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Differences in Allelic Distribution of Two Polymorphisms in the VHL-Associated Gene CUL2 in Pheochromocytoma Patients without Somatic CUL2 Mutations¹

Clinical Cancer Genetics and Human Cancer Genetics Programs, Ohio State University Comprehensive Cancer Center (E.-M.D., O.G., J.B.K., P.L.M.D., C.E.), Columbus, Ohio 43210; Dana-Farber Cancer Institute, Harvard Medical School (E.-M.D., D.S.N., J.B.K., P.L.M.D.), Boston, Massachusetts 02115; University of Bonn School of Medicine (E.-M.D.), 53105 Bonn, Germany; the Section of Medical and Molecular Genetics, Department of Pediatrics and Child Health, University of Birmingham School of Medicine (S.C.C., E.R.M.), Birmingham B15 2TG, United Kingdom; the Endocrine Genetics Unit, University of Sao Paulo School of Medicine (S.P.A.T.), Sao Paulo 54199, Brazil; and the Cancer Research Campaign Human Cancer Genetics Research Group, University of Cambridge (C.E.), Cambridge, United Kingdom CB2 2QQ

Address all correspondence and requests for reprints to: Charis Eng, M.D., Ph.D., F.A.C.P., Human Cancer Genetics Program, Ohio State University Comprehensive Cancer Center, 690C Medical Research Facility, 420 West 12th Avenue, Columbus, Ohio 43210. E-mail: eng-1{at}medctr.osu.edu Or to: Patricia L. M. Dahia, M.D., Ph.D.,

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.

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