Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG→ATG) mutation

Feldman, Gerald L.; Edmonds, M.; Ainsworth, Peter; Schuffenecker, Isabelle; Lenoir, Gilbert; Saxe, Andrew; Talpos, Gary B.; Roberson, Jacquelyn; Petrucelli, Nancie; Jackson, Charles E.

doi:10.1067/msy.2000.107103

Cited by 99 publications

(66 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The reported coding SDHx polymorphisms could also be genetic modifiers for MTC. Such modifying genetic factors are suspected in the familial setting of MEN2, explaining a variable clinical disease penetrance (Feldman et al 2000, Fitze et al 2002, Lombardo et al 2002. Studies in a mouse model of MEN2 also suggest the presence of further genes modifying penetrance and expressivity of MTCs in MEN2 (Cranston & Ponder 2003).…”

Section: Discussionmentioning

confidence: 99%

No mutations but an increased frequency of SDHx polymorphisms in patients with sporadic and familial medullary thyroid carcinoma

Montani¹,

Schmitt²,

Schmid³

et al. 2005

Endocr Relat Cancer

View full text Add to dashboard Cite

Germline mutations of the three succinate dehydrogenase subunits SDHB, SDHC and SDHD have recently been associated with familial pheochromocytoma and paraganglioma. Several reasons make these genes candidate tumor suppressor genes for medullary thyroid carcinoma (MTC): (1) SDHB lies on chromosome 1p, the region known to be deleted most frequently in MTC, (2) MTCs develop from neural crest-derived cells, as do pheochromocytomas and paragangliomas and (3) patients with germline mutations of the Ret-protooncogene develop MTCs as well as pheochromocytomas, indicating a relationship of these tumors on a genetic level. Therefore, we attempted to determine whether the tumor suppressor genes SDHB, SDHC and SDHD are involved in sporadic and familial MTC. Somatic mutations of the SDH subunits were absent in all 35 investigated MTCs. Loss of heterozygosity was found in 27% (SDHB) and 4% (SDHD) respectively. While the frequency of non-coding, intronic polymorphisms did not differ in MTC patients compared with a control population, an accumulation of amino-acid coding polymorphisms (S163P in SDHB as well as G12S and H50R in SDHD) was found among MTC patients especially patients with familial tumors, suggesting a functional connection of coding SDH polymorphisms to activating Ret mutations.

show abstract

Section: Discussionmentioning

confidence: 99%

No mutations but an increased frequency of SDHx polymorphisms in patients with sporadic and familial medullary thyroid carcinoma

Montani¹,

Schmitt²,

Schmid³

et al. 2005

Endocr Relat Cancer

View full text Add to dashboard Cite

show abstract

“…For the c804 mutation, we found highly variable expression of the MTC phenotype (Fig 4), and management of these patients is controversial. 52,65 In c618 patients, 6 of 11 children developed MTC before age of 10. Therefore, children affected with mutations in these 3 codons should undergo ETT after careful screening at latest with 5 years.…”

Section: Discussionmentioning

confidence: 99%

Review of Multiple Endocrine Neoplasia Type 2A in Children: Therapeutic Results of Early Thyroidectomy and Prognostic Value of Codon Analysis

et al. 2003

View full text Add to dashboard Cite

ABSTRACT. Objectives. The aim of this study was first to investigate whether early total thyroidectomy (ETT; 1-5 years of age) can prevent medullary thyroid carcinoma with persistent or recurrent disease (PRD) in pediatric patients with multiple endocrine neoplasia type 2A (MEN-2A) and second, to evaluate the strength of codon analysis in children with MEN-2A as prognostic parameter.Methods. Case reports and review of the literature for pediatric patients with MEN-2A were conducted. Inclusion criteria were age (0 -20 years) and histologic degree of C-cell disease (normal ‫؍‬ N, C-cell hyperplasia ‫؍‬ CCH, medullary thyroid carcinoma ‫؍‬ MTC, metastatic MTC ‫؍‬ MMTC). To evaluate therapeutic results of ETT (1-5 years) versus late total thyroidectomy (LTT; 6 -20 years), age-dependent histologic stages of C-cell disease and postoperative occurrence of PRD were compared. Prognostic value of specific codons, age-dependent histologic distribution, and long-term outcome were analyzed.Results. In a total of 260 cases, 42 (16%) underwent ETT, and 218 (84%) underwent LTT. Histologic analysis showed significant difference between ETT versus LTT (57% vs 76%) regarding malignant stage of C-cell disease (of combined rate of MTC and MMTC). Long-term outcome was documented in 74 patients (28%). During a median follow-up period of 2 years (range: 0 -15 years), 21 of 65 of the LTT group versus 0 of 9 of the ETT group suffered PRD. Information about codon analysis was available in 150 patients (58%). Mutated codons were c634 (63%), c618 (19%), c620 (9%), and c804 (6%). Codonrelated histologic analysis resulted in prognostic differences: 81% of patients with c634-mutation had MCT or MMTC in contrast to c804 (44%), c618 (34%), and c620 (7%). Fifteen of 17 MMTC and 7 of 9 PRD occurred in patients with c634-mutation. 4 Usually, the first tumor occurring during life is medullary thyroid carcinoma (MTC), 5 a neoplasm of parafollicular C-cell origin. Malignant transformation of C-cells is multifocal in both thyroid lobes and characterized by different histologic stages: Diffuse C-cell hyperplasia (carcinoma in situ), uni-and multifocal MTC with or without local (lymph nodes), or distant metastasis (liver, bone). 6 The malignant transformation of the C-cells begins very early in life: in MEN-2B patients, MTC can occur in infancy, whereas MTC is less aggressive in MEN 2A. 7-10 Nevertheless, in children of MEN-2A families thyroidectomized at 1 to 6 years of age, histologic analyses revealed all stages of C-cell disease, even metastatic MTC. [7][8][9][10][11][12] The only potentially curative treatment for medullary thyroid carcinoma is surgical removal of all thyroid tissue, 13-15 a goal that is not regularly achieved in patients with clinically manifest MTC. 16 The molecular bases of MEN-2A and MEN-2B are missense mutations in the RET protooncogene, a transmembrane tyrosine kinase receptor located on chromosome 10q11.2. In MEN 2A, the most frequent germ line mutations involve the extracellular domain of rearranged during transfection (RET...

