[Follicular cell (papillary and follicular) thyroid carcinoma, genetic inheritance, and molecular diagnostic markers].

OBJECTIVE: To determine the genetic forms of follicular cell thyroid carcinoma (FCTC) (papillary and follicular thyroid carcinoma (PTC and FTC)), to identify criteria to individually predict the development of the same disease for relatives, and to assess the role of molecular markers in the diagnosis, prognosis, and treatment of this disease. SUBJECTS AND METHODS: One hundred and ninety adult patients aged 20 to 84 years with histologically verified PTC and FTC and 20 children (12 patients with PTC and 8 with benign thyroid tumors) aged 2 to 16 years were examined. To assess the role of the BRAF gene as a molecular marker for thyroid carcinoma, DNA was isolated from the thyroid tumor tissue of 29 patients, which had been obtained by fine-needle aspiration biopsy (FNAB) and scraping and swabbing the cytological specimen previously showing an area containing tumor cells. A BRAF c.1799T>A (p.V600E) mutation in the FNAB specimens was tested by allele-specific ligation, followed by PCR amplification. RESULTS: The examinees' families were found to have a segregation of benign thyroid tumor and nontumor diseases (13.6%). Neoplasias of different sites were observed in 15% of the patients' relatives. Multiple primary tumors were detected in 6.1% of the patients and in 25% of the examined children (3/12). PTC was ascertained to accumulate as two clinical forms in the families. One form belongs to familial PTC (FPTC) in which two or three generations of relatives in the family are afflicted by only PTC and have a more severe phenotype of the disease. The other includes an association of FPTC with papillary kidney cancer. Furthermore, FPTC and PTC may be a component of multitumor syndromes, such as multiple endocrine neoplasia type 1, Cowden syndrome, and familial adenomatous polyposis. The familial hereditary forms of FCTC were generally revealed in 4.2% of the patients. BRAF v600E mutations were found in only 3 patients with Stages II and III PTC and were not in all the 12 children with PTC. CONCLUSION: The found clinical manifestation of the hereditary forms of FCTC permits the identification of people at high risk for this disease. No correlation between somatic BRAF mutations with a less favorable course in PTC can be noticed because there are few observations. Analysis of published data on the role of molecular markers in FCTC has shown that the existing specific somatic changes complement information in the differential cytological diagnosis when examining FNAB specimens.

[Simultaneous prophylactic surgery for colon cancer in women. Viewpoint of the gynecologist].

A 5-year survival of patients with Stage III colon cancer with prophylactic panhysterectomy in anamnesis was 83.3%, significantly higher than that of patients with Stage III colon cancer without panhysterectomy (69.3%) and than in colon cancer patients with metachronous ovarian metastases (42%). In families of patients with primary multiple malignant tumors (PMMT) of colon, endometrium and/or ovaries as well as in cases of accumulation in the same family of solitary tumors of the above locations it is necessary to carry out genetic testing to identify mutations in genes MSH2, MLH1, MSH6. Carriers of mutations in genes of mismatch repair MSH2, MLH1, MSH6 should be assumed to the high-risk group for the development of malignancies both PMMT of colon and organs of the female reproductive system and solitary tumors of the above locations. All women suffering from colon cancer, especially in the presence of mutations in genes of mismatch repair, in pre- and menopause should be undergone simultaneous prophylactic surgery: panhysterectomy. The question about the greater omentum should be decided situationally.

[Association of polymorphic markers Arg72Pro of TP53 and T309g of MDM2 genes with non small cell lung cancer in Russians of Moscow region].

