Identification of MEN1 and HRPT2 somatic mutations in paraffin-embedded (sporadic) parathyroid carcinomas
Identification of MEN1 and HRPT2 somatic mutations in paraffin-embedded (sporadic) parathyroid carcinomas
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DOI：
10.1111/j.1365-2265.2007.02894.x
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发表时间：
2007-09-01
影响因子：
3.2
通讯作者：
Morreau, H.
中科院分区：
文献类型：
--
作者：
Haven, C. J.;van Puijenbroek, M.;Morreau, H.
甲状旁腺癌仍然难以诊断。最近，它已被证明在HRPT 2基因（编码parafibromin）的突变与甲状旁腺癌的发展。虽然MEN 1通常不被认为与癌的形成有关，但甲状旁腺癌可能是多发性内分泌腺瘤1型（MEN 1）综合征的一个极其罕见的特征。我们最近得出结论，MEN 1基因的杂合性缺失（洛）存在于相对大量的甲状旁腺癌中，通常与HRPT 2位点的洛结合。本研究的目的是评估MEN 1和HRPT 2突变在散发性甲状旁腺肿瘤中的作用，这些肿瘤符合恶性肿瘤的组织学标准，研究了1985-2000年期间在荷兰确定的28例甲状旁腺癌组织的福尔马林固定，石蜡包埋（FFPE）。用直接测序法分析了28例散发性甲状旁腺癌中的27例HRPT 2和23例MEN 1基因突变，其中3例（13%）发现MEN 1基因突变，包括1个错义突变和2个移码突变。后2例中1例在随访中发现淋巴结和肺转移。在4/27例（15%）病例中发现6种HRPT 2突变：5种为截短突变，1种为错义突变。与以前发表的报道一致，我们在散发性甲状旁腺癌中发现了双突变（2x）和种系突变（2x），这些结果表明，不仅HRPT 2，MEN 1突变也可能在散发性甲状旁腺癌的形成中起作用。
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.