Molecular analysis of the RET proto-oncogene in patients with sporadic medullary thyroid carcinoma: a novel point mutation in the extracellular cysteine-rich domain

Bugalho, Maria João; Frade, João P.; Santos, Jorge Rosa; Limbert, Edward; Sobrinho, L. G.

doi:10.1530/eje.0.1360423

Cited by 23 publications

(19 citation statements)

References 13 publications

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“…Eight of the fifty-one cases (Table 1, patients 10, 15, 34, 35, 36, 38, 43 and 45) were earlier published by our group (Bugalho et al, 1997(Bugalho et al, , 2000.…”

Section: Patientsmentioning

confidence: 92%

“…In addition, ethnic or environmental factors, differences in detection or in sampling methods may also account for the reported differences (Uchino et al, 1998;Dvorakova et al, 2008). In some cohorts, besides the Met918Thr mutation, other somatic mutations were also detected, at a lower frequency in exons 10, 11, 12, 13 and 15 (Bugalho et al, 1997;Scurini et al, 1998;Uchino et al, 1999).…”

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confidence: 99%

“…The screening of RET mutations has been carried out in different series of sporadic MTC, however the observed frequencies are variable (12 -100%) (Hofstra et al, 1994;Zedenius et al, 1994;Jhiang et al, 1996;Marsh et al, 1996Marsh et al, , 2003Romei et al, 1996;Wohllk et al, 1996;Bugalho et al, 1997;Scurini et al, 1998;Shan et al, 1998;Uchino et al, 1998Uchino et al, , 1999Bockhorn et al, 1999;Dvorakova et al, 2008;Elisei et al, 2008). Met918Thr RET mutation is the most common somatic mutation in sporadic forms of MTC, and its detection rate varies greatly (5 -66%) in the published literature (Zedenius et al, 1994;Marsh et al, 1996;Romei et al, 1996;Wohllk et al, 1996;Bugalho et al, 1997;Scurini et al, 1998;Uchino et al, 1998Uchino et al, , 1999Dvorakova et al, 2008;Elisei et al, 2008).…”

mentioning

confidence: 99%

“…Met918Thr RET mutation is the most common somatic mutation in sporadic forms of MTC, and its detection rate varies greatly (5 -66%) in the published literature (Zedenius et al, 1994;Marsh et al, 1996;Romei et al, 1996;Wohllk et al, 1996;Bugalho et al, 1997;Scurini et al, 1998;Uchino et al, 1998Uchino et al, , 1999Dvorakova et al, 2008;Elisei et al, 2008). However, in some of these studies, the authors have screened sporadic MTC for only a few specific mutations, mostly in codon 918 (Hofstra et al, 1994;Shan et al, 1998;Bockhorn et al, 1999;Marsh et al, 2003).…”

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confidence: 99%

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Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas

Moura¹,

Cavaco²,

Pinto³

et al. 2009

Br J Cancer

155

124

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Screening of REarranged during Transfection (RET) gene mutations has been carried out in different series of sporadic medullary thyroid carcinomas (MTC). RET-positive tumours seem to be associated to a worse clinical outcome. However, the correlation between the type of RET mutation and the patients' clinicopathological data has not been evaluated yet. We analysed RET exons 5, 8, 10 -16 in fifty-one sporadic MTC, and found somatic mutations in thirty-three (64.7%) tumours. Among the RET-positive cases, exon 16 was the most frequently affected (60.6%). Two novel somatic mutations (Cys630Gly, c.1881del18) were identified. MTC patients were divided into three groups: group 1, with mutations in RET exons 15 and 16; group 2, with other RET mutations; group 3, having no RET mutations. Group 1 had higher prevalence (P ¼ 0.0051) and number of lymph node metastases (P ¼ 0.0017), and presented more often multifocal tumours (P ¼ 0.037) and persistent disease at last control (P ¼ 0.0242) than group 2. Detectable serum calcitonin levels at last screening (P ¼ 0.0119) and stage IV disease (P ¼ 0.0145) were more frequent in group 1, than in the other groups. Our results suggest that, among the sporadic MTC, cases with RET mutations in exons 15 and 16 are associated with the worst prognosis. Cases with other RET mutations have the most indolent course, and those with no RET mutations have an intermediate risk.

