Identification of MEN1 and HRPT2 somatic mutations in paraffin‐embedded (sporadic) parathyroid carcinomas

Abstract

Parathyroid carcinoma remains difficult to diagnose. Recently, it has been shown that mutations in the HRPT2 gene (encoding parafibromin) are associated with the development of parathyroid carcinoma. Although MEN1 is not typically thought to be involved in carcinoma formation, parathyroid carcinoma may be an extremely rare feature of the multiple endocrine neoplasia type 1 (MEN1) syndrome. We recently concluded that loss of heterozygosity (LOH) of the MEN1 gene is present in a relatively large number of parathyroid carcinomas, often in combination with LOH at the HRPT2 locus. The aim of this study was to evaluate the role of MEN1 and HRPT2 mutations in sporadic parathyroid tumours fulfilling histological criteria for malignancy. Formalin-fixed, paraffin-embedded (FFPE) parathyroid carcinoma tissue from 28 cases identified in the period 1985-2000 in the Netherlands was studied. HRPT2 (27/28 cases) and MEN1 (23/28 cases) were analysed by direct sequencing. Somatic MEN1 mutations were found in three of 23 (13%) sporadic parathyroid carcinoma cases; these consisted of one missense and two frameshift mutations. One of the latter two cases displayed lymph-node and lung metastases during follow-up. Six HRPT2 mutations were found in 4/27 cases (15%): five were truncating mutations and one was a missense mutation. Consistent with previously published reports, we found double mutations (2x) and germline mutations (2x) in apparently sporadic parathyroid carcinomas. These results suggest that not only HRPT2 but also MEN1 mutations may play a role in sporadic parathyroid cancer formation.