Genetic variation in DNA repair genes can alter an individual's capacity to repair damaged DNA and influence the risk of cancer. We tested seven polymorphisms in DNA repair genes XRCC1, ERCC2, XRCC3, XRCC2, EXOI and TP53 for a possible association with breast cancer risk in a sample of 672 case and 672 control Russian women. An association was observed for allele A of the polymorphism XRCC1 (R399Q) rs25487 (co-dominant model AA vs. GG: OR 1.76, P = 0.003; additive model OR 1.28, P = 0.005; dominant model: OR 1.29, P = 0.03; recessive model OR 1.63, P = 0.008). Allele T of the polymorphism ERCC2 (D312N) rs1799793 was also associated with breast cancer risk (co-dominant model TT vs. CC: OR 1.43, P = 0.04; additive model OR 1.21, P = 0.02; dominant model: OR 1.30, P = 0.02), but the association became insignificant after applying Bonferroni correction. No association with breast cancer was found for the remaining SNPs. In summary, our study provides evidence that polymorphisms in DNA repair genes may play a role in susceptibility to breast cancer in the population of ethnical Russians.

The CYP2D6, GSTM1, and GSTT1 xenobiotic biotransformation genes are involved in processes of carcinogenesis in humans due to the presence of mutant variants that decrease or block the expression of genes. Since the middle of the 20th century, there has been an extensive increase in cancer morbidity in human populations, including indigenous ethnic groups of Siberia. The problem of ethnic differences in sus ceptibility to cancer is still pressing. The study of polymorphisms of the CYP2D6 (CYP2D6*3 and CYP2D6*4 alleles), GSTM1, and GSTT1 (GSTM1 0/0 and GSTT1 0/0 "null" genotypes) genes (which are considered as genetic markers of the risk of cancer) was conducted for the first time in practically healthy representatives of the Samoyedic ethnic groups (Selkups, Forest Nenets, and Nganasans) and Russians from Siberia. A signif icant variability in the CYP2D6*4 and GSTM1 0/0 frequency distribution in northern populations was detected. At the same time, there are no significant differences in frequencies of the CYP2D6*3 and GSTT1 0/0 variants among indigenous populations of the Selkups, Forest Nenets, and Nganasans. In the CYP2D6*4 allele frequencies, indigenous ethnic groups are intermediate between Russians of Siberia and Mongolians of China. However, frequencies of the null GSTM1 0/0 and GSTT1 0/0 genotypes in indigenous ethnic groups are significantly lower than in populations of Russians of Siberia and Mongoloids of China (p < 0.05). Gen erally, according to all four studied polymorphic variants, it is possible to predict a decreased risk of cancer in indigenous Samoyedic ethnic groups, as compared with Russians of Siberia. The Forest Nenets population, with an increased frequency of the GSTM1 0/0 genotypes, is an exception; this can be caused by the original ity of their marriage structure and increased inbreeding coefficient. The results we obtained can also be important in predicting the probability of complications and a positive response to drugs that are metabolized by the GSTM1, GSTT1, and CYP2D6 enzymes.

Changes (or variants) in BRCA1 and BRCA2 gene sequences can have different lengths and clinical significance: from single nucleotide variants (SNV) and short insertions/deletions (<50 bp) to extended deletions and duplications (so-called copy number variations, or CNV). According to their clinical significance, all variants can be divided into pathogenic, likely pathogenic, variants of uncertain significance, likely benign, and benign. Moreover, variants can be germinal (i.e. inherited from parents) and somatic (arising in the process of development of the organism). A specific somatic event is loss of heterozygosity (LOH), i.e. transition of one or many point and short variants from heterozygous to homozygous state. Such an event can be the key to the development of carcinogenesis for cells carrying a pathogenic variant, if we consider it within the framework of the Knudson's two-hit carcinogenesis theory. We studied the prevalence and nature of LOH in of ovarian cancer samples carrying or not carrying a pathogenic variant. To this end, a full coding sequence of BRCA1/2 genes was determined in 30 pairs of DNA samples isolated from blood cells and paraffinized histological blocks of patients on a MiSeq Illumina instrument. Analyss of the obtained reads revealed 9 pathogenic point and short variants (30% patients): 6 germinal (20%) and 3 somatic (10%), and 8 somatic CNV (3 deletions and 5 duplications of several or all exons of the BRCA1 gene). LOH was detected in 70% patients; among the carriers of pathogenic variants - in 83%. For pathogenic variants, the percentage of reads with the alternative allele increased more often than for benign variants located in another gene, or detected in other patients (67% vs. 44%). However, the difference was statistically insignificant, which can be due to insufficient number of patients. Only in 3 of 21 cases of LOH (14%), it can be attributed to CNV. In other cases, LOH is most likely determined by gene conversion, but further research is needed.