Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, 601 N Caroline St., Baltimore, MD 21287, United States.
Department of Pathology, Johns Hopkins University School of Medicine, 600 N Wolfe St., Baltimore, MD 21287, United States.
Oral Oncol. 2018 Jul;82:168-175. doi: 10.1016/j.oraloncology.2018.05.017. Epub 2018 Jun 1.
Notch signaling is frequently altered in head and neck squamous cell carcinoma (HNSCC). However, the nature and clinical implications of this dysregulation are not well understood. We previously described an association of transcriptionally active NOTCH1 Intracellular Domain (NICD1) immunohistochemical (IHC) expression pattern with high-risk pathologic characteristics. Here we further characterize Notch signaling in HNSCC.
IHC expression patterns and clinicopathologic associations of Notch pathway molecules were evaluated among 78 tumors with known NOTCH1 mutation status. IHC was performed for JAG1, a NOTCH1 activating ligand, and HEY1, an NICD1 transcriptional target and Notch pathway activation marker. IHC pattern and H-score (% staining × intensity) were recorded and compared to clinicopathologic characteristics and survival. Survival was analyzed using Kaplan Meier method and Cox proportional hazards models (HR).
JAG1 and NICD1 expression patterns were highly concordant among tumors without truncating NOTCH1 mutations (p < 0.001), but were dissimilar among tumors with truncating NOTCH1 mutations (p = 0.24). There was evidence for JAG1-independent NOTCH1 activation among seven tumors, all with wild-type NOTCH1. HEY1 expression was associated with neither JAG1 nor NICD1 expression, but was associated with NOTCH1 mutation status (p = 0.03). Twelve (16%) tumors expressed HEY1 but not NICD1. Higher HEY1 H-score was significantly associated with worse overall (adjusted hazard ratio [aHR] 2.0, 95% CI = 1.0-4.2) and disease-specific (aHR = 3.3, 95% CI = 1.4-7.9) survival, whereas JAG1 and NICD1 expression were not associated with survival.
These findings suggest both NOTCH1-dependent and -independent HEY1 regulation, and imply a previously unrecognized prognostic role for HEY1 in HNSCC.
Notch 信号在头颈部鳞状细胞癌（HNSCC）中经常发生改变。然而，这种失调的性质及其临床意义尚不清楚。我们之前描述了转录激活的 Notch1 细胞内结构域（NICD1）免疫组化（IHC）表达模式与高危病理特征之间的关联。在这里，我们进一步研究了 HNSCC 中的 Notch 信号。
在具有已知 NOTCH1 突变状态的 78 例肿瘤中，评估了 Notch 通路分子的 IHC 表达模式及其与临床病理特征的关系。进行了 JAG1（一种 Notch1 激活配体）和 HEY1（NICD1 转录靶标和 Notch 通路激活标志物）的 IHC。记录 IHC 模式和 H 评分（%染色×强度），并与临床病理特征和生存情况进行比较。使用 Kaplan-Meier 方法和 Cox 比例风险模型（HR）进行生存分析。
在没有截断 NOTCH1 突变的肿瘤中，JAG1 和 NICD1 的表达模式高度一致（p<0.001），但在具有截断 NOTCH1 突变的肿瘤中则不同（p=0.24）。在 7 例具有野生型 NOTCH1 的肿瘤中，存在 JAG1 非依赖性 NOTCH1 激活的证据。HEY1 的表达与 JAG1 或 NICD1 的表达均无关，但与 NOTCH1 突变状态相关（p=0.03）。12（16%）例肿瘤表达 HEY1 但不表达 NICD1。较高的 HEY1 H 评分与总体生存率（调整后的危险比[HR]2.0，95%CI=1.0-4.2）和疾病特异性生存率（调整后的 HR=3.3，95%CI=1.4-7.9）显著相关，而 JAG1 和 NICD1 的表达与生存率无关。
这些发现表明存在 Notch1 依赖性和非依赖性的 HEY1 调节，并提示 HEY1 在 HNSCC 中具有先前未被认识的预后作用。
