Population analysis of minor hemoglobin fractions. I. Hemoglobin A2]

The inhabitants of 7 isolated villages (of different nationalities) and of 5 panmictic populations were studied. Populational and segregation analyses of Hb A2 in 3036 normal and 150 heterozygous individuals for beta- and delta beta-thalassemia were carried out. The Hb A2 levels in some populations are established to deviate from the normal distribution. Bimodal dependency of the levels of Hb A2 distribution is demonstrated, which suggests the existance of heterogenous subpopulations by the Hb A2 level. The segregation analysis has revealed distinct genetic determination of Hb A2 levels. There was a good correlation between Hb A2 and Hb F values (r=-0.82).     

Analysis of mutations in the RET proto-oncogene in patients with medullary thyroid tumor

The spectrum of mutations of the RET protooncogene was analyzed in Russian patients with inherited or sporadic medullary thyroid carcinoma (MTC). Four RET exons (11, 13, 15, and 16) were subjected to molecular analysis, and mutations were revealed and identified in 47.4% (9/19) patients with sporadic MTC. In total, six mutations (including three new ones) were observed. The most common mutation affected codon 918 to cause substitution of methionine with threonine and accounted for 31.6% alleles. Analysis of exons 11 and 16 revealed four mutations in patients with inherited multiple endocrine neoplasia type 2 (MEN 2). Mutations were found in each patient. Thyroidectomy was performed in four asymptomatic carriers of RET mutations from three MET 2A families (in two families, affected relatives had bilateral pheochromocytoma). In two patients, analysis of the surgery material revealed MTC microfoci in both lobes of the thyroid gland. The results provide the ground for constructing a bank of genetic information on Russian MTC patients with the clinically verified diagnosis.     

Mapping allelic deletions on the short arm of human chromosome 3 in kidney neoplasms]

Allelic deletions along the short arm of human chromosome 3 were mapped in 57 pairs of DNA samples from tumor and normal tissue of renal carcinoma patients in order to locate potential tumor suppressor genes. Twenty highly polymorphic microsatellite markers were used for deletion mapping. Allelic deletions were found in most of the samples (91%). Extended terminal deletions (56%) prevailed over shorter internal and multiple deletions and dominated (65%) in the most aggressive histopathological kidney cancer subtype, clear-cell carcinoma. Frequency analysis of loss of heterozygosity allowed detection of the human chromosome 3 regions most essential for renal carcinomas: the region adjacent to the gene VHL (3p26-p25), the region of homozygous deletions AP20 (3p22-p21.33), and a new region between markers D3S2420 and D3S2409 (3p21.31, 2.2 Mbp).     

Identification of the hereditary variants of skin melanoma

The identification of hereditary variants of cutaneous melanoma and analysis of the role of hereditary factors and syndromes predisposing to cutaneous melanoma were carried out. The involvement of individual nevus phenotypes in the development of this disease was determined. Based on a survey of recent molecular biological data and our studies, the etiological and genetic heterogeneity of cutaneous melanoma is reported. In relatives of patients with cutaneous melanoma and persons with multiple pigmented nevi, the malignant tumors proved to be differentiated in the direction of the neural crist tissues and/or derivatives of cutaneous mesenchyma. Based on the evidence obtained, the approaches have been developed to formation of risk groups for the purpose of early diagnostics of cutaneous melanoma.     

Clinico-genetical studies of colonic cancer. II. Genetic analysis of predisposition to colonic cancer

The structure of subjection to different clinical forms of colon cancer and to the morbidity as a whole approximates better the quasi-continued phenotypical model within which the contribution of genetic factors reaches 68-84%, that of incidental medium factors being 16-32%. Genetic study of heterogeneity of colon cancer clinical forms revealed that their pathogenetic community was quite high. However, the origin of colon cancer depends strongly on genetic factors (83.7 +/- 7.3%), in comparison with rectal cancer (67.9 +/- 7.1%). The analysis of colon cancer interrelation with other malignant neoplasms (including specific ones for women--breast and uterus cancer) revealed that the development of another malignant neoplasms was the result of the influence of partially common genes (20-50%) which predetermined the development of colon cancer and other malignant neoplasms. According to the data obtained in this study, the tables of repeated risk have been worked out which may be used for medico-genetic consultation.     

