Pheochromocytomas and medullary thyroid cancer (MTCs) occur sporadically, or in the setting of hereditary neoplasia syndromes, including MEN-2A and MEN-2B. In addition, pheochromocytomas occur in patients with neurofibromatosis-1 (NF-1) and von Hippel Lindau syndrome (vHL) and MTCs occur without pheochromocytomas in familial MTC (FMTC). The goal of this project is to identify and characterize genetic abnormalities in pheochromocytomas and MTCs, and determine their biological and clinical significance. The gene(s) responsible for the MEN-2 constitutional predisposition syndromes have been mapped to the pericentromeric region of chromosome 10. However, allelic loss at this locus is rare, and the subsequent genetic events that result in tumor formation in these predisposition syndromes are not well understood. We propose to analyze pheochromocytomas and MTCs from patients with familial and sporadic disease to identify the consistent genetic changes that characterize these tumors. We and others have determined that the most consistent site of allelic loss is on the short arm of chromosome 1 (1p) in pheochromocytomas and MTCs. We hypothesize that this region contains a suppressor gene that is involved in the development of progression of these tumors. We will use a panel of polymorphic probes from 1p to analyze pheochromocytomas and MTCs to localize the region most frequently deleted to a band or subband. Then we will use yeast artificial chromosome cloning technology to physically map the region of interest, as a basis from which to identify and characterize the putative suppressor gene that is lost or inactivated in these tumors. There is frequently hyperplasia of the target tissues (medullary thyroid cells and the adrenal chromaffin cells), implying a failure of complete differentiation or a stimulation of growth of these cells. We will examine the structure and expression of the genes involved in the nerve factor receptor (NGFR) pathway, which appears to be one of the most important ligand/receptor pathways involved in the regulation of growth and differentiation in neuroendocrine tissues. Preliminary evidence from our laboratory suggests that there is little or no expression of the components of the biologically active, high-affinity receptor for NGF. We will perform karyotype analysis on all the tumors that are obtained during the time of this study to identify any consistent cytogenetic changes, especially those involving 1p. In addition, we will assess other chromosome arms for allelic loss to determine if there are other potential suppressor gene loci in these tumors. Finally, we will determine the biological and clinical significance of the above findings by comparing the patterns of genetic change to the histology of the tumor (pheochromocytoma or MTC), and the genetic background of the host (sporadic, MEN-2, NF-1, vHL), as well as the clinical behavior of the tumor. The successful completion of these studies should provide insight into the mechanisms of malignant transformation and progression in these tumors from hyperplasia to neoplasia, as well as potential predictors of clinical behavior in affected patients.
Showing the most recent 10 out of 20 publications
