Department of Human and Experimental Pathology, Institut Pasteur de Tunis, Tunis 1002, Tunisia.
Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, Tunis EL Manar University, Tunis 1002, Tunisia.
Genes (Basel). 2022 Jul 28;13(8):1355. doi: 10.3390/genes13081355.
Several syndromic forms of digestive cancers are known to predispose to early-onset gastric tumors such as Hereditary Diffuse Gastric Cancer (HDGC) and Lynch Syndrome (LS). LSII is an extracolonic cancer syndrome characterized by a tumor spectrum including gastric cancer (GC). In the current work, our main aim was to identify the mutational spectrum underlying the genetic predisposition to diffuse gastric tumors occurring in a Tunisian family suspected of both HDGC and LS II syndromes. We selected the index case “JI-021”, which was a woman diagnosed with a Diffuse Gastric Carcinoma and fulfilling the international guidelines for both HDGC and LSII syndromes. For DNA repair, a custom panel targeting 87 candidate genes recovering the four DNA repair pathways was used. Structural bioinformatics analysis was conducted to predict the effect of the revealed variants on the functional properties of the proteins. DNA repair genes panel screening identified two variants: a rare MSH2 c.728G>A classified as a variant with uncertain significance (VUS) and a novel FANCD2 variant c.1879G>T. The structural prediction model of the MSH2 variant and electrostatic potential calculation showed for the first time that MSH2 c.728G>A is likely pathogenic and is involved in the MSH2-MLH1 complex stability. It appears to affect the MSH2-MLH1 complex as well as DNA-complex stability. The c.1879G>T FANCD2 variant was predicted to destabilize the protein structure. Our results showed that the MSH2 p.R243Q variant is likely pathogenic and is involved in the MSH2-MLH1 complex stability, and molecular modeling analysis highlights a putative impact on the binding with MLH1 by disrupting the electrostatic potential, suggesting the revision of its status from VUS to likely pathogenic. This variant seems to be a shared variant in the Mediterranean region. These findings emphasize the importance of testing DNA repair genes for patients diagnosed with diffuse GC with suspicion of LSII and colorectal cancer allowing better clinical surveillance for more personalized medicine.
已知几种综合征形式的消化道癌易导致早发性胃肿瘤，如遗传性弥漫性胃癌（HDGC）和林奇综合征（LS）。LSII 是一种结外癌症综合征，其肿瘤谱包括胃癌（GC）。在目前的工作中，我们的主要目的是确定发生在一个疑似同时患有 HDGC 和 LS II 综合征的突尼斯家族的弥漫性胃肿瘤遗传易感性的突变谱。我们选择了索引病例“JI-021”，她是一名被诊断为弥漫性胃癌的女性，符合 HDGC 和 LSII 综合征的国际指南。对于 DNA 修复，使用了一个针对 87 个候选基因的定制面板，该面板涵盖了四个 DNA 修复途径。对结构生物信息学分析进行了预测，以揭示变体对蛋白质功能特性的影响。DNA 修复基因面板筛选鉴定出两个变体：一个罕见的 MSH2 c.728G>A 被归类为意义不确定的变体（VUS）和一个新的 FANCD2 变体 c.1879G>T。MSH2 变体的结构预测模型和静电势计算首次表明，MSH2 c.728G>A 可能是致病的，并参与 MSH2-MLH1 复合物的稳定性。它似乎影响 MSH2-MLH1 复合物以及 DNA-复合物的稳定性。c.1879G>T FANCD2 变体被预测会使蛋白质结构不稳定。我们的结果表明，MSH2 p.R243Q 变体可能是致病的，并参与 MSH2-MLH1 复合物的稳定性，分子建模分析突出了与 MLH1 结合的潜在影响，通过破坏静电势，提示将其状态从 VUS 修订为可能致病。这种变体似乎是地中海地区的共享变体。这些发现强调了对怀疑患有 LSII 和结直肠癌的弥漫性 GC 患者进行 DNA 修复基因检测的重要性，以便更好地进行临床监测，实现更个性化的医学治疗。
