Department of Biological Sciences, International Islamic Univeristy, Islamabad 1243, Pakistan.
Department of Clinical Laboratory Sciences, Najran University, Najran 61441, Saudi Arabia.
Exp Oncol. 2023 Oct 11;45(2):170-179. doi: 10.15407/exp-oncology.2023.02.170.
Germline alterations of the CDH1 (E-cadherin) tumor suppressor gene have been reported in several epithelial malignancies like hereditary diffuse gastric cancer and lobular breast cancer. E-cadherin plays a central role in proliferation, maintenance of cell-to-cell adhesion, polarity, and epithelial-mesenchymal transition of tissue cells. It is necessary to analyze the impact of the CDH1 germline sequence variants on protein and predict its clinical significance in breast cancer (BC) progression. The aim of the current study was to evaluate the impact and association of CDH1 gene potentially pathogenic variants/likely pathogenic variants (PVs/LPVs) with the initiation and progression of BC.
In this study, the clinical data of 200 BC patients have been analyzed based on the type of BC, age, grade, stage, hormonal status, and risk factors. Blood samples from 50 healthy donors were used as a control. Furthermore, CDH1 gene molecular analysis, along with in silico analysis, was provided to assess the invasiveness and progression of BC caused by the E-cadherin protein.
Four variants were identified by genetic screening within the CDH1 gene that included variations in exons 7, 8, 10, 11, and 13. Exon 10 had splice site mutation at position c.1337C>A, affecting the protein structure. In exon 11, there was an insertion of T base at position 1669, resulting in truncated protein compared to a normal one that can lead to the disease-causing non- sense-mediated decay and exon 13 variant c.2076T>C has already known polymorphism. In silico analysis of CDH1 showed the presence of the different variants that indicated the overall disruption of protein structure and function.
The further functional analysis of these variants and their association with BC can be ensured by increasing the sample size and in vivo studies using mouse models.
CDH1（E-钙黏蛋白）肿瘤抑制基因的种系改变已在几种上皮恶性肿瘤中报道，如遗传性弥漫性胃癌和乳腺小叶癌。E-钙黏蛋白在细胞增殖、维持细胞间黏附、极性和上皮-间充质转化中发挥核心作用。有必要分析 CDH1 种系序列变异对蛋白质的影响，并预测其在乳腺癌（BC）进展中的临床意义。本研究旨在评估 CDH1 基因潜在致病性变异/可能致病性变异（PV/LPV）对 BC 发生和进展的影响和相关性。
本研究基于 BC 的类型、年龄、分级、分期、激素状态和危险因素，分析了 200 例 BC 患者的临床数据。还使用 50 名健康供者的血液样本作为对照。此外，进行了 CDH1 基因分子分析和计算机分析，以评估 E-钙黏蛋白蛋白引起的 BC 的侵袭性和进展。
在 CDH1 基因中发现了四个变体，包括外显子 7、8、10、11 和 13 的变体。外显子 10 在位置 c.1337C>A 处有剪接位点突变，影响蛋白质结构。在 11 号外显子中，在位置 1669 处插入了 T 碱基，与正常蛋白相比产生截短的蛋白，可导致致病的无义介导的衰变，而外显子 13 的变体 c.2076T>C 是已知的多态性。CDH1 的计算机分析显示存在不同的变体，表明蛋白质结构和功能的整体中断。
通过增加样本量和使用小鼠模型进行体内研究，可以进一步对这些变体进行功能分析及其与 BC 的相关性进行研究。
