Genetics of medullary thyroid cancer: An overview

Accardo, Giacomo; Conzo, Giovanni; Espósito, Daniela; Gambardella, Claudio; Mazzella, Marco; Castaldo, Filomena; Donna, Carlo Di; Polistena, Andrea; Avenia, Nicola; Colantuoni, Vittorio; Giugliano, Dario; Pasquali, Daniela

doi:10.1016/j.ijsu.2017.02.064

Cited by 98 publications

(81 citation statements)

References 34 publications

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“…Medullary thyroid carcinoma is a malignant tumor that originates in the C cells of the thyroid gland that secrete calcitonin. It accounts for 5–8% of all malignant tumors of the thyroid gland . Most cases occur in a sporadic setting with peak onset in the fifth and sixth decade of life.…”

Section: Discussionmentioning

confidence: 99%

“…Familial forms account for ∼25% of cases, usually occur in younger patients, are caused by gain‐of‐function germline mutations in the RET gene and are inherited in an autosomal dominant fashion. They occur as part of three syndromes: multiple endocrine neoplasia type 2A (MEN2A), multiple endocrine neoplasia type 2B (MEN2B), and familial medullary thyroid carcinoma (FMTC) …”

Section: Discussionmentioning

confidence: 99%

“…It accounts for 5-8% of all malignant tumors of the thyroid gland. 5 Most cases occur in a sporadic setting with peak onset in the fifth and sixth decade of life.…”

Section: Discussionmentioning

confidence: 99%

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Intraocular metastasis of medullary thyroid carcinoma investigated by transscleral fine‐needle aspiration. A case report and review of the literature

Gajdzis

Cassoux

Lesnik

et al. 2018

Diagnostic Cytopathology

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Medullary thyroid carcinoma occurs in a sporadic setting and may also be inherited in an autosomal dominant fashion, which is related with germline mutations of the RET gene. Metastases are often present at the time of a diagnosis-most frequently within the cervical lymph nodes, followed by the liver, lungs, and bones. Intraocular metastases are extremely rare. We present a case of choroidal metastasis as a first presentation of disease progression in a patient with Multiple Endocrine Neoplasia type 2A syndrome (MEN2A) who had undergone thyroidectomy 33 years earlier for medullary thyroid carcinoma. Transscleral aspirate smears showed necrotic malignant cells suggesting amelanotic malignant melanoma or metastatic neuroendocrine tumor. The similar cells were found on parotid fine-needle aspiration. The diagnosis of metastatic medullary thyroid carcinoma was definitely established on the parotidectomy specimen based on its characteristic morphological and immunohistochemical features. This is the only case of ocular metastasis from medullary thyroid carcinoma found in the English literature that was investigated by pathological examination using transscleral fine-needle aspiration biopsy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Intraocular metastasis of medullary thyroid carcinoma investigated by transscleral fine‐needle aspiration. A case report and review of the literature

Gajdzis

Cassoux

Lesnik

et al. 2018

Diagnostic Cytopathology

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“…Medullary thyroid carcinoma (MTC) represents a small fraction (∼3%) of all thyroid cancers (Accardo et al, ). MTC is associated with poor prognosis and accounts for a substantial fraction of thyroid cancer mortality.…”

Section: Introductionmentioning

confidence: 99%

Mice conditionally expressing RET(C618F) mutation display C cell hyperplasia and hyperganglionosis of the enteric nervous system

Okamoto

Yoshioka

Murakami

et al. 2019

Genesis

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Summary Medullary thyroid carcinoma (MTC) develops from hyperplasia of thyroid C cells and represents one of the major causes of thyroid cancer mortality. Mutations in the cysteine‐rich domain (CRD) of the RET gene are the most prevalent genetic cause of MTC. The current consensus holds that such cysteine mutations cause ligand‐independent dimerization and constitutive activation of RET. However, given the number of the CRD mutations left uncharacterized, our understanding of the pathogenetic mechanisms by which CRD mutations lead to MTC remains incomplete. We report here that RET(C618F), a mutation identified in MTC patients, displays moderately high basal activity and requires the ligand for its full activation. To assess the biological significance of RET(C618F) in organogenesis, we generated a knock‐in mouse line conditionally expressing RET(C618F) cDNA by the Ret promoter. The RET(C618F) allele can be made to be Ret‐null and express mCherry by Cre‐loxP recombination, which allows the assessment of the biological influence of RET(C618F) in vivo. Mice expressing RET(C618F) display mild C cell hyperplasia and increased numbers of enteric neurons, indicating that RET(C618F) confers gain‐of‐function phenotypes. This mouse line serves as a novel biological platform for investigating pathogenetic mechanisms involved in MTC and enteric hyperganglionosis.

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“…The clinical expression of MEN2 exhibits variable expression with different amino acid RET substitutions at the same codon. Such mutations are explicitly located in cysteines within this extracellular cysteine-rich domain and give rise to the subtype of MEN2A [12]. Codon 618 with p.Cys618Arg, p.Cys618Gly and p.Cys618Ser and to a lesser extent with codons p.Cys618Phe and p.Cys618Tyr, have been associated with the greatest rates of pheo [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

The use of nutraceuticals in male sexual and reproductive disturbances: position statement from the Italian Society of Andrology and Sexual Medicine (SIAMS)

Calogero

Aversa

Vignera

et al. 2017

J Endocrinol Invest

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Purpose Multiple endocrine neoplasia type 2 (MEN2) affects patients with RET proto-oncogene mutations. This cohort study refers to patients who were diagnosed with familial medullary thyroid carcinoma (MTC) and underwent RET genetic testing in Cyprus between years 2002 and 2017. Methods and patients Forty patients underwent RET testing by Sanger sequencing of exons 10-11 and 13-16. Genotyping with STR genetic markers flanking the RET gene along with Y-chromosome genotyping and haplogroup assignment was also performed. Results RET mutations were identified in 40 patients from 11 apparently unrelated Cypriot families and two non-familial sporadic cases. Nine probands (69.2%) were heterozygous for p.Cys618Arg, one (7.7%) for p.Cys634Phe, one (7.7%) for the somatic delE632-L633 and two (15.4%) for p.Met918Thr mutations. The mean age at MTC diagnosis of patients carrying p.Cys618Arg was 36.8 ± 14.2 years. The age of pheo diagnosis ranged from 26 to 43 years and appeared simultaneously with MTC in 5/36 (13.9%) cases. The high frequency of the p.Cys618Arg mutation suggested a possible ancestral mutational event. Haplotype analysis was performed in families with and without p.Cys618Arg. Six microsatellite markers covering the RET gene and neighboring regions identified one core haplotype associated with all patients carrying p.Cys618Arg mutation. Conclusions The mutation p.Cys618Arg is by far the most prevalent mutation in Cyprus followed by other reported mutations of variable clinical significance. The provided molecular evidence speculates p.Cys618Arg mutation as an ancestral mutation that has spread in Cyprus due to a possible founder effect.

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Genetics of medullary thyroid cancer: An overview

Abstract: New genetical testings and therapeutical approaches open new perspectives in MTC management.

Cited by 98 publications

References 34 publications

Intraocular metastasis of medullary thyroid carcinoma investigated by transscleral fine‐needle aspiration. A case report and review of the literature

Intraocular metastasis of medullary thyroid carcinoma investigated by transscleral fine‐needle aspiration. A case report and review of the literature

Mice conditionally expressing RET(C618F) mutation display C cell hyperplasia and hyperganglionosis of the enteric nervous system

The use of nutraceuticals in male sexual and reproductive disturbances: position statement from the Italian Society of Andrology and Sexual Medicine (SIAMS)

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