title: CDC73/HRPT2 CpG island hypermethylation and mutation of 5'-untranslated sequence are uncommon mechanisms of silencing parafibromin in parathyroid tumors.
abstract: The tumor suppressor HRPT2/CDC73 is mutated in constitutive DNA from patients with the familial disorder hyperparathyroidism-jaw tumor syndrome and in approximately 70% of all parathyroid carcinomas. In a number of HRPT2 mutant tumors however, expression of the encoded protein parafibromin is lost in the absence of a clear second event such as HRPT2 allelic loss or the presence of a second mutation in this tumor suppressor gene. We sought to determine whether hypermethylation of a 713 bp CpG island extending 648 nucleotides upstream of the HRPT2 translational start site and 65 nucleotides into exon 1 might be a mechanism contributing to the loss of expression of parafibromin in parathyroid tumors. Furthermore, we asked whether mutations might be present in the 5'-untranslated region (5'-UTR) of HRPT2. We investigated a pool of tissue from 3 normal parathyroid glands, as well as 15 individual parathyroid tumor samples including 6 tumors with known HRPT2 mutations, for hypermethylation of the HRPT2 CpG island. Methylation was not identified in any specimens despite complete loss of parafibromin expression in two parathyroid carcinomas with a single detectable HRPT2 mutation and retention of the wild-type HRPT2 allele. Furthermore, no mutations of a likely pathogenic nature were identified in the 5'-UTR of HRPT2. These data strongly suggest that alternative mechanisms such as mutation in HRPT2 intronic regions, additional epigenetic regulation such as histone modifications, or other regulatory inactivation mechanisms such as targeting by microRNAs may play a role in the loss of parafibromin expression.
authors.affiliation: Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, E25, St Leonards, New South Wales 2065, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hahn
authors.forename: Viive M
authors.initials: VM
authors.lastname: Howell
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Gill
authors.forename: Adele
authors.initials: A
authors.lastname: Clarkson
authors.forename: Graham
authors.initials: G
authors.lastname: Weaire-Buchanan
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Robinson
authors.forename: Leigh
authors.initials: L
authors.lastname: Delbridge
authors.forename: Oliver
authors.initials: O
authors.lastname: Gimm
authors.forename: Wolfgang D
authors.initials: WD
authors.lastname: Schmitt
authors.forename: Bin T
authors.initials: BT
authors.lastname: Teh
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Marsh
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics*; D000236:Adenoma / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000502:physiology; D004252:DNA Mutational Analysis; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology; D010280:Parathyroid Glands / Q000378:metabolism; D010282:Parathyroid Neoplasms / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; C454900:CDC73 protein, human; D025521:Tumor Suppressor Proteins