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Tandem Germline RET Mutations in a Family Pathogenetic for Multiple Endocrine Neoplasia 2B, Confirmed by a Natural

Minoru Kihara1, Akira Miyauchi1, Hiroshi Yoshida2

  • 1Department of Surgery, Kuma Hospital, Kobe, Japan.

European Thyroid Journal
|March 12, 2015
PubMed

Insights

Germline tandem mutations in the RET proto-oncogene (V804M/Y806C) were identified in a family. These double RET mutations are pathogenetic for Multiple Endocrine Neoplasia type 2B (MEN 2B).

Area of Science:

  • Genetics and Molecular Biology
  • Oncology
  • Endocrinology

Background:

  • Germline mutations in the RET proto-oncogene are associated with Multiple Endocrine Neoplasia type 2 (MEN 2).
  • MEN 2B is a rare, aggressive form of MEN 2, often caused by specific RET mutations.
  • The V804M and Y806C mutations have been individually studied, but their co-occurrence on the same allele was less understood.

Purpose of the Study:

  • To investigate the pathogenetic role of tandem V804M/Y806C mutations in the RET proto-oncogene.
  • To correlate in vitro findings with clinical manifestations in a family with these specific mutations.
  • To confirm the role of these double RET mutations in the development of MEN 2B.

Main Methods:

  • Genetic analysis of a family to identify germline mutations.
  • In vitro studies to assess the transforming activity of the mutated RET proto-oncogene.
  • Clinical evaluation of affected family members to correlate genotype with phenotype.

Main Results:

  • Germline tandem V804M and Y806C mutations were found to be present on the same allele of the RET proto-oncogene.
  • The RET proto-oncogene with these tandem mutations exhibited moderate transforming activity in vitro.
  • Clinical features in the offspring confirmed the pathogenetic role of these mutations, acting as a natural experiment.

Conclusions:

  • Tandem double mutations (V804M/Y806C) in the RET proto-oncogene are pathogenetic for MEN 2B.
  • The co-occurrence of these mutations on a single allele contributes to the disease phenotype.
  • This study provides strong evidence linking specific germline tandem RET mutations to MEN 2B development.
Keywords:
De novo mutationMedullary thyroid carcinomaMultiple endocrine neoplasia 2BRETTandem mutations

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