title: Differences in allelic distribution of two polymorphisms in the VHL-associated gene CUL2 in pheochromocytoma patients without somatic CUL2 mutations.
abstract: Although the two major familial forms of pheochromocytomas, multiple endocrine neoplasia type 2 and von-Hippel-Lindau disease (VHL), have been associated with mutations of the RET and VHL genes, respectively, the molecular pathogenesis of sporadic pheochromocytomas is largely unknown. Recently, a putative tumor suppressor gene has been identified, CUL2, whose product has been shown to interact with the VHL tumor suppressor. To examine whether CUL2 plays a role in pheochromocytoma pathogenesis, we analyzed a series of 26 distinct tumor samples for mutations in the whole coding region of this gene. There were no somatic pathogenic mutations in CUL2, except for 1 sporadic tumor that had a hemizygous gene deletion. We also found 3 novel polymorphisms in the gene. One of these variants, IVS5-6C/T, as well as another previously described one, c.2057G/A, were overrepresented among the pheochromocytoma patients compared to that in a control population (P < 0.005 and P < 0.01, respectively). Although our findings suggest that CUL2 does not play a major role in the pathogenesis of pheochromocytomas, it is still unknown whether epigenetic mechanisms are involved in its inactivation in VHL-associated tumors. Furthermore, the potential role for the overrepresented alleles in the pheochromocytoma group requires further investigation.
authors.affiliation: Clinical Cancer Genetics Program, Ohio State University Comprehensive Cancer Center, Columbus 43210, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Duerr
authors.forename: O
authors.initials: O
authors.lastname: Gimm
authors.forename: D S
authors.initials: DS
authors.lastname: Neuberg
authors.forename: J B
authors.initials: JB
authors.lastname: Kum
authors.forename: S C
authors.initials: SC
authors.lastname: Clifford
authors.forename: S P
authors.initials: SP
authors.lastname: Toledo
authors.forename: E R
authors.initials: ER
authors.lastname: Maher
authors.forename: P L
authors.initials: PL
authors.lastname: Dahia
authors.forename: C
authors.initials: C
authors.lastname: Eng
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D044842:Cullin Proteins; D005260:Female; D006720:Homozygote; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010673:Pheochromocytoma / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D006623:von Hippel-Lindau Disease / Q000235:genetics*
chemical_list: C105153:CUL2 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D044842:Cullin Proteins