Molecular analysis of tumors related with Multiple Endocrine Neoplasia type 1. Microsatellite instability: a frequent event in insulinomas

A Cebrián, PhDa , S Ruiz-Llorente, BSca, A Cascon, PhDa, D Telleriaa, J Benitez, PhDa, M Robledo, PhDa

Centro Nacional de Investigaciones Oncologicas Carlos III, Majadahonda, Madrid Spain

AIM: Hyperparathyroidism (HPT), enteropancreatic tumors and pituitary tumors are characteristic of Multiple Endocrine Neoplasia type 1. The majority of these tumors have been studied in their sporadic forms but not in MEN1 patients with germline mutations. In the present study we have looked for molecular alterations in 50 tumors belonging to MEN1 familial and sporadic cases with germline mutations, comparing with the results obtained in sporadic cases without germline mutations. METHODS: The study was performed in 50 MEN1-related tumors from 13 MEN1 families, 8 MEN1 sporadic cases with germline mutation and 5 sporadic cases without mutations. The analysis of LOH and search of somatic mutations was carried out using microsatellite analysis (D11S1883, PYGM, D11S913 and D11S1889) and automatic sequencing. RESULTS: We found somatic mutation in one out of five tumors from the group without germline mutations. On the other hand, we have detected LOH in 57% of tumors from patients with germline mutation (familial and sporadic); and in 40% of tumors from patients without mutation. From these LOH data, we defined a minimal deleted region in HPT tumors flanked by MEN1 gene and D11S913. We have also observed that 39,4% of tumors presented microsatellite instability (MSI). This phenomenon was previously described in sporadic HPT but, so far, this is the first report of MSI affecting tumors from MEN1 families (71% of insulinoma exhibited MSI), suggesting that the DNA repair system is defective in these tumors. CONCLUSIONS: We have confirmed that LOH is the second most common mechanism of inactivation of MEN1 gene. We have found a minimal region of LOH in HPT that may contain other tumor suppressor gene related to this pathogenesis. We have observed that MSI is a common event in MEN1 disease indicating that the DNA repair pathway is affected in this syndrome.

KEY WORDS: Endocrine tumors, Instability microsatellite (MSI).

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Molecular Pathology.