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In-silico analysis to identify the role of MEN1 missense mutations in breast cancer
Journal of Theoretical and Computational Chemistry Pub Date : 2020-06-30 , DOI: 10.1142/s0219633620410023
Satishkumar Ranganathan Ganakammal 1 , Mahesh Koirala 2 , Bohua Wu 2 , Emil Alexov 1, 2
Affiliation  

Background: The multiple endocrine neoplasia type 1 (MEN1) gene located on chromosome 11q13 encodes menin protein. Previously reported mutations were thought to result in loss of function of menin protein and that they are associated with multiple endocrine neoplasia 1 disorder. However, recently menin has also been characterized as an oncosuppressor protein and it was suggested that mutations in it are associated with various other tumors. Studies indicate that the menin protein stimulates the estrogen receptor (ER) that in turn increases the predisposition for inherited breast cancer.Methods: Here, we used our supervised in-house combinatory in-silico predictor method to investigate the impact of unclassified missense mutations in MEN1 gene found in breast cancer tissue. We also examined the biophysical and biochemical properties to predict the effects of these missense variants on the menin protein stability and interactions. The results are compared with the effects of known pathogenic mutations in menin causing neoplasia.Results: Our analysis indicates that some of the variants found in breast cancer tissue show similar pattern of destabilizing the menin protein and its interactions as the pathogenic variants associated with neoplasia. Taking together with the results of our in-silico consensus predictor, we classify missense mutations in menin protein found in breast cancer tissue into pathogenic and benign, and thus, suggesting as an indicator for early detection of elevated breast cancer risk.

中文翻译:

计算机分析以确定 MEN1 错义突变在乳腺癌中的作用

背景:位于染色体 11q13 上的多发性内分泌肿瘤 1 型 (MEN1) 基因编码 menin 蛋白。先前报道的突变被认为会导致 menin 蛋白功能丧失,并且它们与多发性内分泌肿瘤 1 疾病有关。然而,最近menin 也被定性为一种抑癌蛋白,并且有人认为它的突变与各种其他肿瘤有关。研究表明,menin 蛋白会刺激雌激素受体 (ER),进而增加遗传性乳腺癌的易感性。在乳腺癌组织中发现了 MEN1 基因。我们还检查了生物物理和生化特性,以预测这些错义变体对 menin 蛋白稳定性和相互作用的影响。将结果与引起瘤形成的 menin 中已知致病突变的影响进行比较。结果:我们的分析表明,在乳腺癌组织中发现的一些变体显示出与与瘤形成相关的致病变异相似的使 menin 蛋白及其相互作用不稳定的模式。结合我们的 in-silico 共识预测器的结果,我们将乳腺癌组织中发现的 menin 蛋白错义突变分为致病性和良性,因此建议作为早期检测乳腺癌风险升高的指标。将结果与引起瘤形成的 menin 中已知致病突变的影响进行比较。结果:我们的分析表明,在乳腺癌组织中发现的一些变体显示出与与瘤形成相关的致病变异相似的使 menin 蛋白及其相互作用不稳定的模式。结合我们的 in-silico 共识预测器的结果,我们将乳腺癌组织中发现的 menin 蛋白错义突变分为致病性和良性,因此建议作为早期检测乳腺癌风险升高的指标。将结果与引起瘤形成的 menin 中已知致病突变的影响进行比较。结果:我们的分析表明,在乳腺癌组织中发现的一些变体显示出与与瘤形成相关的致病变异相似的使 menin 蛋白及其相互作用不稳定的模式。结合我们的 in-silico 共识预测器的结果,我们将乳腺癌组织中发现的 menin 蛋白错义突变分为致病性和良性,因此建议作为早期检测乳腺癌风险升高的指标。我们的分析表明,在乳腺癌组织中发现的一些变异显示出与与肿瘤相关的致病变异相似的破坏 menin 蛋白及其相互作用的模式。结合我们的 in-silico 共识预测器的结果,我们将乳腺癌组织中发现的 menin 蛋白错义突变分为致病性和良性,因此建议作为早期检测乳腺癌风险升高的指标。我们的分析表明,在乳腺癌组织中发现的一些变异显示出与与肿瘤相关的致病变异相似的破坏 menin 蛋白及其相互作用的模式。结合我们的 in-silico 共识预测器的结果,我们将乳腺癌组织中发现的 menin 蛋白错义突变分为致病性和良性,因此建议作为早期检测乳腺癌风险升高的指标。
更新日期:2020-06-30
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