Somatic and Germ-Line Mutations of theHRPT2Gene in Sporadic Parathyroid Carcinoma

Abstract

Sporadic parathyroid carcinomas frequently have HRPT2 mutations that are likely to be of pathogenetic importance. Certain patients with apparently sporadic parathyroid carcinoma carry germ-line mutations in HRPT2 and may have the HPT-JT syndrome or a phenotypic variant.

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

“…To clarify a possible interaction between HRPT2 and VHL in renal tumorigenesis, all three exons of the VHL gene were also sequenced in tumors that showed a HRPT2 mutation. Primers for PCR and sequencing of involved HRPT2 exons and the VHL gene were used, as previously reported (Schraml et al, 2002;Shattuck et al, 2003). PCR was performed as described above, but without the heteroduplex formation process.…”

“…Germline mutations in the HRPT2 gene have been identified in more than half of the individuals from families with HPT-JT syndrome (Carpten et al, 2002). Unexpectedly, germline HRPT2 mutations were also identified in patients with apparently sporadic parathyroid cancer (Shattuck et al, 2003;Cetani et al, 2004). 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).…”

“…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).…”