Multiple endocrine neoplasia type 1 : clinical and molecular characterization

• This thesis is based on clinicopathologic and genetic studies of MEN1 and MEN1-like syndromes. Linkage to the MENl locus in chromosome 11q13 was confirmed in the largest known MEN1 family and 5 Swedish MEN1 families. An accuracy of >99.5% in predictive testing could be achieved by using the marker systems that were closely linked without cross-overs, and those on the telomeric and centromeric sides of MEN1. As all reported linkage analysis had been performed on MEN1 families of Caucasian origin, non-Caucasian MEN1 families were studied to test for genetic heterogeneity. In two different Malaysian MEN1 families of Chinese origin, linkage to 11q13 was confirmed pointing to a genetically homogenous disease. As a concerted effort of the European Consortium on MEN1, a 5-Mb integrated map of the MENI region was established which formed the groundwork for subsequent cloning of the MENl gene. This was based on the characterization of YACs, cosmids and polymorphic markers by FISH, chromosome 11 somatic cell hybrids, and long range restriction mapping. From 86 MEN1 families, two critical recombinants were identified at markers D11S1883 and D11S449 placing the MEN1 gene in a 2-Mb region around PYGM. Following the identification of the MEN1 gene, mutation analysis was performed in 58 MEN1 families from 6 countries, and 8 sporadic MEN1 patients. Twenty-three different mutations were identified in 27 MEN1 families and 5 sporadic cases. The majority of them are frameshift or nonsense mutations supporting the notion that the gene is a tumor suppressor gene. In addition, one common warm spot and one denovo mutation were found. Clinicopathologic and genetic studies of 20 cases of MEN1-related thymic carcinoids were carried out. Clusterings in close relatives were found: 3 pairs of brothers and three families with first- or second-degree affected relatives. However, no genotype-phenotype correlation was found as mutation analysis of the MEN1 gene in these families revealed mutations in different exons. All 20 patients were male, and either asymptomatic or with minimal symptoms. Local invasion, recurrence and distant metastases were common with a mean survival of 4.5 years. LOH in the MEN1 region was not found in 7 studied tumors but instead, LOH of 1p was found in 2 tumors. These results, together with the male predominance, and clusterings in close relatives, suggested the involvement of modifier gene(s). Finally, clinicopathologic and genetic studies of MEN1-variants, notably familial isolated hyperparathyroidism (FIHP) and familial acromegaly, were carried out. FIHPi s characterized by parathyroid adenoma which is in contrast to MEN1. The latter involves invariably multiglandular disease or hyperplasia and an evidence for this was the finding of a case of solitary parathyroid adenoma in the largest known MEN1family. The patient did not carry the disease gene as the other affected cases who had multiglandular disease. In two FIHP families with a total of 36 members, 10 affected patients with parathyroid adenomas were found but without evidence of other endocrinopathies or neoplasia. Both were linked to the HRPT2 locus in chromosome 1q21-q32. The parathyroid adenoma could either be of chief cell type or oncocytic cell type even in the same family. Three tumors demonstrated loss of the wild-type alleles in the 1q region suggesting that the gene has tumor suppressor activity. In four small FIHP families, mutation of the MEN1 gene was not detected suggesting that the HRPT2 gene may be involved. Finally, mutation analysis of the MEN1 gene in 5 acromegaly families was performed but failed to detect any mutation suggesting that they may constitute a distinct syndrome(s), involving other genetic defect(s) than the MEN1 gene.

Nyckelord

MEN1, PYGM,loss of heterozygosity, thymic carcinoid, HPT-JT,HRPT2, FIHP, familial acromegaly, tumor suppressor gene.

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