Consistent Association of lp Loss of Heterozygosity with Pheochromocytomas from Patients with Multiple Endocrine Neoplasia Type 2 Syndromes

Pheochromocytomas and medullary thyroid cancers (MTCs) are neuroendocrine tumors which arise sporadically or as part of the multiple endocrine neoplasia type 2 (MEN-2) hereditary syndromes. The most consistent molecular genetic abnormality which has been described in these tumors is loss of heterozygosity (LOH) of the short arm of chromosome 1 (lp). This finding is particularly interesting because the predisposition gene for the hereditary form of these rumors has been mapped to chromosome 10, but LOH on chromosome 10 in MEN-2 tumors is found rarely. We have used a battery of lp DNA probes to elucidate the region of loss of lp in 18 pheochromocytomas and 27 MTCs. Using restriction fragment length polymorphism analysis, we identified loss of all or a portion of lp in 12 of 18 pheochromocytomas. lp LOH was identified in nine of nine pheochromocytomas in MEN-2A and -2B patients, compared with only two of seven sporadic pheochromocytomas. We also found lp LOH in one of two von Hippel-Lindau patients. LOH on lp was noted in only three of 24 informative MTCs, and these were from patients with MEN-2A. In most of the pheochromocytomas, the entire short arm of chromosome lp appears to have been lost; however, in three of the non-MEN pheochromocytomas and in three MEN-2A MTCs, the region of loss is smaller, allowing estimation of the smaUest region of overlap. The combined data for MTCs and pheochrom-ocytomas suggest that the smallest region of overlap of LOH is bounded by D1S15 (lpter-p22) and D1Z2 (1P36J), excluding a region around MYCL (lp32). Although other regions of lp should not be completely ruled out, the data suggest that this region may harbor a tumor suppressor gene or genes whose inactivation is important in the development of these rumors. Furthermore, the strong association between lp LOH and the MEN-2 syndromes, especially in pheochromocytomas, suggests a relationship between the predisposition gene on chromosome 10 and the loss of the suppressor gene on lp. Alternatively, other loci may be more important in sporadic disease.