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PubMed1989

The oncogene associated with human papillary thyroid carcinoma (PTC) is assigned to chromosome 10 q11-q12 in the same region as multiple endocrine neoplasia type 2A (MEN2A).

In this report we assigned to chromosome 10q the human oncogene PTC frequently associated with the papillary type of thyroid carcinoma. Using an informative panel of human-mouse somatic cell hybrids and 'in situ' hybridization to human metaphase chromosomes, we localized the PTC gene at bands q11-q12 of chromosome 10. These bands belong to one of the two regions on chromosome 10 linked to the cancer syndrome multiple endocrine neoplasia type 2A (MEN2A). Therefore, it is suggested that genes clustered in certain regions of chromosome 10 could be involved in the developmental regulation of the thyroid gland.

Carcinoma, Papillary↗
PubMedDate not supplied

[Paresthetic notalgia and multiple endocrine neoplasia type 2a (Sipple's syndrome): 3 cases].

INTRODUCTION: Notalgia paresthetica is an isolated sensory mononeuropathy. Patients have a pruritus in the mid-upper back. Its association with multiple endocrine neoplasia type IIA has been reported in a few cases. We report three cases of this association. CASE REPORTS: Case n(o) 1: A 45 year-old woman had multiple endocrine neoplasia type IIA with a medullary thyroid carcinoma and a primary hyperparathyroidism; she had a mid-upper back pigmented lesion. Histological examination showed dermal melanosis and deposits of amyloid in the dermis. Case n(o) 2: A woman had a multiple endocrine neoplasia type IIA which was diagnosed at the age of 60; she had a surgical treatment for a pheochromocytoma, a medullary thyroid carcinoma, and a primary hyperparathyroidism; she had dermatological examination for a pruriginous lesion of the mid-upper back. Case n(o) 3: The daughter of the patient n(o) 2 had had a surgical cure for a medullary thyroid carcinoma and a pheochromocytoma at the age of 31; she had a papulous and pruriginous lesion in the left scapular area. Her daughter and her sister had a multiple endocrine neoplasia type IIA without notalgia paresthetica. DISCUSSION: Notalgia paresthetica is a benign cutaneous disorder which can be associated with multiple endocrine neoplasia type IIA. It can be considered that notalgia paresthetica is an early clinical marker of multiple endocrine neoplasia type IIA. Patients with a familial history of notalgia paresthetica or with an onset of notalgia paresthetica in childhood should be screened for multiple endocrine neoplasia type IIA. Patients with multiple endocrine neoplasia must also been screened for notalgia paresthetica because its finding is an argument for a familial form of multiple endocrine neoplasia type IIA. Dermatologists should be aware of this association.

Adrenal Gland Neoplasms↗
PubMed1998

Molecular diagnosis of multiple endocrine neoplasia type 2A.

OBJECTIVE: To identify by means of genetic analyses individuals who are at risk of developing medullary thyroid cancer that is a component of multiple endocrine neoplasia. SUBJECTS: A three-generation kindred with clinically and biochemically diagnosed medullary thyroid cancer. METHOD: Identification of a heterozygote mutation by nucleic acid sequencing and restriction analyses. RESULTS: A heterozygote T-->C (Cys-->Arg) mutation at codon 618 in exon 10 of the RET proto-oncogene was identified in 4 family members who had previously been diagnosed with medullary thyroid cancer. The same mutation was also found in one of the proband's presymptomatic children who subsequently underwent a pre-emptive thyroidectomy. The genetic diagnosis was confirmed by histology. No mutations were detected in any other family members. CONCLUSION: Identification of heterozygote germline mutations in multiple endocrine neoplasia is direct, highly accurate and cost-effective. This study demonstrates that, appropriately used, molecular diagnosis can supersede conventional biochemical methods in the management of patients with inherited cancers.

Adult↗
PubMed1996

Mutation analysis of the RET proto-oncogene in Dutch families with MEN 2A, MEN 2B and FMTC: two novel mutations and one de novo mutation for MEN 2A.

Hereditary C-cell carcinoma is encountered in multiple endocrine neoplasia type 2A (MEN 2A), MEN 2B, and familial medullary thyroid carcinoma (FMTC). Mutations of the RET proto-oncogene are associated with all three diseases. To obtain an insight into the molecular heterogeneity of MEN 2 syndromes and FMTC in the Netherlands, probands of 20 MEN 2A families, two FMTC families, and seven MEN 2B families were analyzed by the polymerase chain reaction (PCR), DNA sequencing, and restriction enzyme digestion for abnormalities in the RET proto-oncogene. RET mutations were found in all cases. All MEN 2A families had a mutation involving one of five cysteine codons in exons 10 and 11 of RET. Two novel dinucleotide mutations and a de novo mutation were found. Both FMTC families had a mutation of the Cys at codon 618. All MEN 2B probands carried a Met to Thr mutation in exon 16. All mutations could be confirmed by restriction enzyme digestion of PCR amplicons. Identification of the RET mutation in the Dutch population with hereditary C-cell carcinoma facilitates genetic testing for families or individuals at risk for MEN 2A, FMTC, and MEN 2B.

