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 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.
Duerr
E M
EM
Clinical Cancer Genetics Program, Ohio State University Comprehensive Cancer Center, Columbus 43210, USA.
Gimm
O
O
Neuberg
D S
DS
Kum
J B
JB
Clifford
S C
SC
Toledo
S P
SP
Maher
E R
ER
Dahia
P L
PL
Eng
C
C
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*
C105153:CUL2 protein, human; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D044842:Cullin Proteins