1) To find the role of polymorphisms within RET proto-oncogene as modifying factors in the pathogenesis of medullary thyroid carcinoma and papillary thyroid carcinoma. To compare the frequencies with healthy controls. 2) To detect main genetic causes ofpapillary thyroid carcinomas (BRAF gene mutation, RET/PTC rearrangements, RAS mutations), their clinical features, and prognostic characteristics. 3) To detect RAS mutations (HRAS, NRAS, KRAS) and PAX8/PPARgamma rearrangement and to compare their frequencies in follicular thyroid carcinoma, follicular adenomas and follicular variant of papillary thyroid carcinoma. 4) Molecular genetic analysis of thyroid cancer could help to find causes of carcinogenesis, but also to precise diagnosis, prognosis and prediction of the disease.

1) Studovat roli polymorfismů RET proto-onkogenu jakožto modifikujících faktorů v patogenezi medulárního a papilárního karcinomu štítné žlázy. Porovnat jejich frekvenci s kontrolní skupinou. 2) Detekovat hlavní genetické příčiny papilárního karcinomu štítné žlázy (mutace BRAF genu, RET/PTC přeskupení, mutace RAS genů) a studovat jejich vliv na klinické projevy a prognostické charakteristiky. 3) Stanovit mutace RAS (HRAS, NRAS, KRAS) genů a detekovat fúzní gen PAX8/PPARgama a porovnat jejich frekvence ufolikulárního karcinomu, folikulárního adenomu, případně folikulární varianty papilárního karcinomu štítné žlázy. 4) Molekulárně genetická analýza nádorů štítné žlázy přispěje nejen k ozřejmení příčin karcinogeneze, ale přispěje i k zpřesnění diagnostiky, prognózy onemocnění a k jeho predikci.

• MeSH
• genetická predispozice k nemoci MeSH
• nádory štítné žlázy diagnóza   genetika   terapie   MeSH
• polymorfismus genetický MeSH
• protoonkogenní proteiny c-ret MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• NLK Obory
• endokrinologie
• onkologie
• biologie
• genetika, lékařská genetika
• NLK Publikační typ
• závěrečné zprávy o řešení grantu IGA MZ ČR

BACKGROUND: Activating point mutation of the BRAF gene, the most common genetic alteration reported in papillary thyroid carcinomas (PTC), has been associated with poor prognostic characteristics. AIM: Our objective was to determine the frequency of BRAFV600E mutation in PTC tumor tissues from the period 1960-2007 and to correlate it with clinicopathological parameters. SUBJECTS AND METHODS: DNAs were extracted from 242 PTCs, 23 sporadic medullary carcinomas, one anaplastic carcinoma and 6 poorly differentiated carcinomas. The presence of BRAFV600E mutation was determined using single strand conformation polymorphism method and verified by direct sequencing. RESULTS: BRAFV600E mutation was detected in 81 of 242 PTCs (33.5%), in one of 6 poorly differentiated carcinomas (16.7%) and in anaplastic carcinoma. BRAFV600E mutation was much less frequent in the follicular variant compared to classical variant and mixed follicular- classical variant of PTCs (p=0.001). BRAFV600E mutation was significantly associated with presence of nodal metastasis (p=0.029), more advanced TNM stage (p=0.014) and recurrence of disease (p=0.008). The mutation correlated with a higher age at diagnosis (p=0.049) and with a greater tumor size (p=0.041). Multivariate analysis confirmed these findings. The prevalence of BRAFV600E mutation before 1986 was significantly lower than after it (p=0.008). CONCLUSIONS: Our data suggest that BRAFV600E mutation is associated with high-risk clinicopathological characteristics of PTC and worse prognosis of patients. The frequency of the mutation significantly varied during the observed period but rather because of the different age distribution of patients in particular periods than as a consequence of Chernobyl accident.

• MeSH
• černobylská havárie MeSH
• DNA nádorová biosyntéza   genetika   MeSH
• dospělí MeSH
• exony genetika   MeSH
• frekvence genu MeSH
• invazivní růst nádoru genetika   MeSH
• kodon genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace fyziologie   MeSH
• nádory štítné žlázy epidemiologie   genetika   patologie   MeSH
• papilární karcinom epidemiologie   genetika   patologie   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• polymorfismus konformace jednovláknové DNA genetika   MeSH
• protoonkogenní proteiny B-raf genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• věkové faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

Activating germline RET mutations are presented in patients with familial medullary thyroid carcinoma (FMTC) and multiple endocrine neoplasia (MEN) types 2A and 2B, whereas inactivating germline mutations in patients with Hirschsprung's disease (HSCR). The aim of this study was to evaluate genotype-phenotype correlations of the frequently discussed Tyr791Phe mutation in exon 13 of the RET proto-oncogene. Screening of three groups of patients was performed (276 families with medullary thyroid carcinoma (MTC), 122 families with HSCR, and 29 patients with pheochromocytoma). We found this mutation in 3 families with apparently sporadic MTC, 3 families with FMTC/MEN2, 1 patient with pheochromocytoma, and 3 families with HSCR. All gene mutation carriers have a silent polymorphism Leu769Leu in exon 13. In three families second germline mutations were detected: Cys620Phe (exon 10) in MEN2A family, Met918Thr (exon 16) in MEN2B family, and Ser649Leu (exon 11) in HSCR patient. Detection of the Tyr791Phe mutation in MEN2/MTC and also in HSCR families leads to the question whether this mutation has a dual character (gain-of-function as well as loss-of-function). A rare case of malignant pheochromocytoma in a patient with the Tyr791Phe mutation is presented. This study shows various clinical characteristics of the frequently discussed Tyr791Phe mutation.