show abstract

“…Os exons mais comumente afetados são o 10, 11 e 16 (23,27,(36)(37)(38). No entanto, mutações nos exons 5, 8, 13, 14 e 15 podem ser encontradas mais raramente (39)(40)(41)(42)(43)(44)(45)(46)(47). Na imensa maioria dos casos, os pacientes com NEM 2A e CMTF têm a mutação em um de cinco códons (hot points), codificadores dos resíduos de cisteína localizados no domínio extracelular do RET, sendo eles o 609, 611, 618 e 620 (exon 10) e o 634 (exon 11) (37,38,(48)(49)(50)(51).…”

Section: Quais As Bases Genéticas Do Carcinoma Medular De Tireóide?unclassified

Polimorfismos genéticos: implicações na patogênese do carcinoma medular de tireóide

Rocha

Magalhães

Maia

et al. 2007

Arq Bras Endocrinol Metab

View full text Add to dashboard Cite

RESUMOO carcinoma medular de tireóide (CMT) é uma neoplasia maligna rara, ocorrendo na forma esporádica ou hereditária. Mutações germinativas no proto-oncogene RET são responsáveis pelo CMT hereditário. No entanto, a maioria dos casos de CMT ocorre em indivíduos sem história familiar, na qual a patogênese da doença ainda é pouco compreendida. Os polimorfismos do gene RET são descritos na população geral assim como em pacientes com CMT. Embora estas variações alélicas aparentemente não confiram qualquer atividade transformadora no receptor RET, estudos sugerem que essas alterações genéticas podem modificar a suscetibilidade à doença e o fenótipo clínico em pacientes com CMT esporádico ou hereditário. Uma maior freqüência dos polimorfismos localizados nos exons 11 (G691S), 13 (L769L), 14 (S836S) e 15 (S904) é descrita em pacientes com CMT provenientes de países americanos e europeus. Na presente revisão, analisamos criticamente os resultados obtidos nos diferentes estudos e descrevemos a freqüência dos polimorfismos do RET em pacientes brasileiros com CMT esporádico. Medullary thyroid carcinoma (MTC) is a rare malignant neoplasia, which may occur on sporadic form or on a hereditary basis. Germ line mutations in the RET proto-oncogene is responsible for hereditary MTC. However, most MTC occur in individuals without family history where the pathogenesis is still unclear. Single nucleotide polymorphisms (SNPs) of the RET gene have been described in the general population as well as in patients with MTC. Even though these allelic variants do not seem to confer any transforming activity to the tyrosine kinase domain of the RET protein, cumulative studies suggest that they could modify disease susceptibility and clinical phenotype in patients with sporadic or hereditary MTC. Polymorphisms located in exons 11 (G691S), 13 (L769L), 14 (S836S), and 15 (S904S) seem to be over-represented in sporadic MTC patients from American and European countries. Here, we discuss the results obtained in different studies as well as describe the frequency of RET polymorphisms in Brazilian patients with sporadic MTC.

show abstract

Variable expressivity of familial medullary thyroid carcinoma (FMTC) due to a RET V804M (GTG→ATG) mutation

Cited by 99 publications

References 24 publications

No mutations but an increased frequency of SDHx polymorphisms in patients with sporadic and familial medullary thyroid carcinoma

No mutations but an increased frequency of SDHx polymorphisms in patients with sporadic and familial medullary thyroid carcinoma

Review of Multiple Endocrine Neoplasia Type 2A in Children: Therapeutic Results of Early Thyroidectomy and Prognostic Value of Codon Analysis

Polimorfismos genéticos: implicações na patogênese do carcinoma medular de tireóide

Contact Info

Product

Resources

About