-
Views
-
Cite
Cite
Sarah R. McWhinney, Getachew Boru, Philip K. Binkley, Mariola Peczkowska, Andrzej A. Januszewicz, Hartmut P. H. Neumann, Charis Eng, Intronic Single Nucleotide Polymorphisms in the RET Protooncogene Are Associated with a Subset of Apparently Sporadic Pheochromocytoma and May Modulate Age of Onset, The Journal of Clinical Endocrinology & Metabolism, Volume 88, Issue 10, 1 October 2003, Pages 4911–4916, https://doi.org/10.1210/jc.2003-030245
Close - Share Icon Share
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.
