ALLELIC DELETIONS ON CHROMOSOME 11Q13 IN MULTIPLE TUMORS FROM INDIVIDUAL MEN1 PATIENTS

Familial multiple endocrine neoplasia type 1 is an autosomal dominant hereditary disorder characterized by multiple parathyroid, pancreatic, duodenal, and pituitary tumors. The parathyroid tumors may arise as d iffuse areas of hyperplasia, whereas the pancreatic and duodenal tumor s usually form as discrete nodules. Except for a single report, tumor loss of heterozygosity (LOH) mapping of the putative MEN1 suppressor g ene on chromosome 11q13 in the past has been restricted by analysis of a single tumor from individual patients and somatic cellular contamin ation. For this reason, it has not been possible to analyze the clonal ity of the emerging MEN1 neoplasms. Furthermore, it has been previousl y unknown whether the LOH pattern varies between individual MEN1 tumor s in a given patient or among tumors of different histological origins within unrelated patients. To address these previous limitations, the present study introduces a refinement in microdissection in which end othelial cells are stained and selectively excluded. Tissue microdisse ction was applied to study LOH patterns on chromosome 11q13 using 8 po lymorphic DNA markers in 44 different MEN1 tumors from parathyroid, pa ncreas, and duodenum in nine unrelated patients. In addition, X-chromo some inactivation clonal analysis was applied to 16 individual microdi ssected regions from seven parathyroid glands in three female patients . The LOH rates of parathyroid lesions (100%) and endocrine tumors of the pancreas (83%) were strikingly different from the LOH rate of gast rinomas (21%), suggesting that the mechanism that drives LOH may be in fluenced by the tissue context. Moreover, combined LOH and X-chromosom e inactivation scoring of the same microdissected region revealed that parathyroid MEN1 neoplasms can consist of more than one clone. In thi s study, the centromeric boundary of the putative MEN1 gene was PYGM. Analysis of differential LOH patterns in multiple microdissected tumor s in the same patient constitutes a novel approach to suppressor gene mapping.