Sporadic and familial pheochromocytomas are associated with loss of at least two discrete intervals on chromosome 1p

Pheochromocytomas are tumors of the adrenal medulla originating in the chro maffin cells derived from the neural crest. Ten % of these tumors are assoc iated with the familial cancer syndromes multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and rarely, neurofibromatosis type 1, i n which germ-line mutations have been identified in RET, VHL, and NF1, resp ectively. In both the sporadic and familial forms of pheochromocytoma, alle lic loss at 1p, 3p, 17p, and 22q has been reported, yet the molecular patho genesis of these tumors is largely unknown. Allelic loss at chromosome 1p h as also been reported in other endocrine tumors, such as medullary thyroid cancer and tumors of the parathyroid gland, as well as in tumors of neural crest origin including neuroblastoma and malignant melanoma, In this study, we performed fine structure mapping of deletions at chromosome 1p in famil ial and sporadic pheochromocytomas to identify discrete regions likely hous ing tumor suppressor genes involved in the development of these tumors. Ten microsatellite markers spanning a region of similar to 70 cM (Ipter to 1p3 4.3) were used to screen 20 pheochromocytomas from 19 unrelated patients fo r loss of heterozygosity (LOH). LOH was detected at five or more loci in 8 of 13 (61%)sporadic samples and at five or more loci in four of five (80%) tumor samples from patients with multiple endocrine neoplasia type 2. No LO H at 1p was detected in pheochromocytomas from two VHL patients, Analysis o f the combined sporadic and familial tumor data suggested three possible re gions of common somatic loss, designated as PCI (D1S243 to D1S244), PC2 (D1 S228 to D1S507), and PC3 (D1S507 toward the centromere). We propose that ch romosome Ip may be the site of at least three putative tumor suppressor loc i involved in the tumorigenesis of pheochromocytomas. At least one of these loci, PC2 spanning an interval of <3.8 cM, is Likely to have a broader rol e in the development of endocrine malignancies.