State Research Center "GosNIIgenetika", Moscow, 117545 Russia). Association of polymorphic markers Arg72Pro of TP53 gene and T309G of MDM2 gene with risk of non small cell lung cancer has been studied in Russians of Moscow region. We found an association of minor Pro/Pro genotype of polymorphic marker Arg72Pro (OR = 5.46, p = 8 x 10(-6)) and TG genotype of polymorphic marker T309G (OR = 5.57, p = 0.007) with non small cell lung cancer development. We have also showed a strong association of both Pro/Pro and TG genotypes with development of adenocarcinoma (OR = 8.71, p = 3 x 10(-6) and OR = 8.13, p = 0.003) and squamous-cell lung cancer (OR = 4.2, p = 0.001 and OR = 7.02, p = 0.002). We have finally found highly reliable association of combined susceptible genotypes of polymorphic markers Arg72Pro and T309G of TP53 and MDM2 genes with non small cell lung cancer and both its subtypes (OR = 7.9, p = 0.01; OR = 9.12,p = 0.02; OR = 7.31, p = 0.03, respectively).

[Genotyping of BRCA1, BRCA2 and CHEK2 germline mutations in Russian breast cancer patients using diagnostic biochips].

Germline mutations of BRCA1/2 genes cause the predisposition of their carriers to breast or/and ovary cancers (BC or/and OC) during the lifetime. Identification of these mutations is a basis of molecular diagnosis for BC susceptibility. Rapid genotyping technique using microarrays for identification of BRCA1 185delAG, 300T>G, 4153delA, 5382insC mutations and 4158 A>G sequence variant; BRCA2 695insT and 6174delT mutations; 1100delC mutation in CHEK2 gene was applied for 412 randomly collected breast cancer samples from the central region of European area of Russia. In 25 (6.0%) patients (6.0%) BC was associated with other tumours: OC, cervical cancer, colorectal cancer etc. BRCA1/2 and CHEK2 mutations were found in 33 (8.0%) BC patients. The most frequent mutation was BRCA1 5382insC, occurred in 16 (3.9%) BC patients, and CHEK2 1100delC, revealed in 7 (1.7%) BC patients. An application of diagnostic BC-microarray for genetic testing of BRCA1/2 and CHEK2 founder mutations has been discussed.

[Methylation profile of group of miRNA genes in clear cell renal cell carcinoma; involvement in cancer progression].

MicroRNA regulates gene expression, is involved in many cellular processes, and plays an important role in the development of cancer. The regulation of the expression of miRNA genes can be achieved by methylating their CpG islands, which is shown in different types of tumors. The methylation of miRNA genes in clear cell renal cell carcinoma (CCRCC) has mainly been studied for the miR-9 and miR-34 families. The methylation of six miRNA genes (miR-124a-2, -124a-3, -9-1, -9-3, -34b/c, -129-2) was investigated with the use of representative set of CCRCC samples (46 cases). Methylation of three genes miR-124a-2, -124a-3, and -129-2 was studied in kidney tumors for the first time. Methylation analysis was performed using methyl specific PCR. It is shown that the frequency of methylation of six genes (miR-124a-2, -124a-3, -9-1, -9-3, -34b/c and -129-2) was significantly higher in tumor samples than in samples of histologically normal tissue (P < 3 x 10(-5) by Fisher's exact test). These results suggest the properties of tumor suppressors for the six miRNA genes indicated in CCRCC. We also found correlations between the methylation frequency of some miRNA genes and signs of the progression of CCRCC (tumor size, clinical stage, loss of differentiation, and metastasis).

[Methylation of some miRNA genes is involved in the regulation of their target genes RAR-beta2 and NKIRAS1 expression in lung cancer].

