Screening of the MEN1 gene and discovery of germ-line and somatic mutations in apparently sporadic parathyroid tumors

Hyperparathyroidism is the first manifestation in a majority of multiple en docrine neoplasia (MEN1) patients. To discriminate between sporadic and her editary parathyroid tumors and characterize MEN1 somatic mutations, we exam ined MEN1 gene mutations in patients who had undergone surgery for sporadic parathyroid tumors. DNA was extracted from fresh frozen parathyroid tumor specimens from 112 patients as well as from peripheral blood Leukocytes fro m 64 of the 112 patients, Sequence analysis was performed to examine exons 2-10 of the MEN1 gene for mutations, Loss of heterozygosity (LOH) was also examined by an analysis of codon 418 and 541, which lie within a polymorphi c region of MEN1, Somatic MEN1 mutations were found in 25 of the 112 patien ts (22%), Two patients had two point mutations (508del33 and Y341X and 363i nsT and 1767delT, respectively). A total of 27 mutations were characterized , 20 of which have not been reported previously. There were 7 nonsense muta tions, 10 frameshift mutations, 2 splice site deletions, 5 missense mutatio ns, and 3 in-frame mutations. Nineteen mutations (70%) predicted truncation of the menin protein. Germ-line MEN1 mutations were found in 3 of 64 patie nts (5%) who had no family history of endocrine tumors associated with MEN1 , and these patients were identified as MEN1 gene probands, LOH at the MEN1 locus was detected in three parathyroid tumors showing germ-line mutation. LOH was significantly frequent in parathyroid tumors with somatic MEN1 mut ations (15 of 22 tumors, 68%) but not in those without germ-line or somatic MEN1 mutations (14 of 51 tumors, 28%; P = 0.0011), Our findings suggest th at alterations of both alleles of the MEN1 gene may be associated not only with endocrine tumors of affected MEN1 patients but also with sporadic para thyroid tumors. Germ-line MEN1 gene analysis can distinguish heritable from nonheritable parathyroid tumors, and MEN1 gene evaluation of patients with apparently sporadic parathyroid tumor is recommended before parathyroid su rgery.