Different somatic alterations of the HRPT2 gene in a patient with recurrent sporadic primary hyperparathyroidism carrying an HRPT2 germline mutation

Abstract

Early onset of primary hyperparathyroidism (PHPT) and multiglandular involvement suggest a familial form in which germline mutation of a PHPT-related gene(s) and a somatic event at the same locus can be often demonstrated. We investigated the involvement of multiple endocrine neoplasia type 1 (MEN1) and HRPT2 genes in a 39-year-old man with recurrent PHPT. PHPT was firstly diagnosed at the age of 21 and the patient had two recurrences separated by extended periods of normocalcemia. This unusual history prompted us to investigate other family members and study the MEN1 and HRPT2 genes. An HRPT2 germline missense mutation in exon 3 (R91P) was found in the index case, which was associated with different HRPT2 somatic alterations in each of the three examined parathyroid tumors. These findings are consistent with Knudson's 'two hit' concept of biallelic inactivation of classical tumor suppressor genes. Screening of 15 asymptomatic relatives was negative for the R91P germline mutation. All the three abnormal parathyroid specimens showed cystic features at histology and were negative for parafibromin immunostaining. In one specimen, diffuse parafibromin staining was evident in a rim of normal parathyroid tissue surrounding the adenomatous lesion. Our study shows that different somatic genetic events at the HRPT2 locus are responsible for the asynchronous occurrence of multiple adenomas in a patient carrying an HRPT2 germline mutation. The finding of diffuse parafibromin staining in a rim of normal parathyroid tissue, but not in the contiguous adenomatous lesion, reinforces the concept that loss of parafibromin expression is responsible for the development of parathyroid tumors in this setting.

Cell division cycle protein 73 homolog (CDC73) mutations in the hyperparathyroidism-jaw tumor syndrome (HPT-JT) and parathyroid tumors

“…Germline mutations have also been identified in sporadic parathyroid carcinomas [Cetani et al, 2004;Shattuck et al, 2003], suggesting that patients with apparent sporadic parathyroid carcinoma, and their relatives should be assessed for HPT-JT-associated tumors and offered mutational analysis. The observation of combined somatic and germline mutations in a subset of sporadic parathyroid carcinomas as well as HPT-JT-associated parathyroid tumors provides evidence for biallelic CDC73 inactivation that is consistent with Knudson's ''two-hit'' model of inherited cancer and a tumor suppressor role for CDC73 and its encoded protein, parafibromin Cetani et al, 2007b;Howell et al, 2003;Knudson, 1971;Moon et al, 2005;Shattuck et al, 2003]. Such a tumor suppressor role is further supported by the reports of a LOH involving the CDC73 locus in $50% of HPT-JT-associated tumors [Carpten et al, 2002;Teh et al, 1996Teh et al, , 1998]; and a loss of parafibromin immunoreactivity in 13 out of 17 parathyroid tumors from HPT-JT kindreds with CDC73 mutations, and in 65-95% of sporadic parathyroid carcinomas [Cetani et al, 2007a;Gill et al, 2006;Juhlin et al, 2006Juhlin et al, , 2007.…”

CDC73/HRPT2 CpG island hypermethylation and mutation of 5′-untranslated sequence are uncommon mechanisms of silencing parafibromin in parathyroid tumors

“…Loss of heterozygosity at the HRPT2 locus and 'second-hit' mutations in the coding region of HRPT2 have been reported and are consistent with Knudson's 'two-hit' hypothesis for inactivation of tumor suppressor genes (Howell et al 2003, Bradley et al 2006, Kelly et al 2006, Cetani et al 2007). However, allelic loss at the HRPT2 locus is not always observed in parathyroid tumors with either a known or suspected HRPT2 mutation (Carpten et al 2002, Howell et al 2003, Shattuck et al 2003.…”

Identification of De Novo Germline Mutations in the HRPT2 Gene in Two Apparently Sporadic Cases with Challenging Parathyroid Tumor Diagnoses

“…2). This nonsense mutation, which is predicted to cause a premature termination of translation in codon 54, has been previously reported in three sporadic parathyroid tumors (two carcinomas and one adenoma) [7,8,31].…”