Clonality of Parathyroid Tumors in Familial Multiple Endocrine Neoplasia Type 1

Abstract

Familial multiple endocrine neoplasia type 1 (MEN-1) is characterized by tumors of the parathyroids, endocrine pancreas, and anterior pituitary. Since the gene associated with MEN-1, located on chromosome 11 (11q13), may normally inhibit tumor proliferation, tumors could arise from inactivation of one or both of the alleles. However, parathyroid tumors in patients with MEN-1 have been considered to result from polyclonal hyperplasia. Using genetic probes, we tested parathyroid tumors for a monoclonal component, represented by a loss of alleles at any of eight loci along chromosome 11. Ten of 16 tumors from 14 patients with familial MEN-1 had losses of alleles from chromosome 11. Tumors with losses were larger than those without (1.6 vs. 0.2 g; P less than 0.002), suggesting that a monoclonal adenoma may develop after a phase of polyclonal hyperplasia. In 7 of 10 tumors, the subregion of loss was less than the full length of chromosome 11 but always included one copy of the MEN-1 locus. Of 34 sporadic adenomas from patients without MEN-1, 9 showed similar allelic losses in chromosome 11; in 7 the losses included the apparent MEN-1 locus. We conclude that many "hyperplastic" parathyroid tumors in familial MEN-1 are in fact monoclonal and may progress or even begin to develop by inactivation of the MEN-1 gene (at 11q13) in a precursor cell. Some sporadic adenomas have allelic losses on chromosome 11, which may also involve the MEN-1 gene.

Clonal loss of INT-2 alleles in sporadic and familial pancreatic endocrine tumours

“…The sporadic pancreatic tumour presumably involved a mutation and a deletion of the normal allele in a similar manner except that both these chromosomal alterations occurred in the somatic cells. These conclusions are consistent with Knudson's two-hit theory of carcinogenesis (Knudson et al, 1976) and are supported by the findings for sporadic and familial (MEN-l associated) parathyroid tumours which have also been shown to have allelic loss within chromosome band 11q13 (Friedman et al, 1989;Thakker et al, 1989). It is possible in MEN-1, however, that the second lesion may not be at the putative disease locus, a situation analagous to that found in Wilm's tumour, where there is loss of heterozygosity which does not seem to be at the site of the gene which leads to inherited susceptibility.…”

“…Recently, both parathyroid and pancreatic lesions in MEN-1 have been reported to show allelic loss of heterozygosity on chromosome 11 (Larson et al, 1988;Friedman et al, 1989;Thakker et al, 1989;Yoshimoto et al, 1989). In the case of the parathyroid, a similar change was reported with sporadic adenoma (Friedman et al, 1989). We believe the present study is the first report of allelic loss in a sporadic pancreatic endocrine tumour.…”

Clonality as Expression of Distinctive Cell Kinetics Patterns in Nodular Hyperplasias and Adenomas of the Adrenal Cortex

“…[31][32][33] Those findings support the concept of multistep tumorigenesis and Knudson's hypothesis. 34 However, monoclonal hyperplasias (parathyroid, in multiple endocrine neoplasia type 1 (MEN-1) and uremic patients, and multinodular goiters) 33,35 and polyclonal adenomas (parathyroid and thyroid) 30 have also been reported. Therefore, it has been concluded that clonality assay itself is of limited utility in differentiating hyperplastic from neoplastic conditions.…”

Characterization of the mouse Men1 gene and its expression during development

“…The gene had been postulated to be a tumour suppressor, as loss of the wild-type allele was found in tumours from MEN1 patients (Larsson et al, 1988). Additional support for its role as a tumour suppressor gene came from the demonstration of loss of heterozygosity in sporadic tumours (Friedman et al, 1989;Thakker et al, 1989;Sawicki et al, 1992;Debelenko et al, 1997b) and is now con®rmed by the identi®cation of somatic MEN1 mutations Zhuang et al, 1997a, b;Toilat et al, 1997;Debelenko et al, 1997a;Farnebo et al, 1998). Inactivating mutations have been reported in half of the parathyroid, pituitary and pancreatic tumours which exhibit a concomitant loss of one MEN1 allele.…”