To date, there are more than two thousand human miRNAs, each of them may be involved in the regulation of hundreds of protein coding target genes. Methylation of CpG-islands, in turn, affects miRNAs gene expression. Our aim was to evaluate the role of methylation in the regulation of miRNA gene expression and, consequently, in the regulation of expression of target genes in primary lung tumors. Using a common collection of non-small cell lung cancer samples we performed a comprehensive study, including analysis of the methylation status and expression levels of some miRNA genes and their potential target genes on chromosome 3: RAR-beta2 and NKIRAS1. Increased frequency of methylation in lung tumors compared to histologically normal tissue was revealed for miR-9-1 and miR-34b/c genes with significant statistics (P < or = 0.05 by Fisher exact test) and for miR-9-3 and miR-193a was marginally significant (P < or = 0.1). Significant correlation was revealed between alterations of methylation and expression level of miR-9-1 gene (P = 5 x 10(-12) by Spearman) in the lung tumors, this suggests the role of methylation in the regulation of expression of this miRNA genes. Besides, a statistically significant negative correlation (P = 3 x 10(-12)-5 x 10(-13) by Spearman) was found between alterations of expression levels of miR-9-1 and miR-17and RAR-beta2 target gene and also between expression level alterations of miR-17 and NKIRAS1 that was not previously analyzed. The inverse relationship between expression levels of miRNA genes and their target genes is consistent with the known mechanism of suppression of protein coding genes expression under the action of miRNAs. For the first time significant correlations (P = 3 x 10(-10)-4 x 10(-13) by Spearman) were shown between alterations of methylation status of miRNA genes (miR-9-1, miR-9-3, miR-34b/c, miR-193a) and the expression level of RAR-beta2 target gene and between alterations of methylation status of miR-34b/c, and miR-193a and the expression level of NKIRAS1 target gene in the primary lung tumors, which suggests the possibility of indirect effects of methylation of miRNA genes on expression level of target genes.

[Alterations of expression level of RASSFIA gene in primary epithelial tumors of various locations].

Tumor-suppressor activity was established for RASSF1A gene by in vitro and in vivo including studies of knock-out mutated mice cells. Data on methylation of promoter region and expression decrease revealed mainly in cancer cell lines were reported. Here, analysis of RASSF1A mRNA quantity was performed for the first time in primary epithelial malignant tumors of five various locations from 130 patients by semi-quantitative RT-PCR. Representative sets of kidney, lung and breast carcinomas samples were studied. Preliminary data for RASSF1A expression in ovarian and colorectal carcinomas are also reported. Our system studies showed unexpected expression profiles, namely mRNA level increase more frequently (2-7 times) than decrease in renal, breast, ovarian, and colorectal carcinomas. Increasing RASSF1A mRNA level was revealed significantly more frequently in renal cell carcinoma (24/38, 63% vs. 8/38, 21%, P = 0.0004, by Fisher exact test) and ovarian carcinomas (8/13, 62% vs. 2/13, 15%, P = 0.0114). Only in non-small cell lung cancer decreasing and increasing of RASSF1A expression were observed with equal frequency (16/38, 42%). Noteworthy, for early clinical stages prevalence of increasing expression both in squamous cell lung cancer and in adenocarcinoma was revealed, and for advanced clinical stages evident prevalence of decreasing RASSF1A expression was established. Cases with increasing expression both in early and advanced stages of clear cell renal cell carcinoma were in prevalence, in advanced stages it was proved significantly (P = 0.0094). These data suggested that RASSF1A expression alterations were tumor specific. Mentioned above regularity could point onto ambivalent RASSF1A functions in tumors--a tumor-suppressor gene and a proto-oncogene as well.

[Detection of KRAS mutations in tumor cells using biochips].

Somatic mutations in the KRAS gene are important markers of some types of tumors, for example, pancreatic cancer, and may be useful in early diagnostics. A biochip has been developed which allows determining most frequent mutations in 12, 13 and 61 codons of the KRAS gene. To increase the sensitivity of the method and to make possible the analysis of minor fractions of tumor cells in clinical samples the method of blocking a wild type sequence PCR amplification by LNA-oligonucleotides has been used. The product of LNA-clamp PCR was further hybridized with oligonucleotide probes, immobilized on biochip. Biochip was tested with 42 clinical DNA samples from patients with pancreatic cancer, mostly ductal adenocarcinomas. As reference methods, the RFLP analysis and sequencing were used. The developed approach allows detecting somatic mutations in the KRAS gene if the portion of tumor cells with mutation is at least 1% of whole cell population.

