title: HRPT2 mutations are associated with malignancy in sporadic parathyroid tumours.
abstract: BACKGROUND
  Hyperparathyroidism is a common endocrinopathy characterised by the formation of parathyroid tumours. In this study, we determine the role of the recently identified gene, HRPT2, in parathyroid tumorigenesis.
  
  
  METHODS
  Mutation analysis of HRPT2 was undertaken in 60 parathyroid tumours: five HPT-JT, three FIHP, three MEN 1, one MEN 2A, 25 sporadic adenomas, 17 hyperplastic glands, two lithium associated tumours, and four sporadic carcinomas. Loss of heterozygosity at 1q24-32 was performed on a subset of these tumours.
  
  
  RESULTS
  HRPT2 somatic mutations were detected in four of four sporadic parathyroid carcinoma samples, and germline mutations were found in five of five HPT-JT parathyroid tumours (two families) and two parathyroid tumours from one FIHP family. One HPT-JT tumour with germline mutation also harboured a somatic mutation. In total, seven novel and one previously reported mutation were identified. "Two-hits" (double mutations or one mutation and loss of heterozygosity at 1q24-32) affecting HRPT2 were found in two sporadic carcinomas, two HPT-JT-related and two FIHP related tumours.
  
  
  CONCLUSIONS
  The results in this study support the role of HRPT2 as a tumour suppressor gene in sporadic parathyroid carcinoma, and provide further evidence for HRPT2 as the causative gene in HPT-JT, and a subset of FIHP. In light of the strong association between mutations of HRPT2 and sporadic parathyroid carcinoma demonstrated in this study, it is hypothesised that HRPT2 mutation is an early event that may lead to parathyroid malignancy and suggest intragenic mutation of HRPT2 as a marker of malignant potential in both familial and sporadic parathyroid tumours.
authors.affiliation: Laboratory of Cancer Genetics, Van Andel Research Institute, 333 Bostwick NE, Grand Rapids, Michigan 49503, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Howell
authors.forename: C J
authors.initials: CJ
authors.lastname: Haven
authors.forename: K
authors.initials: K
authors.lastname: Kahnoski
authors.forename: S K
authors.initials: SK
authors.lastname: Khoo
authors.forename: D
authors.initials: D
authors.lastname: Petillo
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.forename: G J
authors.initials: GJ
authors.lastname: Fleuren
authors.forename: B G
authors.initials: BG
authors.lastname: Robinson
authors.forename: L W
authors.initials: LW
authors.lastname: Delbridge
authors.forename: J
authors.initials: J
authors.lastname: Philips
authors.forename: A E
authors.initials: AE
authors.lastname: Nelson
authors.forename: U
authors.initials: U
authors.lastname: Krause
authors.forename: K
authors.initials: K
authors.lastname: Hammje
authors.forename: H
authors.initials: H
authors.lastname: Dralle
authors.forename: C
authors.initials: C
authors.lastname: Hoang-Vu
authors.forename: O
authors.initials: O
authors.lastname: Gimm
authors.forename: D J
authors.initials: DJ
authors.lastname: Marsh
authors.forename: H
authors.initials: H
authors.lastname: Morreau
authors.forename: B T
authors.initials: BT
authors.lastname: Teh
mesh_terms: D000328:Adult; D000368:Aged; D016009:Chi-Square Distribution; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D005192:Family Health; D005260:Female; D006801:Humans; D006961:Hyperparathyroidism / Q000235:genetics; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D010282:Parathyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics*; D013577:Syndrome; D025521:Tumor Suppressor Proteins
chemical_list: C454900:CDC73 protein, human; D018076:DNA, Complementary; D004273:DNA, Neoplasm; D011506:Proteins; D025521:Tumor Suppressor Proteins