Amino Acid Sequence↗
PubMed1993

Cervical neuroblastoma and multiple endocrine neoplasia type 2a.

The authors report the case of a female infant who was referred at the age of 18 months for a left latero-cervical mass. This child belongs to a family with a history of multiple endocrine neoplasia (MEN) type 2a (10 persons in 4 generations had medullary thyroid carcinoma and/or pheochromocytoma). Surgery was performed with complete excision of an encapsulated tumor and pathological examination reported a typical ganglioneuroblastoma. No amplification of N-myc oncogene was observed. The probability of the child carrying a MEN-2a gene is estimated 2 to 4%, by DNA analysis. The patient has received no further treatment and is still free of disease 4 years later. The diagnostic problems of this tumor after basic tests were between neuroblastoma and medullary thyroid carcinoma. The link between neuroblastoma and MEN-2a syndrome is discussed because both diseases belong to the group of neural crest tumors.

Female↗
PubMed2001

Molecular genetic diagnostic program of multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma syndromes in Hungary.

Medullary thyroid carcinoma (MTC) occurs usually in sporadic form, but about a quarter of the cases are hereditary and appear as part of one of the multiple endocrine neoplasia type 2 (MEN2) syndromes. Mutations in the RET protooncogene are known to be the cause of the MEN2A and familial medullary thyroid carcinoma (FMTC) syndromes in the majority of the families. Direct DNA testing allows prophylactic thyroidectomy to be offered to individuals carrying a mutation in the above codons, and in mutation-negative cases it reduces the yearly screening-related burden on family members at risk of the disease. By DNA sequencing and PCR-restriction fragment length polymorphisms, 65 MTC probands were examined for mutations in residues 609, 611, 618, 620 of exon 10, and in residues 634, 768, 804 of exons 11, 13, and 14 respectively of the RET protooncogene. In our study, mutations in the above codons were detected in all of the 14 clinically MEN2A and FMTC families. One of these mutations, TGC609 TCC has not been reported previously. Of the 14 probands with the mutation, 25 relatives also had the identified mutation and 18 relatives proved to be non-carriers. Among the 51 probands with clinically sporadic MTC, none was found to carry a mutation in the above positions even if indirect signs of MTC, pheochromocytoma or hyperparathyroidism could be detected in some families. The frequency of the TGC634AGC mutation is unexpectedly high in our samples, which can probably be attributed to a founder effect. We conclude that screening for mutations in these codons is effective in families fulfilling the strict clinical criteria of MEN2A or FMTC.

Adult↗
PubMed1995

Putting the bits and pieces of the RET proto-oncogene puzzle together.

The RET proto-oncogene has been implicated in the causation of papillary thyroid carcinoma, multiple endocrine neoplasia types 2A (MEN 2A) and 2B (MEN 2B), and Hirschsprung's disease. The mutations in these syndromes can be categorized into activating or inactivating mutations. Activating mutations of a cysteine-rich extracellular region cause enhanced dimerization of the RET tyrosine kinase receptor and autophosphorylation, and are causative for MEN 2A and familial medullary thyroid carcinoma (FMTC). An activating mutation of the tyrosine kinase domain causes increased autophosphorylation but does not affect the state of dimerization. A variety of inactivating mutations of the RET proto-oncogene, which result in defective protein formation, are causative for Hirschsprung's disease.

Amino Acid Sequence↗
PubMed1995

The RET proto-oncogene and cancer.

The RET proto-oncogene, a receptor tyrosine kinase, has been evaluated as a candidate gene for multiple endocrine neoplasia type 2A and type 2B (MEN 2A and MEN 2B), for familial medullary thyroid carcinoma (FMTC), and for sporadic cases of medullary thyroid carcinoma (MTC) and pheochromocytomas. We determined the genomic structure of RET and used single-strand conformational polymorphism (SSCP) analysis to identify sequence variants in genomic DNA from families segregating MEN 2 and FMTC. In addition, we examined paired tumour and lymphocyte genomic DNAs from individuals with sporadic cases of MTC and pheochromocytoma. Altogether, we and others found 21 missense mutations in five cysteines clustered in the extra-cellular domain of RET (exons 10 and 11) associated with 111 MEN 2A and FMTC families. In contrast, a single point mutation that results in the substitution of threonine for methionine within the catalytic core of the tyrosine kinase domain (codon 918, exon 16) is responsible for all 66 reported cases of MEN 2B. Two missense mutations and a six base-pair deletion were identified in MTC tumour DNA, but no mutations were identified from pheochromocytoma tumour DNAs. A predictive DNA test for MEN 2A-associated mutations in RET has been developed that is based on detection of missense mutations by polymerase chain reaction (PCR) amplification and restriction endonuclease cleavage. A dominant oncogene model for the action of the RET gene product is proposed as a mechanism of action in MEN 2A, MEN 2B, FMTC and for at least some cases of sporadic MTC.

