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.

Parafibromin is a nuclear protein with a functional monopartite nuclear localization signal

“…Loss of heterozygosity of the gene causing HPT-JT, which is referred to as HRPT2 and is located on chromosome 1q31.2, has been observed in HPT-JTassociated tumours, thereby indicating that HRPT2 is likely to be a tumour suppressor (Teh et al, 1996;Haven et al, 2000). A tumour suppressor role for HRPT2 is further supported by reports that the majority of HRPT2 mutations are predicted to result in a functional loss of parafibromin, and that some HPT-JT tumours harbour both germline and somatic mutations (Howell et al, 2003;Shattuck et al, 2003;Bradley et al, 2006), which are consistent with Knudson's 'two-hit' hypothesis (Knudson, 1971). The HRPT2 gene, which consists of 17 exons and is ubiquitously expressed, encodes an evolutionarily conserved 531 amino-acid protein, parafibromin (Carpten et al, 2002).…”

“…Mutations of the gene encoding parafibromin, a 531 amino-acid protein, are associated with hereditary and non-hereditary forms of parathyroid carcinomas, and the hyperparathyroidism-jaw tumour (HPT-JT) syndrome, which is characterized by the combined occurrence of parathyroid tumours and ossifying fibromas of the jaw (Cavaco et al, 2001;Carpten et al, 2002;Howell et al, 2003;Shattuck et al, 2003). In addition, some patients with the HPT-JT syndrome may also develop uterine tumours and renal abnormalities, which include Wilms' tumours, hamartomas and polycystic disease (Szabo et al, 1995;Teh et al, 1996;Haven et al, 2000;Cavaco et al, 2001;Bradley et al, 2005).…”

Sporadic human renal tumors display frequent allelic imbalances and novel mutations of the HRPT2 gene

“…Somatic mutations of the HRPT2 gene have been found in up to 67% of sporadic parathyroid carcinomas, but rarely detected in parathyroid adenomas, indicating a strong association with tumor malignancy (Howell et al, 2003;Shattuck et al, 2003). LOH of the wild-type allele in the chromosomal region of 1q21-q32 with retention of the mutant allele, which was detected in individuals from some HPT-JT families and frequent biallelic inactivation of the HRPT2 gene in sporadic parathyroid tumors indicate that HRPT2 acts as a tumor suppressor gene (Carpten et al, 2002;Howell et al, 2003;Shattuck et al, 2003).…”

Parathyroid carcinoma

“…In addition to intragenic mutations, gross deletions of CDC73 have also been reported [17][18][19] . Biallelic inactivation of CDC73 can be demonstrated in many parathyroid cancers [13][14][15] . A substantial subset of patients with sporadically-presenting parathyroid carcinoma possess germline CDC73 mutations, and may represent new index cases of HPT-JT or a phenotypic variant [13,15,20,21] .…”

“…A wide range of mutation frequencies (13%-100%) have been reported [13][14][15][16] across studies, likely due to inconsistencies in selection criteria. Among studies using the most stringent diagnostic criteria for parathyroid cancer, namely extracapsular invasion and/or distant metastasis, the mutation frequency is 77% [13][14][15] . In addition to intragenic mutations, gross deletions of CDC73 have also been reported [17][18][19] .…”