[Analysis of K-ras, BRCA1/2, CHEK2 mutations and microsatellite markers (loss of heterozygosity at 9p, 17p and 18q) in sporadic pancreas adenocarcinomas].

The purpose of this study was to investigate informativety and clinical significance of most frequent somatic alterations in K-ras, TP53, CDKN2A, MADH4 and more uncommon mutations in BRCA1, BRCA2, CHEK2 genes, which arise on preinvasive stage in sporadic pancreatic adenocarcinomas (PA), in Russian patients. We examined surgically resected and manually microdissected primary PA tissue samples and samples of normal pancreatic tissue for 37 individuals. K-ras mutations in codon 12 were found in 24 tumors (0.65) and none of normal tissue samples. No mutations were detected in BRCA1(185delAG, 300T > G, 4153delA, 4158A > G,5382insC), BRCA2 (695insT, 6174delT) and CHEK2 (1100delC) genes. Informativety for allelic loss of three tumor suppressor genes studied had not statistically significant differences: 60% - for TP53 (GDB186817) and CDKN2A (D9S974 + D9S162); and 65.7% - for MADH4 (D18S363 + D18S474) (t = 0.48). Maximal frequency of loss of heterozygosity (LOH) was observed for CDKN2A - 0.95. For TP53 and MADH4 it was 0.62 and 0.70 respectively. The tumors included 80% cases showing LOH on different chromosomal loci. The combination of K-ras mutations (c.12) and LOH at 9p, 17p and 18q resulted in a high informativety of selected molecular markers: 85.7%. Instability of microsatellites was found only in 9% of PA.

[Methylation of promoter region of RASSF1A gene and frequencies of allelic imbalances in chromosome 3 critical regions are correlated with progression of clear cell renal cell carcinoma].

The short arm of chromosome 3 (3p) contains several critical regions harboring the set of genes with tumor suppressor activities. The RASSF1A gene (LUCA region, 3p21.31) shows various functions which can be associated with tumorigenesis. Among 3p genes this gene can be most frequently methylated in epithelial tumors of various locations. Here two independent methods (methyl-specific PCR and methyl-sensitive restriction analysis) were used to show significant correlation of methylation level of promoter region of this gene with grade and clinical stage of clear cell renal cell carcinoma (RCC) for the first time. Analysis of 23 polymorphic markers of 3p using the representative set of samples (80 cases RCC), described clinically and histological, permitted to reveal significant correlation between frequency of allelic alterations in some critical regions of 3p (LUCA and AP20) and RCC progression, as distinct from the whole 3p. These data suggest that methylation of promoter region of the RASSF1A gene is associated with RCC progression, and besides, structure-functional alterations in other 3p genes can be also related with RCC progression. In addition, significant correlation between RASSF1A methylation events and allelic losses in the close polymorphic marker was shown here, pointing to the role of "two hit" model for this tumor-suppressor gene inactivation in RCC.

[Alteration of SEMA3B gene expression levels in epithelial tumors].

Gene expression decreasing in tumors permits to suggest tumor-suppressor activities for these genes. Thus, mRNA quantity decrease was found for SEMA3B gene in many cell lines of small cell (SCLC) and non-small cell lung carcinoma (NSCLC) and it is well-known that SEMA3B suppresses growth of the NCI-H1299 non-small cell lung carcinoma (NSCLC) cell line and tumor formation in nude mice. The aim of this work was to study spectrum of SEMA3B expression level in epithelial tumors of various locations. Using semi-quantitative RT-PCR it was shown for the first time decrease of SEMA3B mRNA quantity (10-250 times as much) in cell lines of renal, breast and ovarian tumors (4/11, 36%). SEMA3B expression profiles in primary tumors of five locations (kidney, lung, breast, ovary and colon) were studied for the first time. This analysis revealed decrease of mRNA quantity (5-1000 times as much) in clear cell renal cell carcinomas with significant high frequency: 25/51, 49% (cases with decrease of mRNA quantity) and 5/51, 10% (cases with increase), P < 0.0001 by Fisher exact test. In addition, the first data about comparatively frequent decrease of mRNA quantity in ovarian (5/16, 31% vs. 2/16, 12%) and colorectal carcinomas (6/11, 54% vs. 2/11,18%) were shown. These results permitted to suggest a possible role of SEMA3B in inhibiting of growth of renal, ovarian and colorectal cancer cells.

