POSTER NO: 265

DNA-polymorphisms of CYP17, CYP19, CYP1A1, NQ01 and predisposition to breast cancer risk

¹V.V. Artamonov, ²L.N. Liubchenko, ¹O.V. Babenko, ¹M.V. Nemtsova, ¹D.V. Zaletayev
¹Research Centre for Medical Genetics, RAMS, Moskvorechie sr. 1, Moscow, Russian Federation, ²Research Centre for Oncology, RAMS, Kashirskoe sh., Moscow, Russian Federation

Breast cancer is one of the most frequently diagnosed malignancies in women in the world, and responsible for approximately 20% of deaths from cancer in women. The exact causes of sporadic breast cancer are unknown, but both environmental and genetic factors are involved. Genetic influences predisposing to breast cancer include specific mutations in high penetrance genes such as BRCA1 and BRCA2. However, these mutations are relatively rare (about 5%), and the identification of polymorphisms in less penetrant 'susceptibility' genes is likely to be more important on a population basis. Candidate low penetrance genes are involved in a variety of pathways, ranging from xenobiotic metabolism to steroid hormone metabolism. DNA sequences containing polymorphisms may alter functional properties of proteins, leading to alterations in metabolic or xenobiotic pathways. This in turn may influence carcinogenesis, and are likely to be important as markers for susceptibility to disease and disease outcome, as well as markers for response to specific therapies. There is substantial evidence indicating that estrogens are important mitogenic stimulants in breast cancer. As increased exposure to estrogens is considered to be a risk factor for breast cancer, the human aromatize gene (Cyp19) and gene cytochrome P450c17a (Cyp17) are plausible candidates for low penetrance breast cancer susceptibility. These enzymes catalyze the conversion of androgens to estrogens and estradiols synthesis in the estrogen biosynthesis pathway. We have assessed the frequency of allelic variants of the Cyp19 intron 4 (TTTA)n repeat in 174 breast cancer cases and 110 controls. According to literature information the (TTTA)10 repeat and (TTTA)8 repeat variants represent low penetrance breast cancer susceptibility alleles. Our breast cancer cases had a statistically significant positive association with the (TTTA)8 allele (10,9 versus 6,4%, P<0,95). In Cyp17 we studied SNP T27C (MspA1). Cyp17 genotypes (A2/A2 and A2/A1 alleles) were associated with an increased risk of breast cancer (for A2 (MspA1+): P<0,05). Exogenous substances detoxification enzymes genes polymorphisms might also be associated with development of breast cancer. We studied SNP T6235C (Msp1) in AHH gene (Cyp1A1) and SNP C609T (Hinf1) in Nad(P)H-oxyquinonereductase gene (NQ01). It was revealed, that in our sampling allele C6235 has insignificant frequency and cannot be a marker of breast cancer. For NQ01 we show association of C609-allele with risk of breast cancer (P<0,05).