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  • Review Article
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Molecular genetics of multiple endocrine neoplasia types 1 and 2

Nature Reviews Cancer volume 5, pages 367–375 (2005)Cite this article

A Correction to this article was published on 01 August 2005

Key Points

  • Multiple endocrine neoplasia (MEN) type 1 (MEN1) and MEN type 2 (MEN2) are the most striking MEN syndromes in terms of hormonal excesses. They differ in that both are potentially lethal from associated cancer but only MEN2-related cancer can be prevented. Similar names cause confusion between them.

  • MEN1 sequencing gives useful information about the MEN1 carrier status. This test is not a clinical requirement for relatives of individuals with MEN1 as it is not a major guide for therapy.

  • Men1+/− mice are a good model of MEN1. Features that differ from MEN1 loss in man include a higher penetrance of pheochromocytoma and a stage of polyclonal hyperplasia in pancreatic islet cells as the precursor to insulinoma.

  • RET mutations cause three variants of MEN2 with three grades of calcitonin-producingcell (C-cell) cancer and with a strong correlation of RET genotype to phenotype.

  • RET sequencing is recommended in relatives of individuals with MEN2 as a guide for the successful management for C-cell cancer and pheochromocytoma.

  • Tumorigenesis after mutation of MEN1 (a tumour suppressor) follows a typical twohit loss-of-function process.

  • Tumorigenesis after mutation of RET (an oncogene) follows a stepwise process; sometimes this involves a second hit in a RET allele. This probably causes further imbalance towards RET gain of function.

  • The roles of menin (the protein encoded by MEN1) in tumorigenesis are obscured by its large number of candidate partners and candidate physiologies. A specific anti-MEN1 drug cannot be contemplated until MEN1 function is better understood.

  • RET mutations are oncogenic owing to a gain of function in RET's intrinsic receptor tyrosine kinase activity. Tyrosine-kinase inhibitors are in clinical trials for RET-related neoplasms.

Abstract

Six multiple endocrine neoplasia (MEN) syndromes have received a level of attention that might seem disproportionate to their low prevalence. The attention has been given because their hormonal excesses cause striking metabolic expressions and because they might clarify pathways disrupted in more common tumours. The recent discovery of the main gene in each MEN syndrome has furthered our understanding of not only hereditary but also sporadic tumours and has fostered new avenues of research.

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Figure 1: Endocrine tumours expressed in multiple endocrine neoplasia types 1 and 2.
Figure 2: Logarithmic distribution of mutations in the MEN1 gene or the RET gene.
Figure 4: Molecules and interactions of the RET complex.
Figure 3: The genetic activation of RET.

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Acknowledgements

I thank many colleagues for collaborations and discussions. In particular, these include the participants in the National Institutes of Health (NIH) Campus Collaborative Group on MEN1 and the participants in the NIH Interinstitute Endocrine Training Program. I also thank S. Agarwal and L. Mulligan for analysing data to develop Figure 2.

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DATABASES

Entrez Gene

Cdkn1a

CDKN2C

JUND

MEN1

RET

OMIM

Hirschsprung disease

RET-PTCs

MEN type 1

MEN type 2

MEN2B

FURTHER INFORMATION

An academic type review of MEN2 from GeneTests

NIDDK page on MEN1

The Association for Multiple Endocrine Neoplasia Disorders

Glossary

HYPERPARATHYROIDISM

The overproduction of parathormone by the parathyroid glands. Usually secondary to an adenoma (an unregulated glandular tumour that produces parathormone in an increased quantity).

LOSS OF HETEROZYGOSITY

In cells that carry a mutated allele of a tumour-suppressor gene, the gene becomes fully inactivated when the cell loses a large part of the chromosome carrying the wild-type allele. Regions with high frequency of loss of heterozygosity might harbour tumour-suppressor genes.

PENETRANCE

The frequency with which individuals who carry a given mutation show the manifestations associated with that mutation. If the penetrance of a disease allele is 100%, then all individuals carrying that allele will express the associated phenotype.

PHEOCHROMOCYTOMA

A neuroendocrine tumour that typically arises in the adrenal medulla. These tumours can be benign or malignant. Symptoms often relate to the ability of these tumours to secrete catecholamines.

HIRSCHSPRUNG DISEASE

Hirschsprung disease is characterized by a congenital absence of ganglion cells in the distal colon, resulting in a functional obstruction. Both the myenteric (Auerbach) and submucosal (Meissner) plexus are absent, resulting in reduced bowel peristalsis and function.

C-CELLS

Calcitonin-producing cells. These form a distinct extrathyroidal gland (the ultimobranchial gland) in all lower vertebrates such as fish and amphibians but are dispersed and entirely within the thyroid gland in mammals. In this latter location, they are also termed parafollicular cells.

MEDULLARY THYROID CANCER

Medullary (or C-cell) thyroid cancer. A neoplasm of the calcitonin-producing C-cells in the thyroid gland.

FAMILIAL MEDULLARY THYROID CANCER

A variant of multiple endocrine neoplasia type 2 (MEN2) that can also be considered as a very mild extreme of MEN2A.

PENTAGASTRIN

A synthetic polypeptide that has effects like gastrin. It stimulates the secretion of gastric acid, pepsin and intrinsic factor, and has been used as a diagnostic aid for multiple endocrine neoplasia type 2 by promoting calcitonin secretion.

PERIADRENAL GANGLIONEUROMA

A tumour (neuroma) containing ganglion cells that arises from nerves in the periadrenal tissue.

SECOND-HIT

In most medical contexts, this step is a mutation in the remaining normal allele. Gene methylation is an epigenetic step that can have similar consequences.

COMPASS

A multisubunit transcriptional complex in yeast with histone-methyltransferase activity. All yeast lack menin, but most of the COMPASS subunits have homologues in mammals. The human proteins include menin, MLL, ASH2L, RBBP5, WDR5, HCF1 and PolII.

MLL

Encodes a part of the COMPASS-like complex. It contributes the carboxy-terminal part of an oncogene in a fusion protein, causing leukaemia/lymphoma.

GFRα

Glial-cell-derived neurotrophic factor family receptor-α. A glycosylphosphatidylinositol-anchored plasma membrane extracellular co-receptor. It binds an extracellular ligand, and it is able to interact directly with RET.

CHROMAFFIN TUMOUR

A neoplasm composed of chromaffin cells occurring in the medullae of adrenal glands, the organs of Zuckerkandl, or the paraganglia of the thoracolumbar sympathetic chain. Some chromaffin tumours secrete catecholamines.

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Marx, S. Molecular genetics of multiple endocrine neoplasia types 1 and 2. Nat Rev Cancer 5, 367–375 (2005). https://doi.org/10.1038/nrc1610

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