Homozygous inactivation of the MEN1 gene as a specific somatic event in a case of secondary hyperparathyroidism

Department of Molecular Medicine, Endocrine Tumor Unit, Karolinska Hospital CMM L8:01, SE-171 76 Stockholm, Sweden. lars.forsberg@cmm.ki.se

BACKGROUND: Most patients who have been surgically treated for secondary hyperparathyroidism (HPT) harbor at least one pathological parathyroid gland with a tumor of monoclonal origin. OBJECTIVE: To elucidate the underlying genetic mechanisms behind secondary HPT, by studying a panel of such tumors for numerical alterations. METHODS: Sixteen parathyroid glands from eight patients (median age 58 years, range 31-74 years), were screened for numerical chromosomal imbalances, using comparative genomic hybridization (CGH). Mutation analysis of the multiple endocrine neoplasia type 1 gene (MEN1) was also performed by sequencing of the coding region. RESULTS: The results show that gross chromosomal alterations occur rarely in secondary HPT. In one of the three glands analyzed from one patient, a complete loss of chromosome 11 was detected. This gland also had an inactivating nonsense mutation, E469X, of the MEN1 gene. The mutation was present neither in the other two glands, nor in the constitutional tissue of the same patient, thus confirming its somatic origin. CONCLUSIONS: The relative lack of numerical chromosomal alterations would suggest that more discrete genetic alterations are responsible for the monoclonal growth in the majority of cases of secondary HPT. Furthermore, somatic inactivation of the MEN1 tumor suppressor gene contributes to the tumorigenesis in a small proportion of the cases.

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