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“…Eight of the fifty-one cases (Table 1, patients 10, 15, 34, 35, 36, 38, 43 and 45) were earlier published by our group (Bugalho et al, 1997(Bugalho et al, , 2000.…”

Section: Patientsmentioning

confidence: 92%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas

Moura¹,

Cavaco²,

Pinto³

et al. 2009

Br J Cancer

155

124

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“…In the cysteine-rich domain, mutations in codons 630 and 634, and deletion of nucleotides have been reported. [24][25][26][27][28][29] In the intracellular tyrosine kinase domain, somatic mutations in codons 768 and 883 have been found in sporadic MTC, and are also found in FMTC and MEN 2B, respectively. 20,30) In approximately one-third of sporadic MTCs, a somatic M918T mutation, which is also found in most MEN 2B families, has been reported, 12-14, 18, 22, 31, 32) and this mutation has been corre- 4 To whom correspondence should be addressed.…”

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confidence: 99%

Somatic Mutations in RET Exons 12 and 15 in Sporadic Medullary Thyroid Carcinomas: Different Spectrum of Mutations in Sporadic Type from Hereditary Type

Uchino

Noguchi

Yamashita

et al. 1999

Japanese Journal of Cancer Research

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Germline mutations in the RET proto-oncogene are responsible for multiple endocrine neoplasia type 2 (MEN 2A and 2B) and familial medullary thyroid carcinoma (FMTC). Point mutations or in-frame deletions of exons 10, 11, 13, 14 and 16 are associated with sporadic medullary thyroid carcinoma (MTC). To understand further the role of the RET gene in sporadic MTC, we examined mutations in exons 12 and 15 of RET in patients with sporadic MTC. DNAs were extracted from 39 formalin-fixed tumor tissues and corresponding normal thyroid tissues or peripheral blood leukocytes. DNA sequencing was used to identify mutations in exons 12 and 15 of RET. In this study, one novel somatic mutation was found in exon 12 and five novel mutations or deletions were found in exon 15. Of the patients with mutations, one had an in-frame 12-bp deletion (nt. 2625-2636), one had point mutations in both codons 884 and 908, and the remaining three had point mutations in codons 748, 876 and 901, respectively. Together with our previous identification of somatic mutations in exons 10, 11, 13, 14 and 16, somatic alterations were found in 10 out of 39 (25.6%) sporadic MTCs. There was no association of RET gene mutations with tumor recurrence or prognosis. These results suggest that mutations occur frequently in the RET coding region in addition to the previously reported mutation hot spots, and there is a different spectrum of mutations between sporadic and hereditary MTC.Key words: Sporadic medullary thyroid carcinoma -RET gene -Point mutation -Multiple endocrine neoplasia -Tyrosine kinase domainThe RET proto-oncogene on human chromosome 10q11.2 encodes a protein receptor tyrosine kinase that includes an extracellular region with a cysteine-rich domain, a transmembrane region and an intracellular region with a tyrosine kinase domain. Germline point mutations in RET have been found to cause MEN 2A, 2B and FMTC.1, 2) RET gene was first isolated by transfection of NIH 3T3 cells with a human T-cell lymphoma DNA, and was activated by fusion of the tyrosine kinase domain of this gene to the 5′-terminal portion of another gene, 3) i.e., H4 gene (RET/PTC1) 4) the regulatory subunit RIα of cAMP-dependent protein kinase A (RET/PTC2), 5) ELE1 gene (RET/PTC3 and RET/PTC4) [6][7][8] and RFG5 gene (RET/PTC5). 9) In MEN 2A families, germline mutations are concentrated in five cysteine codons: codons 609, 611, 618 and 620 in exon 10, and codon 634 in exon 11. 10) A small number of MEN2A families has germline mutations at codons 790. 11) In MEN 2B, approximately 95% of families have an M918T germline mutation in exon 16, [12][13][14] and recent research revealed A883F and V804M with Y806C germline mutation as another cause of MEN 2B. [15][16][17] Germline mutations in RET have been found in 88% of FMTC families, and the majority of mutations in FMTC occur in the same five cysteine codons altered in MEN 2A.10) C630F, C630Y, E768D, L790F, Y791F, V804L, V804M and S891A germline mutations have been found in some FMTC families. 11,[18][19][20][21][22][23] Various somat...

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Diagnostic and surgical dilemmas in hereditary medullary thyroid carcinoma

et al. 2009

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Medullary thyroid carcinoma (MTC) is a rare malignancy arising from the parafollicular C cells within the thyroid gland. The majority of cases are sporadic, but at least 30% are hereditary in nature. Inherited forms of MTC occur as familial MTC or as a manifestation of multiple endocrine neoplasia type 2. Early diagnosis and aggressive surgical management, including prophylactic thyroidectomy, improve the prognosis of patients with hereditary MTC. Several issues regarding the diagnosis and treatment of MTC remain controversial. Genetic penetrance and virulence are variable. We present an index case of familial MTC to illustrate common difficulties in the initial diagnosis and dilemmas in the surgical approach, followed by a review of current literature relevant to the management of hereditary MTC.

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Molecular analysis of the RET proto-oncogene in patients with sporadic medullary thyroid carcinoma: a novel point mutation in the extracellular cysteine-rich domain

Cited by 23 publications

References 13 publications

Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas

Correlation of RET somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas

Somatic Mutations in RET Exons 12 and 15 in Sporadic Medullary Thyroid Carcinomas: Different Spectrum of Mutations in Sporadic Type from Hereditary Type

Diagnostic and surgical dilemmas in hereditary medullary thyroid carcinoma

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