Multiple endocrine neoplasia type 1 : clinical and molecular characterization

Sammanfattning: Multiple Endocrine Neoplasia Type 1 - Clinical and Molecular Characterization by Bin Tean Teh, Department of Molecular Medicine, Endocrine Tumor Unit, KarolinskaInstitute, Stockholm, Sweden This thesis is based on clinicopathologic and genetic studies of MEN1 and MEN1-likesyndromes. Linkage to the MENl locus in chromosome 11q13 was cofirmed in the largestknown MEN1 family and 5 Swedish MEN1 families. An accuracy of >99.5% in predictivetesting could be achieved by using the marker systems that were closely linked withoutcross-overs, and those on the telomeric and centromeric sides of MEN1. As all reportedlinkage analysis had been performed on MEN1 families of Caucasian origin, non-CaucasianMEN1 families were studied to test for genetic heterogeneity. In two different MalaysianMEN1 families of Chinese origin, linkage to 11q13 was confirmed pointing to a geneticallyhomogenous disease. As a concerted effort of the European Consortium on MEN1, a 5-Mbintegrated map of the MENI region was established which formed the groundwork forsubsequent cloning of the MENl gene. This was based on the characterization of YACs,cosmids and polymorphic markers by FISH, chromosome 11 somatic cell hybrids, andlong range restriction mapping. From 86 MEN1 families, two critical recombinantswere identified at markers D11S1883 and D11S449 placing the MEN1 gene in a 2-Mb regionaround PYGM. Following the identification of the MEN1 gene, mutation analysis wasperformed in 58 MEN1 families from 6 countries, and 8 sporadic MEN1 patients. Twenty-threedifferent mutations were identified in 27 MEN1 families and 5 sporadic cases. Themajority of them are frameshift or nonsense mutations supporting the notion thatthe 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 carcinoidswere carried out. Clusterings in close relatives were found: 3 pairs of brothersand three families with first- or second-degree affected relatives. However, no genotype-phenotypecorrelation was found as mutation analysis of the MEN1 gene in these families revealedmutations in different exons. All 20 patients were male, and either asymptomaticor with minimal symptoms. Local invasion, recurrence and distant metastases werecommon with a mean survival of 4.5 years. LOH in the MEN1 region was not found in7 studied tumors but instead, LOH of 1p was found in 2 tumors. These results, togetherwith the male predominance, and clusterings in close relatives, suggested the involvementof modifier gene(s). Finally, clinicopathologic and genetic studies of MEN1-variants, notably familialisolated hyperparathyroidism (FIHP) and familial acromegaly, were carried out. FIHPi s characterized by parathyroid adenoma which is in contrast to MEN1. The latterinvolves invariably multiglandular disease or hyperplasia and an evidence for thiswas 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 whohad multiglandular disease. In two FIHP families with a total of 36 members, 10 affectedpatients with parathyroid adenomas were found but without evidence of other endocrinopathiesor neoplasia. Both were linked to the HRPT2 locus in chromosome 1q21-q32. The parathyroidadenoma could either be of chief cell type or oncocytic cell type even in the samefamily. Three tumors demonstrated loss of the wild-type alleles in the 1q regionsuggesting 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 beinvolved. Finally, mutation analysis of the MEN1 gene in 5 acromegaly families wasperformed but failed to detect any mutation suggesting that they may constitute adistinct syndrome(s), involving other genetic defect(s) than the MEN1 gene. Keywords: MEN1, PYGM,loss of heterozygosity, thymic carcinoid, HPT-JT,HRPT2, FIHP, familial acromegaly, tumor suppressor gene. ISBN 91-628-2726-X Stockholm 1997