Adrenal Gland Neoplasms↗
PubMed1998

Molecular mechanisms of development of multiple endocrine neoplasia 2 by RET mutations.

Biological and biochemical effects of multiple endocrine neoplasia type 2A (MEN-2A), type 2B (MEN-2B) and familial medullary thyroid carcinoma (FMTC) mutations on Ret function were investigated by transfection of NIH 3T3 cells. All mutations examined conferred transforming activity on Ret at variable levels. Cysteine mutations detected in MEN-2A and FMTC induced disulphide-linked homodimers of Ret on the cell surface, leading to activation of its intrinsic tyrosine kinase. Of these cysteine-mutated proteins, Ret with a codon 634 mutation had the highest transforming activity. The activity of Ret with a codon 609, 611, 618 or 620 mutation was approximately three- to five-fold lower than that of Ret with a codon 634 mutation. The first four mutations impaired the Ret cell surface expression or its correct maturation, resulting in the low transforming activity. On the other hand, the MEN-2B mutation appeared to activate Ret by an intramolecular mechanism without dimerization. In addition, we investigated the role of tyrosines present in the intracellular domain for the transforming activity of the mutant Ret proteins. As a result, we found that tyrosine 905 is essential for the transforming activity of the MEN-2A-Ret mutant protein whereas tyrosines 864 and 952 are critical for that of the MEN-2B-Ret mutant protein. Moreover, it turned out that tyrosine 1062 regulates the activity of both MEN-2A-Ret and MEN-2B-Ret and represents a binding site for the Shc adaptor protein.

Carcinoma, Medullary↗
PubMed2004

[The RET gene in multiple endocrine neoplasia type 2 (MEN 2)].

Multiple endocrine neoplasia types 2A and 2B(MEN 2A and MEN 2B), and familial medullary thyroid carcinoma(FMTC) are autosomal, dominantly inherited syndromes involving endocrine tumors. MEN 2A is characterized by medullary thyroid carcinoma(MTC), pheochromocytoma(pheo), and parathyroid hyperplasia; MEN 2B is characterized by MTC, pheo, mucosal ganglioneuroma, and marfanoid habitus. Affected individuals in FMTC families develop MTC without any other abnormalities. MEN 2A and MEN 2B and FMTC are caused by germline mutations in the RET proto-oncogene. To investigate the spectrum of RET mutations among Japanese patients, we analyzed the RET gene 118 patients with MEN 2 or FMTC.

Germ-Line Mutation↗
PubMed2006

[Characterization of RET proto-oncogene C634Y mutation in a Moroccan family with multiple endocrine neoplasia type 2A].

Medullary thyroid carcinoma (MTC) is a rare cancer which originates from the calcitonin producing "C" cells of thyroid gland. It presents in as isolated form or as part of the multiple endocrine neoplasia type 2 (MEN 2). The familial form of MTC which frequency remains underestimated, account for 25 to 40% of all MTC presentations. All hereditary forms are transmitted in an autosomal dominant manner and are due to proto-oncogene RET germ line mutations. Although MCT is relatively rare, preclinical or prebiological diagnosis can be achieved with genetic screening with high specificity and sensitivity. Early diagnosis is crucial for disease prevention. In this study we identified the first RET mutation underlying NEM 2A in Morocco. The C634Y mutation was present in the heterozygous state in a Moroccan family with MEN 2A. Genetic screening showed that six asymptomatic members of this family were not C364Y carriers. This report should contribute to the development of genetic screening for NEM 2 and F-MTC in Morocco.

Algeria↗
PubMed2004

Biological effects of the dual phenotypic Janus mutation of ret cosegregating with both multiple endocrine neoplasia type 2 and Hirschsprung's disease.

Gain-of-function mutations of ret receptor tyrosine kinase, the signaling receptor for glial cell line-derived neurotrophic factor, cause sporadic thyroid and adrenal malignancies as well as endocrine cancer syndromes, such as multiple endocrine neoplasia types 2A and 2B (MEN 2A and MEN 2B) and familial medullary thyroid carcinoma. Loss-of-function mutations of ret cause Hirschsprung's disease (HSCR) or colonic aganglionosis. In 20-30% of families with a mutation at residues 609, 611, 618, or 620 of RET, MEN 2A and familial medullary thyroid carcinoma cosegregate with HSCR. These mutations constitutively activate RET due to aberrant disulfide homodimerization and diminish the level of RET at the plasma membrane. It is not known how these mutations simultaneously lead to both gain- and loss-of-function RET-associated diseases. We provide an explanation for the dual phenotypic Janus mutation at Cys620 of RET. In Madin-Darby canine kidney (MDCK) cells, the Janus mutation impairs the glial cell line-derived neurotrophic factor-induced effects of RET on cell migration, differentiation, and survival but simultaneously promotes rapid cell proliferation.

Animals↗