title: Intronic single nucleotide polymorphisms in the RET protooncogene are associated with a subset of apparently sporadic pheochromocytoma and may modulate age of onset.
abstract: 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.
authors.affiliation: Department of Molecular Genetics, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: McWhinney
authors.forename: Getachew
authors.initials: G
authors.lastname: Boru
authors.forename: Philip K
authors.initials: PK
authors.lastname: Binkley
authors.forename: Mariola
authors.initials: M
authors.lastname: Peczkowska
authors.forename: Andrzej A
authors.initials: AA
authors.lastname: Januszewicz
authors.forename: Hartmut P H
authors.initials: HP
authors.lastname: Neumann
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D017668:Age of Onset; D018276:Carcinoma, Medullary / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006627:Hirschsprung Disease / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D015810:Linkage Disequilibrium; D008875:Middle Aged; D015513:Oncogene Proteins / Q000235:genetics*; D019683:Penetrance; D010673:Pheochromocytoma / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics
chemical_list: D015513:Oncogene Proteins; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; D020794:Receptor Protein-Tyrosine Kinases