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Intronic Single Nucleotide Polymorphisms in the RET Protooncogene Are Associated with a Subset of Apparently Sporadic Pheochromocytoma and May Modulate Age of Onset

Department of Molecular Genetics (S.R.M., C.E.); Divisions of Human Genetics (P.K.B., C.E.) and Cardiovascular Medicine (P.K.B.), Department of Internal Medicine; Division of Human Cancer Genetics (G.B., C.E.), Department of Molecular Virology, Immunology, and Medical Genetics; Clinical Cancer Genetics Program (C.E.) and Human Cancer Genetics Program (S.R.M., G.B., C.E.), Comprehensive Cancer Center; and Dorothy M. Davis Heart and Lung Research Institute (P.K.B., C.E.), The Ohio State University, Columbus, Ohio 43210; Department of Hypertension (M.P., A.A.J.), Institute of Cardiology, Warsaw, Poland; Department of Internal Medicine IV Nephrology and Hypertension (H.P.H.N.), Albert-Ludwigs-University of Freiburg, D-79106 Freiburg im Bresgau, Germany; and Cancer Research UK Human Cancer Genetics Research Group (C.E.), University of Cambridge, Cambridge CB2 2XZ, United Kingdom

Address all correspondence and requests for reprints to: Charis Eng, M.D., Ph.D., Human Cancer Genetics Program and Division of Human Genetics, The Ohio State University, 420 West 12th Avenue, Suite 690, Tzagournis Medical Research Facility, Columbus, Ohio 43210. E-mail: eng-1{at}medctr.osu.edu, or Hartmut P. H. Neumann, M.D., Medizinische Universitätsklinik, Hugstetterstrasse 55, D-79106 Freiburg im Bresgau, Germany.

Approximately 75% of pheochromocytomas are sporadic. Germline mutations in RET, VHL, SDHB, and SDHD have been shown to cause the 25% that are hereditary. Germline high penetrance gain-of-function RET mutations cause multiple endocrine neoplasia type 2, of which medullary thyroid carcinoma (MTC) and pheochromocytoma are components, whereas loss-of-function mutations cause Hirschprung disease (HSCR). A low-penetrance founder locus, in linkage disequilibrium with a RET ancestral haplotype comprising specific alleles at three intron (IVS) 1 single nucleotide polymorphisms (SNPs) (haplotype 0) and SNP A45A, predisposes to the majority of isolated HSCR. A different low-penetrance locus, in linkage disequilibrium with IVS 1 haplotype 2 and SNP S836S, was associated with a subset of sporadic MTC. We, therefore, sought to determine whether RET might also be a low-penetrance gene for apparently sporadic pheochromocytoma. We analyzed 104 pheochromocytoma cases without germline mutations in RET, VHL, SDHD, and SDHB for their status at A45, S836, three IVS 1 SNPs, and a novel upstream insertion/deletion variant. Pheochromocytoma cases were not associated with either A45A or S836S, but we found that cases were associated with haplotype 0 (P = 0.032). However, unlike HSCR, this pheochromocytoma-associated haplotype 0 was not associated with A45A. Taken together with the strengthening of association with the addition of the 5' insertion/deletion variant data (P = 0.016), our observations suggest the presence of a low-penetrance pheochromocytoma susceptibility locus in a region upstream of the putative loci for HSCR and apparently sporadic MTC.

This work was partially funded by Grants R01HD39058 (to C.E.) and R01HD39058-02S1 (to G.B.) from the National Institutes of Health, Grant P30CA16058 from the National Cancer Institute (to The Ohio State University Comprehensive Cancer Center), and Grants NE571/5-1 and NE571/4-4 from the Deutsche Forschungsgemeinschaft (to H.P.H.N.).

C.E. is the recipient of a Doris Duke Distinguished Clinical Scientist Award.

Abbreviations: CI, Confidence interval(s); HSCR, Hirschsprung disease; IVS, intron; MTC, medullary thyroid cancer; SNP, single nucleotide polymorphisms.

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