistically important increase of the breast cancer occurrence risk was shown in case of persons, in which the occurrence of polymorphic variants was shown: rs1801320, rs2412546, rs4417527, rs861539, rs144848 in genes coding for RAD51, XRCC3 and BRCA2 proteins, taking a part in homologous recombination and in case of variants: rs2267437. rs2075685 in Ku70 and XRCC4 genes, coding for proteins taking a part in DNA repair by non homologous end joining. Breast cancer is the polygenic disease, therefore is particularly interesting to investigate of SNPs in multiple loci from the same or metabolically connected genes. In case of genes coding for proteins of the DNA repair by homologous recombination is particularly worthy to notice the fact, that the same polymorphic variants differentially affect breast cancer risk in carriers of specified mutations in BRA 1 and BRCA2 genes and in persons without such mutations and polymorphisms discovered. These differences can reflect different significance of SNP for occurrence and development of sporadic and hereditary breast cancers. The inclusion of SNP variant in disease risk factors is not possible only on the basis on occurring the statistically important difference in polymorphism frequency in groups of sick and healthy persons. From clinical point of view polymrphic variant can be accepted as the real disease development factor if we know physiological mechanism of its influence on the disease origin. At present stage, investigations focus first of all on the selection of all possible polymorphic variants and their combinations, potentially able to contribute in breast cancer development. The great progress in this area surely provide DNA microarrays, that allow in short time period genotype of hundreds polymorphic sites.