Human chromosome 3P regions of putative tumor-suppressor genes in renal, breast, and ovarian carcinomas

Allelic imbalances (AI) of polymorphic markers at the short arm of chromosome 3 (3p) were mapped using DNA samples of renal cell carcinoma (RCC, 80 cases), breast carcinoma (BC, 95 cases), and epithelial ovarian cancer (EOC, 50 cases) at the same dense panel of markers (up to 24 loci). Six regions with the increased AI frequency (versus the average values determined for all the analyzed 3p markers) at RCC, BC or EOC were found in 3p chromosome. Four 3p regions presumably contain suppressor genes of tumor growth (TSG) observed in the epithelial tumors of various types. Region between D3S2409 and D3S3667 markers in the 3q21.31 region was identified in this study for the first time. The AI peak in D3S2409-D3S3667 region was statistically significant (P < 0.001, according to Fisher) when representative sample of 95 BC patients was analyzed. The data on increased frequency of polymorphic marker allele amplification suggest that the D3S2409-D3S3667 region contains both putative TSG and protooncogenes.     

Population genetic analysis of the association between the BRCA1 and P53 gene polymorphisms and the risk of sporadic breast cancer

Polymorphism of two tumor-suppressor genes, BRCA1 and P53, was examined. DNA was extracted from blood leukocytes of the women affected with breast cancer (N = 151) and of the women with no clinical symptoms of tumor diseases (N = 191). Typing of the polymorphic variants was performed using PCR-RFLP method. It was demonstrated that the genetic structure of the patient group (taking into consideration BRCA1 and P53 polymorphic variants) differed from that of the control group. The group of genotypes, found exclusively among the patients, as well as the group of "resistant" genotypes revealed predominantly among the controls, was described. Detection of the genotype A1A1 B1B1 S1S1 C1C1 F1F1 J2J2, whose frequency in control group was eight times higher than in the patient group, was an additional confirmation of the existence of "resistant" genotypes. These findings point to the association between the combinations of the BRCA1 and P53 allelic variants and the risk of breast cancer.     

Clinico-genetical studies of colonic cancer. III. Primary multiple malignant neoplasms

The results of clinico-genealogic analysis of 46 patients with primary-multiple malignant neoplasms are given (among them 16 patients with primary-multiple malignant neoplasms of colon cancer and 30 patients with one or more neoplasms in combination with different malignant tumors of other organs). The values of segregation rates obtained for primary-multiple malignant neoplasms are lower than theoretically expected for simple monogeneous types of inheritance. The relation analysis of primary-multiple malignant neoplasms and colon cancer revealed that these tumors are likely to appear among relatives of probands under the influence of the same genetic system of determination. Risk of the colon cancer development for relatives of the patients with primary-multiple malignant neoplasms is higher than for relatives of the patients with colon cancer.     

Methylation of promoter region of RAR-beta2 gene in renal cell, breast, and ovarian carcinomas

The protein encoded by RAR-beta (retinoic acid receptor) gene is a member of the superfamily, of nuclear receptors of retinoids which are involved in regulation of cell differentiation and proliferation. The level of RAR-beta2 mRNA is downregulated in a number of cell lines derived from human epithelial tumors. Inactivation of the RAR-beta2 gene is associated with methylation of its promoter region, which is observed in various carcinomas at a frequency of 30-70%. In renal and ovarian tumors, methylation at this region is poorly studied, the data being contradictory. We report a high methylation frequency in the gene promoter region in RCC (59%, 36/61) and a somewhat lower frequency in EOC (30%, 15/50). Methylation frequency in BC (46%, 26/56) is consistent with the published data. Significant correlation of methylation frequency in promoter region of RAR-beta2 gene with RCC progression (P < or = 0.005 by Fisher's exact test) was established.     

Medico-genetic study of the population of Uzbekistan. VI. Hereditary pathology among the populations of 4 regions of the Kashkadarinskaia area]

The screening for families burdened with multiple cases of non-infectious diseases, the diagnostic of those diseases and the investigation of relations between the population structure and the distribution of hereditary diseases in 4 districts of the Kashkadarja province were carried out. On the basis of the data obtained the load of excessive hereditary diseases was calculated and nosological spectrum was described; it included more than 30 different diseases. The study of spatial distribution of recessive diseases has shown that the load of hereditary diseases may be accounted for the positive assortative matings. The high level of interpopulation migration prevents from the local accumulation of a certain hereditary disease.