Molecular genetics of multiple endocrine neoplasia types 1 and 2

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Abstract
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.