Genetic Analyses of theHRPT2Gene in Primary Hyperparathyroidism: Germline and Somatic Mutations in Familial and Sporadic Parathyroid Tumors

Abstract

We investigated the involvement of the HRPT2 gene by loss of heterozygosity analysis and direct sequencing in a kindred with hyperparathyroidism-jaw tumor syndrome (HPT-JT) and three kindreds with familial isolated primary hyperparathyroidism (FIHP). Seven patients with sporadic parathyroid cancers and 35 with parathyroid adenomas with no family history of primary hyperparathyroidism or HPT-JT were also studied. A germline heterozygous substitution G to A was found in the donor splice site of intron 1 in one of the three FIHP families. No mutations were identified in the HPT-JT kindred. A somatic HRPT2 mutation was found in four of seven patients with parathyroid cancers, two of which were unreported frameshift mutations (195insT and 195insA) in exon 2. Consistent with recent findings, two of seven patients with sporadic parathyroid cancer had germline mutations. Four adenomas showed loss of heterozygosity at HRPT2, whereas a somatic HRPT2 mutation was found in one. In conclusion, we provide additional evidence for a strong association between HRPT2 gene mutations and sporadic parathyroid cancer. The finding that two of the seven patients with sporadic parathyroid cancer carried an HRPT2 germline mutation suggests that they might have occult HPT-JT. Our results also confirm the need for testing HRPT2 gene in FIHP families.

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

“…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).…”

The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene

“…The major features are primary hyperparathyroidism (including 15% of all affected by HPT-JT with parathyroid cancer), jaw tumors, bilateral renal cysts, and, less commonly, solid renal tumors (2,3). Germline inactivating HRPT2 mutation has also been reported in a minority of kindreds with familial isolated hyperparathyroidism (FIHP) (1,4) and in up to 30% of patients with apparently sporadic parathyroid cancer (5,6).…”

Parathyroid carcinoma

“…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] .…”

“…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] .…”

“…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] . Most parathyroid carcinomas also exhibit aberrant immunohistochemical staining for parafibromin, the protein product of CDC73; complete loss of parafibromin expression is the most common staining pattern.…”