Association of Parathyroid Tumors in Multiple Endocrine Neoplasia Type 1 with Loss of Alleles on Chromosome 11

Abstract

Familial multiple endocrine neoplasia type 1 (MEN-1) is an autosomal dominant disorder characterized by the combined occurrence of tumors of the parathyroid glands, the pancreas, and the pituitary gland. Pancreatic tumors have previously been shown to be associated with the loss of alleles on chromosome 11; we therefore looked for similar genetic alterations in specimens of parathyroid tumors, which are the most common feature of MEN-1. We obtained parathyroid tumors and peripheral-blood leukocytes from six patients with MEN-1; 18 cloned human DNA sequences from chromosome 11 were then used to identify restriction-fragment-length polymorphisms. A loss of heterozygosity was detected in parathyroid tumors from three of the six patients with MEN-1; this finding demonstrated that allelic deletions on chromosome 11 are involved in the monoclonal development of parathyroid tumors in patients with MEN-1. In addition, studies of three affected families (with 17 affected members and 51 unaffected members) established linkage with the oncogene INT2 (peak lod score, 3.30, at 0 percent recombination); the MEN-1 gene was thus mapped to the pericentromeric region of the long arm of chromosome 11 (11q13). Our location of the MEN-1 gene at 11q13 is close to the location previously reported. We conclude that a single inherited locus on chromosome 11, band q13, causes MEN-1 and that the monoclonal development of parathyroid and pancreatic tumors in patients with MEN-1 involves similar allelic deletions on chromosome 11.

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).…”

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.…”

Loss of heterozygosity and amplification on chromosome 11q in human ovarian cancer

“…The multiple endocrine neoplasia type 1 (MENI) gene maps to 1 1q13 (Larsson et al, 1988;Fujimori et al, 1992) and LOH on 1 lq has been reported in MENl-associated tumours (Friedman et al, 1989;Thakker et al, 1989). In most cases, all informative probes on 1 lq showed LOH, but given the linkage data, the tumour suppressor gene is likely to be in 1Iq13.…”