Differences in allelic distribution of two polymorphisms in the VHL-associated gene CUL2 in pheochromocytoma patients without somatic CUL2 mutations

Although the two major familial forms of pheochromocytomas, multiple endocr ine neoplasia type 2 and von-Hippel-Lindau disease (VHL), have been associa ted with mutations of the RET and VHL genes, respectively, the molecular pa thogenesis of sporadic pheochromocytomas is largely unknown. Recently, a pu tative tumor suppressor gene has been identified, CUL2, whose product has b een shown to interact with the VHL tumor suppressor. To examine whether CUL 2 plays a role in pheochromocytoma pathogenesis, we analyzed a series of 26 distinct tumor samples for mutations in the whole coding region of this ge ne. There were no somatic pathogenic mutations in CUL2, except for 1 sporad ic tumor that had a hemizygous gene deletion. We also found 3 novel polymor phisms in the gene. One of these variants, IVS5-6C/T, as well as another pr eviously described one, c.2057G/A, were overrepresented among the pheochrom ocytoma patients compared to that in a control population (P < 0.005 and P < 0.01, respectively). Although our findings suggest that CUL2 does not pla y a major role in the pathogenesis of pheochromocytomas, it is still unknow n whether epigenetic mechanisms are involved in its inactivation in VHL-ass ociated tumors. Furthermore, the potential role for the overrepresented all eles in the pheochromocytoma group requires further investigation.