[Two CpG-islands of SEMA3B gene: methylation in clear cell renal cell carcinoma].

Earlier in some small cell lung (SCLC) and non-small cell lung carcinoma (NSCLC) cell lines, methylation of CpG-island was found in the SEMA3B region, which belongs to the first intron according to the NCBI data base (Build 36). The aim of this work was to study methylation of two SEMA3B CpG-islands: promoter and intronic in clear cell renal cell carcinoma (RCC). Using methyl specific PCR and bisulfite sequencing, it was shown for the first time that promoter CpG-island was methylated in RCC with high frequency 56% (34/61), and intronic CpG-island - with somewhat lower frequency 35% (17/48). Significant reverse correlation was estimated between mRNA level decrease and methylation of promoter CpG-island in RCC for the first time (P < or = 0.05 by Fisher's exact test), no correlation was determined for intronic CpG-island. This result suggested that methylation of promoter CpG-island contributed into inactivation of SEMA3B gene-suppressor in RCC.

[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.

[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.

[Analysis of BRCA1/2 and CHEK2 mutations in ovarian cancer and primary multiple tumors involving the ovaries. Patients of Russian population using biochips].

Ovarian cancer (OC) is one of the leading cause of cancer death in women. Inherited BRCA1 and BRCA2 mutations strikingly increase OC risk (with lifetime risk estimates ranging at 10-60%). Mutation 1100delC in CHEK2 gene was shown to be associated with breast cancer in women carrying this mutation. Knowledge of the nature and frequency of population-specific mutations in these genes is a critical step in the development of simple and inexpensive diagnostic approaches to DNA analysis. The frequencies of 185delAG, 300T>G, 4153delA, 4158A>G, 5382insC mutations in BRCA1 gene, 695insT and 6174delT mutations in BRCA2 gene and 1100delC mutation in CHEK2 gene were analyzed using biochips in Russian OC patients. We studied 68 women who received a diagnosis of epithelial OC and 19 women with primary multiple tumors involving the ovaries. The 185delAG, 300T>G, 4153delA and 5382insC in BRCA1 gene were identified. The most prevailing mutation was 5382insC in BRCA1 gene (87.5% of all BRCA1 mutations OC patients, 50.0% in patients with primary multiple tumors involving the ovaries). No mutations in BRCA2 and CHEK2 genes were detected.

[Association of polymorphisms in SULT1A1 and UGT1A1 Genes with breast cancer risk and phenotypes in Russian women].

Estrogens are critical for breast cancer initiation and development. Sulfotransferase 1A1 (SULT1A1) and UDP-glucuronosyltransferase 1A1 (UGT1A1) conjugate and inactivate both estrogens and their metabolites, thus preventing estrogen-mediated mitosis and mutagenesis. SULT1A1 and UGT1A1 genes are both polymorphic, and different alleles encode functionally different allozymes. We hypothesize that low activity alleles SULT1A1*2 and UGT1A1*28 are associated with the higher risk for breast cancer and more severe breast tumor phenotypes. We performed a case-control study, which included 119 women of Russian ancestry with breast cancer and 121 age-matched Russian female controls. We used PCR, followed by pyrosequencing to determine SULT1A1 and UGT1A1 genotypes. Our data showed that UGT1A1*28 allele was presented at a higher frequency than the wild type UGT1A1*1 allele in breast cancer patients as compared to controls (p = 0.002, OR = 1.79, CI 1.23-2.63). Consistently, the frequency of genotypes that contain the UGT1A1*28 allele in the homozygous or heterozygous state was greater than the frequency of the wild type UGT1A1*1/*1 genotype in breast cancer patients as compared to controls (p = 0.003, OR = 4.00, CI 1.49-11.11 and p = 0.014, OR = 2.04, CI 1.14-3.57, respectively). The group of individuals, carrying the UGT1A1*28 allele in the homo- or heterozygous state also presented larger breast tumors (>2 cm) as compared to the group with high enzymatic activity genotypes p = 0.011, OR = 3.44, CI 1.42-8.36). No association was observed between any of the SULT1A1 genotypes and breast cancer risk or phenotypes. Our data suggest that UGT1A1 but not SULT1A1 genotype might be important for breast cancer risk and phenotype in Russian women.

