Sporadic endocrine tumours and their relationship to the hereditary endocrine neoplasia syndromes.

Abstract

In the last years of the previous century the genes involved in the aetiology of five endocrine tumour syndromes have been identified. The tumour-suppressor gene that is responsible for Von Hippel-Lindau Disease was cloned in 1993; multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid carcinoma were found to be caused by activating mutations in the ret proto-oncogene in 1993 and 1994, and most recently the menin-gene, another tumour-suppressor gene, was shown to be associated with MEN-1. As usual, the answer to one question leads to innumerable new questions. And so, now we want to know the extent to which germ-line mutations (de novo, or otherwise previously undetected) in these genes play a role in the occurrence of the various endocrine tumours that are associated with these syndromes in apparently sporadic cases. We also want to know if the nature of the (germ-line) mutation conveys any information about the characteristics (phenotype) of the disease. We want to know the role of somatic mutations in these genes in truly sporadic tumours. And finally we want to know the exact function of the proteins that are encoded by these genes. The paper by Roijers et al. [1] elsewhere in this issue is an example of a small but well-directed step on the way to address some of these questions with respect to the menin-gene. It addresses the problem of patient selection when looking for germ-line mutations in apparently sporadic MEN-1 patients. In this review we want to give a brief summary of the present status with regard to some of the questions mentioned above, in relation to the endocrine tumour syndromes caused by the vhl, ret and menin genes.