• MeSH
• crista neuralis patologie   MeSH
• dítě MeSH
• dospělí MeSH
• fenylalanin genetika   MeSH
• genetické asociační studie MeSH
• Hirschsprungova nemoc genetika   MeSH
• jednonukleotidový polymorfismus fyziologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• medulární karcinom genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mnohočetná endokrinní neoplazie typ 2A genetika   MeSH
• nádory štítné žlázy genetika   MeSH
• nemoc genetika   MeSH
• protoonkogenní proteiny c-ret genetika   MeSH
• rodina MeSH
• senioři MeSH
• substituce aminokyselin genetika   MeSH
• tyrosin genetika   MeSH
• zárodečné mutace MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

OBJECTIVES: Two cases of an extremely rare paraganglioma-like variant of medullary thyroid carcinoma (MTC) are reported. METHODS: The patients were a 65-year-old male (case 1) and a 14-year-old female (case 2). Unilateral thyroid nodule and homolateral cervical lymphadenopathy was present in case 1; bilateral thyroid nodules were seen in case 2. Fine needle aspiration cytology (FNAC) was performed from thyroid nodules (in both cases) and from a cervical lymph node (in case 1). RESULTS: The cytological smears contained predominantly ovoid to spindled epithelial cells arranged in cohesive three-dimensional clusters with sharp margins; isolated individual cells were seen only rarely. No colloid or other material was present in the background. The tumour cells showed significant nuclear atypia with occasional bizarre and/or binucleated cells. The nuclear chromatin was coarse and granular, sometimes with grooves and intranuclear inclusions. The cytoplasm was inconspicuous. Polygonal or triangular cells, amyloid and azurophillic cytoplasmic granules were absent in both cases. Calcitonin expression was demonstrated in case 2. Histological examination confirmed the paraganglioma variant of MTC in both cases. Mutation of RET proto-oncogene in exon 16 (Met918Thr) - germline in case 2 and somatic in case 1 was detected by sequencing of DNA in both cases. CONCLUSIONS: This is the first description of cytological findings in the paraganglioma-like variant of MTC. Despite its rarity, it can be reliably diagnosed by FNAC if material for immunocytochemistry is obtained.

• MeSH
• fatální výsledek MeSH
• lidé MeSH
• medulární karcinom diagnóza   genetika   patologie   ultrasonografie   MeSH
• mladiství MeSH
• mutace MeSH
• mutační analýza DNA MeSH
• nádory plic sekundární   MeSH
• nádory štítné žlázy diagnóza   genetika   patologie   ultrasonografie   MeSH
• paragangliom diagnóza   genetika   patologie   ultrasonografie   MeSH
• protoonkogenní proteiny c-ret genetika   MeSH
• sekvence nukleotidů MeSH
• senioři MeSH
• tenkojehlová biopsie MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

• Publikační typ
• abstrakty MeSH

• Publikační typ
• abstrakty MeSH

• MeSH
• lidé MeSH
• mnohočetná endokrinní neoplazie typ 2A MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

RET testing in multiple endocrine neoplasia type 2 for molecular diagnosis is the paradigm for the practice of clinical cancer genetics. However, precise data for distinct mutation-based risk profiles are not available. Here, we survey the clinical profile for one specific genotype as a model, TGC to TGG in codon 634 (C634W). By international efforts, we ascertained all available carriers of the RET C634W mutation. Age at diagnosis, penetrance, and clinical complications were analyzed for medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT), as well as overall survival. Our series comprises 92 carriers from 20 unrelated families worldwide. Sixty-eight subjects had MTC diagnosed at age 3-72 years (mean 29). Lymph node metastases were observed in 16 subjects aged 20-72 and distant metastases in 4 subjects aged 28-69. Forty-one subjects had pheochromocytoma detected at age 18-67 (mean 36). Amongst the 28 subjects with MTC and pheochromocytoma, six developed pheochromocytoma before MTC. Six subjects had HPT diagnosed at age 26-52 (mean 39). Eighteen subjects died; of the 16 with known causes of death, 8 died of pheochromocytoma and 4 of MTC. Penetrance for MTC is 52% by age 30 and 83% by age 50, for pheochromocytoma penetrance is 20% by age 30 and 67% by age 50, and for HPT penetrance is 3% by age 30 and 21% by age 50. These data provide, for the first time, RET C634W-specific neoplastic risk and age-related penetrance profiles. The data may facilitate risk assessment and genetic counseling.

• MeSH
• dítě MeSH
• dospělí MeSH
• feochromocytom * genetika   patologie   MeSH
• hyperparatyreóza * genetika   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• medulární karcinom * genetika   patologie   MeSH
• míra přežití MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mnohočetná endokrinní neoplazie typ 2A * genetika   patologie   MeSH
• nádory štítné žlázy * genetika   patologie   MeSH
• penetrance MeSH
• předškolní dítě MeSH
• příčina smrti MeSH
• protoonkogenní proteiny c-ret * genetika   MeSH
• rizikové faktory MeSH
• senioři MeSH
• stárnutí * fyziologie   MeSH
• zárodečné mutace * genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH

• Publikační typ
• abstrakty MeSH

• Publikační typ
• abstrakty MeSH