[Methylation of the promoter region of the RASSF1A gene, a candidate tumor suppressor, in primary epithelial tumors]. / Uroven' metilirovaniia promotornoi oblasti gena RASSF1A v pervichnykh épitelial'nykh opukholikh.

Methylation of the promoter CpG-islands of the candidate tumor suppressor gene RASSF1A (3p21.31) was studied in primary tumors of kidney, breast and ovary (172 cases). Methylation-specific PCR (MSP) and methyl-sensitive restriction endonuclease digestion followed by PCR (MSRA) were applied. Statistically significant correlation (P << 10(-6)) was shown for the results of the MSP and MSRA, and the data of bisulfite sequencing reported earlier. The frequency of RASSF1A methylation according to MSP and MSRA was 86% (25/29) and 94% (50/53) in renal cell carcinoma (RCC) and 64% (18/28) and 78% (32/41)--in breast carcinoma (BC) samples, and 59% (17/29) and 73% (33/45) in ovarian epithelial tumors (OET), respectively. The use of several methyl-sensitive restriction enzymes (HpaII, HhaI, Bsh12361, AciI) enhanced the sensitivity of MSRA and allowed to analyze methylation status of 18 CpG-pairs in the RASSF1A CpG-island. Density of methylation of the RASSF1A CpG-island was 72% (644/900) in RCC, 63% (361/576) in BC, and 58% (346/594) in OET samples (18 CpG-pairs multiplied to the number of samples shown methylation were assumed as 100%). The RASSF1A gene methylation was also observed in samples of morphologically normal tissues adjacent to corresponding tumors (11-35%), but it was not detected in blood DNAs of healthy donors (0/15). The RASSF1A methylation frequency did not show significant correlation to tumor stage, grade and metastases (P = 0.3-1.0). The RASSF1A gene methylation was observed more frequently than other investigated aberrations--hemi- and homozygous deletions inside or around this gene. These observations are consistent with the hypothesis that the RASSF1A gene methylation is an early event in the carcinogenesis and one of the dominant ways of its inactivation.

[Identification of the hereditary variants of skin melanoma]. / Identifikatsiia nasledstvennykh variantov melanomy kozhi.

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.

[Analysis of mutations in the RET proto-oncogene in patients with medullary thyroid tumor]. / Analiz mutatsii v protoonkogene RET u bol'nykh s medulliarnym rakom shchitovidnoi zhelezy.

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.

[Hereditary cancer: identification, genetic heterogeneity, medico-genetic consult]. / Nasledstvennyi rak: identifikatsiia, geneticheskaia geterogennost', mediko-geneticheskoe konsul'tirovanie.

The paper deals with a role of inherited factors responsible for the occurrence of malignant tumors. Inherited types of cancer are shown to occur virtually at its sites and averaged 5-15%. Formalized criteria for identifying inherited cancer diseases and their etiological and genetic heterogeneity are presented. A role of genes that genetically predispose to particular forms of cancer is shown, which allows for early (preclinical) diagnosis and prevention of cancer diseases.