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Clonality of parathyroid tumors in familial multiple endocrine neoplasia type 1
E Friedman1, K Sakaguchi, A E Bale
1Molecular Pathophysiology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md.
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.
Insights
Multiple endocrine neoplasia type 1 (MEN-1) parathyroid tumors are often monoclonal, not polyclonal. Inactivation of the MEN-1 gene on chromosome 11 drives tumor growth in familial MEN-1.
Area of Science:
- Endocrinology
- Human Genetics
- Oncology
Background:
- Familial multiple endocrine neoplasia type 1 (MEN-1) involves tumors of the parathyroids, pancreas, and pituitary.
- The MEN-1 gene, located at 11q13, is thought to inhibit tumor proliferation.
- Parathyroid tumors in MEN-1 have been traditionally viewed as polyclonal hyperplasia.
Purpose of the Study:
- To investigate the cellularity (monoclonal vs. polyclonal) of parathyroid tumors in familial MEN-1.
- To determine if allelic losses on chromosome 11 correlate with tumor characteristics in MEN-1.
- To examine chromosome 11 allelic losses in sporadic parathyroid adenomas.
Main Methods:
- Genetic probes were used to test 16 familial MEN-1 parathyroid tumors for allelic loss on chromosome 11.
- Tumor size was compared between tumors with and without allelic losses.
- 34 sporadic parathyroid adenomas were analyzed for similar allelic losses.
Main Results:
- Ten of 16 (63%) familial MEN-1 tumors showed allelic losses on chromosome 11.
- Tumors with allelic losses were significantly larger than those without (1.6g vs. 0.2g).
- Nine of 34 sporadic adenomas exhibited allelic losses on chromosome 11, with 7 including the MEN-1 locus.
Conclusions:
- Many "hyperplastic" parathyroid tumors in familial MEN-1 are monoclonal.
- Tumor progression in familial MEN-1 may involve MEN-1 gene inactivation in precursor cells.
- Allelic losses on chromosome 11, potentially involving the MEN-1 gene, occur in some sporadic parathyroid adenomas.