Department of Medical Research and Development, Chang Gung Memorial Hospital at Linko, Taoyuan, Taiwan.
Department of Medical Oncology, Chang Gung Memorial Hospital at Linkou and Chang Gung University, Taoyuan, Taiwan.
Pathol Res Pract. 2021 Jul;223:153474. doi: 10.1016/j.prp.2021.153474. Epub 2021 May 10.
Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity with poor prognosis. The dysregulation of Notch signaling pathway has been implicated in the OSCC tumorigenesis. However, the clinical implication of NOTCH1 mutation status in OSCC remains unelucidated. We extracted the NOTCH1 gene mutations from a whole exome sequencing dataset of 168 frozen OSCC tumor specimens and validated these NOTCH1 gene mutations by Sanger sequencing. We also assessed these NOTCH1 gene mutations and its pathological significance in our OSCC tumor tissues using immunohistochemistry. Univariate and multivariate analyses were also used to determine whether the association between NOTCH1 mutation status and prognostic factors was independent of other parameters. In this study, we have identified 44 (26.19 %) NOTCH1 gene mutations from a whole-exome sequencing of 168 OSCC formalin-fixed, paraffin-embedded (FFPE) tissue specimen. These mutations distributed in different NOTCH1 function domains, including the EGF-like repeats region, negative regulatory region, and Ankyrin repeats region. The immunohistochemical staining analysis revealed that NOTCH1 expression was increased in oral cancer tissues. In addition, of the 43 OSCC tumors with NOTCH1 mutations, we observed that the majority were negative for NOTCH1 intracellular domain 1 (NICD1) staining (76.74 %), and 10 tumors were positive for NICD1 staining (23.26 %). In conclusion, our study suggested that NOTCH1 expression is associated with the progression of OSCC. We also demonstrated that presence of a mutated NOTCH1 gene will help prognostic stratification in OSCC when combined with other clinicopathologic parameters.
口腔鳞状细胞癌 (OSCC) 是口腔最常见的恶性肿瘤，预后不良。 Notch 信号通路的失调与 OSCC 的肿瘤发生有关。然而，NOTCH1 突变状态在 OSCC 中的临床意义仍不清楚。我们从 168 例冷冻 OSCC 肿瘤标本的全外显子测序数据集中提取了 NOTCH1 基因突变，并通过 Sanger 测序对这些 NOTCH1 基因突变进行了验证。我们还使用免疫组织化学评估了我们的 OSCC 肿瘤组织中的这些 NOTCH1 基因突变及其病理意义。单因素和多因素分析也用于确定 NOTCH1 突变状态与预后因素之间的关联是否独立于其他参数。在这项研究中，我们从 168 例福尔马林固定、石蜡包埋 (FFPE) 的 OSCC 组织标本的全外显子测序中鉴定出 44 个（26.19%）NOTCH1 基因突变。这些突变分布在不同的 NOTCH1 功能域，包括 EGF 样重复区、负调控区和锚蛋白重复区。免疫组织化学染色分析显示 NOTCH1 表达在口腔癌组织中增加。此外，在 43 例有 NOTCH1 突变的 OSCC 肿瘤中，我们观察到大多数 NOTCH1 细胞内结构域 1（NICD1）染色阴性（76.74%），10 例肿瘤 NICD1 染色阳性（23.26%）。总之，我们的研究表明 NOTCH1 表达与 OSCC 的进展有关。我们还表明，当与其他临床病理参数结合时，存在突变的 NOTCH1 基因将有助于 OSCC 的预后分层。
