The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis.

@article{Eng1996TheRB,
  title={The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis.},
  author={Charis Eng and David Clayton and Isabelle Schuffenecker and Gilbert M. Lenoir and Gilbert J Cote and Robert F. Gagel and Hans Kristian Ploos van Amstel and C. J. Lips and Isamu Nishisho and S Takai and Deborah J. Marsh and Bruce G. Robinson and Karin Frank‐Raue and Frank Raue and Feng Xue and Walter W. Noll and Cristina Romei and Furio Pacini and Martina Fink and Bruno Niederle and Jan Zedenius and Magnus Nordenskj{\"o}ld and Paul Komminoth and Geoffrey N Hendy and Lois M. Mulligan},
  journal={JAMA},
  year={1996},
  volume={276 19},
  pages={
          1575-9
        }
}
OBJECTIVE Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominant disorder. The 3 recognized subtypes include MEN 2A, characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (pheo), and hyperparathyroidism (HPT); MEN 2B, by MTC, pheo, and characteristic stigmata; and familial MTC (FMTC), by the presence of MTC only. The purpose of this study was to establish the relationship between specific mutations and the presence of certain disease features in MEN 2 which could… 

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Compared to standard presymptomatic biochemical screening, genetic testing and consecutive prophylactic treatment contribute to better outcome of individuals at risk for MTC.

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Despite success in implementation of mutation detection in clinical laboratory, this study illustrates the difficulty in acceptance of prophylactic thyroidectomy.

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TLDR
Genotype-phenotype correlations exist with respect to clinical subtype, age at onset, and aggressiveness of MTC in MEN2, and a recent report showed that in sporadic MTC, CDKN1B V109G polymorphism correlates with a more favorable disease progression than the wild-type allele and might be considered a new promising prognostic marker.
...

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Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC

TLDR
The data show a strong correlation between disease phenotype and the nature and position of theRET mutation, suggesting that a simple, constitutive activation of the RET tyrosine kinase is unlikely to explain the events leading to MEN 2A and FMTC.

A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma

TLDR
It is shown that MEN 2B is also associated with mutation of the RET proto-oncogene, and a mutation in codon 664, causing the substitution of a threonine for a methionine in the tyrosine kinase domain of the protein, was found in all nine unrelated men 2B patients studied.

RET proto-oncogene mutations in French MEN 2A and FMTC families.

TLDR
Although direct sequencing of RET exons 10 and 11 allows the identification of a constitutional mutation in a large proportion of MEN 2A and FMTC families, the data sustain the existence of other MTC predisposing mutations elsewhere in RET coding or regulating region.

Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A

TLDR
This work has identified missense mutations of the RET proto-oncogene in 20 of 23 apparently distinct MEN 2A families, but not in 23 normal controls, and found that 19 of these 20 mutations affect the same conserved cysteine residue at the boundary of theRET extracellular and transmembrane domains.

Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.

TLDR
Evidence is presented that sequence changes within the coding region of the RET proto-oncogene, a putative transmembrane tyrosine kinase, may be responsible for the development of neoplasia in these inherited disorders.

Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B.

TLDR
It is proposed that a point mutation in the RET protooncogene results in the replacement of methionine with threonine within the catalytic core region of the tyrosine kinase domain, which results in dominant oncogenic activity by the RET protein.

Mutations of codon 918 in the RET proto-oncogene correlate to poor prognosis in sporadic medullary thyroid carcinomas.

TLDR
The RET codon 918 mutation may have prognostic impact, and therefore preoperative assessment may influence decision-making in the treatment of patients suffering from MTC.

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TLDR
It is suggested that specific mutations in cysteine codons 618 and 620 result in MEN 2A or FMTC, but can also predispose to HSCR with low penetrance.

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TLDR
It is demonstrated by a sensitive, semiquantitative RT-PCR technique and in situ hybridization, that RET is expressed in MEN 2A parathyroid tumors and in sporadic adenomas, and that MEN 2 mutations in RET rarely play a part in the pathogenesis of sporadic parathyro tumors.