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Genetic Analyses of the HRPT2 Gene in Primary Hyperparathyroidism: Germline and Somatic Mutations in Familial and Sporadic Parathyroid Tumors

Departments of Endocrinology and Metabolism (F.C., E.P., S.B., G.D., L.C., E.A., A.P., C.M.), Oncology, Section of Pathology (P.V.), and Surgery (P.B., P.M.), University of Pisa, 56124 Pisa, Italy; Endocrine and Metabolic Sciences, University of Genoa (E.G.), 16132 Genoa, Italy; and Nephrology Unit, Circolo Hospital and Macchi Foundation (G.C.), 21100 Varese, Italy

Address all correspondence and requests for reprints to: Dr. Filomena Cetani, Dipartimento di Endocrinologia e Metabolismo, Università di Pisa, Via Paradisa 2, 56124 Pisa, Italy. E-mail: cetani{at}endoc.med.unipi.it.

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.

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