Department of Surgery and Translational Medicine, University of Florence, Florence, Italy.
Familial Cancer Clinic, Veneto Institute of Oncology IRCCS, Padua, Italy.
Endocrine. 2018 Oct;62(1):215-233. doi: 10.1007/s12020-018-1566-8. Epub 2018 Mar 1.
Multiple endocrine neoplasia type 1 (MEN1) is caused by germline inactivating mutations of the MEN1 gene. Currently, no direct genotype-phenotype correlation is identified. We aim to analyze MEN1 mutation site and features, and possible correlations between the mutation type and/or the affected menin functional domain and clinical presentation in patients from the Italian multicenter MEN1 database, one of the largest worldwide MEN1 mutation series published to date.
The study included the analysis of MEN1 mutation profile in 410 MEN1 patients [370 familial cases from 123 different pedigrees (48 still asymptomatic at the time of this study) and 40 single cases].
We identified 99 different mutations: 41 frameshift [small intra-exon deletions (28) or insertions (13)], 13 nonsense, 26 missense and 11 splicing site mutations, 4 in-frame small deletions, and 4 intragenic large deletions spanning more than one exon. One family had two different inactivating MEN1 mutations on the same allele. Gastro-entero-pancreatic tumors resulted more frequent in patients with a nonsense mutation, and thoracic neuroendocrine tumors in individuals bearing a splicing-site mutation.
Our data regarding mutation type frequency and distribution are in accordance with previously published data: MEN1 mutations are scattered through the entire coding region, and truncating mutations are the most common in MEN1 syndrome. A specific direct correlation between MEN1 genotype and clinical phenotype was not found in all our families, and wide intra-familial clinical variability and variable disease penetrance were both confirmed, suggesting a role for modifying, still undetermined, factors, explaining the variable MEN1 tumorigenesis.
多发性内分泌腺瘤病 1 型（MEN1）是由 MEN1 基因突变引起的。目前，尚未确定直接的基因型-表型相关性。我们旨在分析意大利多中心 MEN1 数据库中患者的 MEN1 突变位点和特征，以及突变类型和/或受影响的门冬氨酸功能域与临床表型之间的可能相关性，该数据库是迄今为止发表的最大的 MEN1 突变系列之一。
本研究分析了 410 例 MEN1 患者的 MEN1 突变谱[370 例来自 123 个不同家系的家族性病例（48 例在本研究时仍无症状）和 40 例单病例]。
我们鉴定了 99 种不同的突变：41 种移码[小内含子缺失（28 种）或插入（13 种）]、13 种无义突变、26 种错义突变和 11 种剪接位点突变、4 种框内小缺失和 4 种跨越一个以上外显子的基因内大片段缺失。一个家系在同一等位基因上有两种不同的失活 MEN1 突变。具有无义突变的患者胃-肠-胰肿瘤更为常见，而具有剪接位点突变的个体则发生胸内神经内分泌肿瘤。
我们关于突变类型频率和分布的数据与之前发表的数据一致：MEN1 突变散布在整个编码区，截短突变是 MEN1 综合征中最常见的突变。在我们所有的家系中，都没有发现 MEN1 基因型与临床表型之间的特定直接相关性，并且证实了广泛的家系内临床变异性和可变的疾病外显率，这表明存在修饰因素（仍未确定），这些因素解释了 MEN1 肿瘤发生的可变性。
