[Rare hereditary syndromes associated with polyposis and the development of malignant tumors].

UNLABELLED: Familial adenomatous polyposis (FAP) and Peutz-Jeghers syndrome are genetic diseases characterized by gastrointestinal polyps, extraintestinal manifestations, and autosomal dominant inheritance. The carriers of these diseases from early childhood are at risk for neoplasias at different sites, which are symptomatic at various ages. AIM: to study the clinical organ-specific manifestations in patients with FAP and Peutz-Jeghers, genetics update and possibilities of diagnosis, monitoring, and treatment of these diseases. MATERIAL AND METHODS: The authors give the results of their examination and follow-up of children with FAP and Peutz-Jeghers hamartoma-polypous syndrome. In addition, current data from PubMed, Medline (including reviews, original articles and case reports) were used. RESULTS: The main clinical organ-specific signs of multiple tumors in FAP and Peutz-Jeghers syndrome are shown. Data on the assessment of a risk for malignant tumors at various sites in the affected patients and their family members at different ages are provided. Each of these syndromes has a dissimilar genetic foundation. FAP is caused by the germline mutations in the APC gene, Peutz-Jeghers syndrome is by the STK11 gene, which predispose individuals to specifically associated neoplasias and require different follow-up strategies. Information on a phenotype-genotype correlation may serve as a reference point for the possible severity and various manifestations of a disease. An update on the molecular pathogenesis of these diseases is considered. CONCLUSION: Molecular genetic testing of the genes associated with FAP and Peutz-Jeghers syndromes makes it possible to timely recognize family members at high risk, to plan therapeutic strategy and to affect the course of a disease. The joint participation of pediatricians, proctologists, oncologists, morphologists, geneticists, and molecular biologists is essential to timely recognize the carriers of the syndromes and a better prognosis in these patients.

[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.

[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.

[Spectrum and frequencies of RB1 gene structural defects in retinoblastoma]. / Spektr i chastota strukturnoi patologii gena RB1 pri retinoblastome.

The spectrum and frequencies of RB1 structural defects were studied in tumors and peripheral blood lymphocytes of patients with various forms of retinoblastoma. Single strand conformation polymorphism (SSCP) and heteroduplex (HA) analyses, along with direct sequencing, revealed 47 mutations, including 24 new ones. Of these, 42.5% were nonsense mutations, 15% were missense mutations, 15% affected splicing sites, and 27.5% were frameshifts resulting from microdeletions or microinsertions. Six polymorphisms were found, including three new ones located in the coding region. Microsatellite analysis with markers Rbint2, Rbint20, D13S262, and D13S284 revealed a loss of heterozygosity for at least one marker in 71% tumors.

[Molecular diagnosis of retinoblastoma. First experience in Russia]. / Molekuliarnaia diagnostika retinoblastomy. Pervyi opyt v Rossii.

The first experience with molecular diagnosis of retinoblastoma (RB) in Russia is presented. A protocol based on the use of up-to-date molecular diagnostic methods helps detect structural and functional abnormalities in RB1 gene, diagnose RB in disputable cases and at early stages of the disease. Forty-five families with various forms of RB were examined. Twenty-three mutations in various sites of RB1 gene were characterized. Abnormal methylation in the promotor area of RB1 gene was detected in 20% cases and loss of heterozysity by intragene microsatellite markers was detected in 70% cases. Hence, the causes of RB were detected in 80% families, which led to early diagnosis in close relatives of patients and helped evaluate the repeated risk of the tumor in families of patients with RB.

Diagnosis and prevention of lysosomal storage diseases in Russia.

A special programme for the diagnosis and prevention of lysosomal storage diseases (LSD) was developed in the former USSR. All the patients from 814 families at risk were investigated using biochemical techniques. In total, 363 patients with mucopolysaccharidoses (MPS), mucolipidoses, glycoproteinoses, sphingolipidoses and other LSD were diagnosed; 55 families at risk sought prenatal diagnosis and 67 fetuses were investigated for MPS (types I, II, IIIA and IIIB, VI), Tay-Sachs disease, Sandhoff disease, GM1-gangliosidosis, metachromatic leukodystrophy, mannosidosis, Gaucher disease and multiple sulphatidosis; 17 affected fetuses were diagnosed and aborted. There was an ethnic distribution of different lysosomal storage diseases in the former USSR.

[Biochemical diagnosis of mucosulfatidosis]. / Biokhimicheskaia diagnostika mukosul'fatidoza.

Biochemical anomalies in proband involved alterations in the spectrum of glycosaminoglycans (GAG) excreted with urine as well as a decrease in activity of lysosomal sulfatases (arylsulfatases A and B, heparan-N-sulfatase) in homogenates of leukocytes and cultivated fibroblasts. In healthy parents of the proband activity of the sulfatases was lower than in control donors but higher as compared with the proband. Antenatal diagnostics of mucosulfatidosis was carried out in fetus during the repeated pregnancy. The following biochemical anomalies were noted: alteration in the GAG spectrum in amniotic fluid, decrease in activity of lysosomal sulfatases in cultivated cells of the amniotic fluid. The pregnancy lead to a premature birth at 31st week of a girl. No alterations were observed in the spectrum of GAG's excreted with urine and in intracellular accumulation of 35S-GAG in the newborn child. Measurement of sulfatases activity in leukocytes enabled to identify conclusively that the child was a heterozygotic bearer mucosulfatidosis.