Grolmusz Vince Kornél, Borka Katalin, Kövesdi Annamária, Németh Kinga, Balogh Katalin, Dékány Csaba, Kiss András, Szentpéteri Anna, Sármán Beatrix, Somogyi Anikó, Csajbók Éva, Valkusz Zsuzsanna, Tóth Miklós, Igaz Péter, Rácz Károly, Patócs Attila
2nd Department of Medicine, Semmelweis University, Szentkirályi utca 46, Budapest, 1088, Hungary.
"Lendület" Hereditary Endocrine Tumours Research Group, Hungarian Academy of Sciences, Semmelweis University, Szentkirályi utca 46, Budapest, H-1088, Hungary.
Virchows Arch. 2017 Sep;471(3):401-411. doi: 10.1007/s00428-017-2158-3. Epub 2017 Jun 8.
Inherited, germline mutations of menin-coding MEN1 gene cause multiple endocrine neoplasia type 1 (MEN1), while somatic MEN1 mutations are the sole main driver mutations in sporadic primary hyperparathyroidism (PHPT), suggesting that menin deficiency has a central role in the pathogenesis of PHPT. MiRNAs are small, noncoding RNAs posttranscriptionally regulating gene expression. Our aim was to investigate both the role of MEN1 mutations and potentially MEN1-targeting miRNAs as the underlying cause of menin deficiency in MEN1-associated and sporadic PHPT tissues. Fifty six PHPT tissues, including 16 MEN1-associated tissues, were evaluated. Diagnosis of MEN1 syndrome was based on identification of germline MEN1 mutations. In silico target prediction was used to identify miRNAs potentially targeting MEN1. Menin expression was determined by immunohistochemistry while expression of miRNAs was analyzed by quantitative real-time PCR. Sporadic PHPT tissues were subjected to somatic MEN1 mutation analysis as well. Lack of nuclear menin was identified in all MEN1-associated and in 28% of sporadic PHPT tissues. Somatic MEN1 mutations were found in 25% of sporadic PHPTs. The sensitivity and specificity of menin immunohistochemistry to detect a MEN1 mutation were 86 and 87%, respectively. Expression levels of hsa-miR-24 and hsa-miR-28 were higher in sporadic compared to MEN1-associated PHPT tissues; however, no difference in miRNA levels occurred between menin-positive and menin-negative PHPT tissues. Menin deficiency is the consequence of a MEN1 mutation in most menin-negative PHPT tissues. Elevated expression of hsa-miR-24 and hsa-miR-28 mark the first epigenetic changes observed between sporadic and MEN1-associated PHPT.
编码Menin的MEN1基因的遗传性种系突变会导致1型多发性内分泌肿瘤（MEN1），而体细胞MEN1突变是散发性原发性甲状旁腺功能亢进症（PHPT）中唯一的主要驱动突变，这表明Menin缺乏在PHPT的发病机制中起核心作用。微小RNA（miRNA）是一类小的非编码RNA，可在转录后调节基因表达。我们的目的是研究MEN1突变以及潜在靶向MEN1的miRNA在MEN1相关和散发性PHPT组织中Menin缺乏的潜在原因。对56例PHPT组织进行了评估，其中包括16例MEN1相关组织。MEN1综合征的诊断基于种系MEN1突变的鉴定。通过计算机模拟靶点预测来鉴定可能靶向MEN1的miRNA。通过免疫组织化学测定Menin表达，同时通过定量实时PCR分析miRNA的表达。散发性PHPT组织也进行了体细胞MEN1突变分析。在所有MEN1相关组织以及28%的散发性PHPT组织中均发现核Menin缺失。在25%的散发性PHPT中发现了体细胞MEN1突变。Menin免疫组织化学检测MEN1突变的敏感性和特异性分别为86%和87%。与MEN1相关的PHPT组织相比，散发性PHPT组织中hsa-miR-24和hsa-miR-28的表达水平更高；然而，Menin阳性和Menin阴性PHPT组织之间的miRNA水平没有差异。在大多数Menin阴性的PHPT组织中，Menin缺乏是MEN1突变的结果。hsa-miR-24和hsa-miR-28表达升高标志着散发性和MEN1相关PHPT之间首次观察到的表观遗传变化。
