Clonality of Parathyroid Tumors in Familial Multiple Endocrine Neoplasia Type 1

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<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 11ϥ13) in a precursor cell. Some sporadic adenomas have allelic losses on chromosome 11, which may also involve the MEN-1 gene. PRIMARY hyperparathyroidism is a common disorder caused either by an adenoma of a single parathyroid gland or by tumors, usually referred to as hyperplasia, of all four glands.^1,2 Arnold et al.³ showed that at least six of eight sporadic parathyroid adenomas that they studied contained a large monoclonal component, on the basis of testing of DNA for X-chromosome-inactivation patterns and clonal rearrangements of the parathyroid hormone gene. Primary parathyroid hyperplasia is generally believed not to be represented as a monoclonal tumor^4,5; indeed, analysis of DNA from five hyperplastic parathyroid glands did not suggest that a monoclonal component was present…