Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama , Doenças Genéticas Inatas , Mutação , Neoplasias Ovarianas , Proteínas Reguladoras de Apoptose , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Neoplasias da Mama/terapia , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Humanos , Masculino , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/prevenção & controle , Neoplasias Ovarianas/terapiaRESUMO
The role of RET and GFRA1 germline polymorphisms in predisposition to sporadic medullary thyroid cancer (MTC) and polymorphisms' modulation effect on clinical features of inherited and sporadic MTC were investigated. Blood samples from 67 MTC patients (22 hereditary and 45 sporadic), 3 asymptomatic mutant RET gene carriers and 178 ethnically matched healthy control individuals were tested. Screening of RET exons and portion of introns 1, 8, 10, 13, 14, 15, 16 and GFRA1 5'-UTR was performed by means of direct sequencing and PCR-RFLP. 8 polymorphic variants of RET gene (exons 11, 13, 14, 15 and introns 1, 8, 13, 14) and 4 GFRA1 polymorphisms in GFRA1 were detected. Linkage disequilibrium was found between RET variants G691S and S904S, L769L and IVS8, S836S and IVS13. In sporadic MTCs, allelic frequency of only one polymorphic RET variant, L769L, was significantly decreased versus control group. In hereditary MTCs, a significant over-representation of S836S and under-representation of S904S sequence variants were observed as compared to sporadic MTCs and controls. No co-segregation was found between individual polymorphisms and phenotype of sporadic MTC. In patients with inherited MTC whose genotype was presented with polymorphic L769L and wild-type S836S, disease onset occurred 20 years later than in individuals with polymorphic L769L and S836S or wild-type L769L (p = 0.01) suggestive of a possible protective role of L769L in MTC development and modulating effect of a combination of L769L with wild-type S836S on clinical outcome of inherited MTC.
Assuntos
Carcinoma Medular/genética , Predisposição Genética para Doença , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Proteínas de Neoplasias/genética , Polimorfismo de Fragmento de Restrição , Neoplasias da Glândula Tireoide/genética , Adolescente , Adulto , Alelos , Criança , Feminino , Frequência do Gene/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de TempoRESUMO
Frequency of RET/PTC rearrangement and somatic BRAF mutation was investigated in patients with papillary thyroid cancer (PTC) vis-a-vis relevant demographic and clinico-pathological features. The study group included 76 patients with a female/male ratio of 4.8:1; mean age - 45.7 +/- 9.7 yrs. BRAF mutation was identified in 49 (65%) (V600E--47, KSRWS600--1 and E585K--1). RET rearrangement was detected in 9 (12%): RET/PTC1--5, RET/PTC3--2, unspecified RET/PTC--1 and delta RET/PTC--1. It was age at diagnosis alone that proved to be consistently associated with BRAF mutations (p = 0.017). Younger tumor patients were mostly prone to RET/PTC rearrangement (p = 0.08). No correlation between mutation and clinico-pathological features was established.
Assuntos
Carcinoma Papilar/genética , Rearranjo Gênico , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/genética , Adulto , Distribuição por Idade , Carcinoma Papilar/epidemiologia , Carcinoma Papilar/patologia , Feminino , Frequência do Gene , Humanos , Masculino , Pessoa de Meia-Idade , Federação Russa/epidemiologia , Neoplasias da Glândula Tireoide/epidemiologia , Neoplasias da Glândula Tireoide/patologiaRESUMO
Rearrangements of the RET proto-oncogene (RET/PTC) and BRAF gene mutations are the major genetic alterations in the etiopathogenesis of papillary thyroid carcinoma (PTC). We have analyzed a series of 118 benign and malignant follicular cell-derived thyroid tumors for RET/PTC rearrangements and BRAF gene mutations. Oncogenic rearrangements of RET proto-oncogene was revealed by semiquantitative RT-PCR of simultaneously generated fragments corresponding to tyrosine kinase (TK) and extracellular RET domains. The clear quantitative shift toward the TK fragment is indicative for the presence of RET rearrangements. The overall frequency of RET/PTC rearrangements in PTC was 14% (12 of 85), including 7 RET/PTC1, 2 RET/PTC3, 1 deltaRFP/RET and 2 apparently uncharacterized rearrangements. The most common T1796A transversion in BRAF gene was detected in 55 of 91 PTC (60%) using mutant-allele-specific PCR. We also identified two additional mutations: the substitution G1753A (E585K) and a case of 12-bp deletion in BRAF exon 15. Moreover, there was no overlap between PTC harboring BRAF and RET/PTC mutations, which altogether were present in 75.8% of cases (69 of 91). Taken together, our observations are consistent with the notion that BRAF mutations appear to be an alternative pathway to oncogenic MAPK activation in PTCs without RET/PTC activation. Neither RET/PTC rearrangements nor BRAF muta-tions were detected in any of 3 follicular thyroid carcinomas, 11 follicular adenomas and 13 nodular goiters. The high prevalence of BRAF mutations and RET/PTC rearrangements in PTCs and the specificity of these alterations to PTC make them potentially important markers for the preoperative tumor diagnosis.
Assuntos
Carcinoma Papilar/genética , Genoma Humano , Neoplasias da Glândula Tireoide/genética , Sequência de Bases , Primers do DNA , Rearranjo Gênico , Humanos , Mutação , Proteínas Oncogênicas/genética , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-ret , Receptores Proteína Tirosina Quinases/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Fine-needle aspiration biopsy of cervical lymph nodes was carried out in 22 patients with suspected metastatic involvement with medullary thyroid carcinoma (MTS). It was followed by cytopathological examination of aspirates and assay of of thyrocalcitonin (TCT) in fine-needle washings. TCT determinations proved highly informative as well as significantly high in all seven cases of MTS involvement (26-8,484.87 pg/ml, mean 2,208 +/- 1,722 pg/ml).
