Department of Otorhinolaryngology, Juntendo University, Faculty of Medicine, Tokyo, Japan.
Department of Human Pathology, Juntendo University School of Medicine, Building A 10F, Hongo 2-1-1, Bunkyo-ku, Tokyo, 113-8421, Japan.
Head Neck Pathol. 2021 Sep;15(3):743-756. doi: 10.1007/s12105-020-01261-w. Epub 2021 Jan 11.
The epidermal growth factor receptor (EGFR) pathway is important in tumorigenesis of oropharyngeal carcinoma (OPC). However, the molecular mechanisms contributing to EGFR expression in OPC are not well-known. To detect relating factors and clinicopathological impact of EGFR protein expression in OPC, gene amplification/loss, point mutations including synonymous mutations, and promoter methylation of EGFR, and the viral genome load of human papillomavirus type 16 (HPV16)-E5, -E6, and -E7, after extracting HPV16-related OPCs with qPCR of HPV16-E6 and E7, were investigated in 74 OPC surgical cases, including 52 HPV-related (HPV-OPC) and 22 HPV-unrelated (nHPV-OPC). Immunohistochemical (IHC) data of EGFR expression (high, weak, and negative), validated by the qPCR of EGFR mRNA, were compared with molecular, viral, and clinicopathological data of patients. All nHPV-OPC cases were EGFR-IHC-high, whereas 21.2%, 65.4%, and 13.5% of HPV-OPC cases showed EGFR-IHC-high, -weak, -negative (p < 0.01), respectively. In HPV-OPC cases, EGFR-IHC-weak/negative status was related to promoter methylation of EGFR (p = 0.009), but not with gene amplification/loss or the point mutation of EGFR and was more often seen in HPV16-OPC cases (p = 0.049). Among HPV16-OPC cases, EGFR-IHC-weak/negative was related to high E6 expression. EGFR protein-loss was related to the tumor histology of non-keratinizing squamous cell carcinoma (SCC) (p = 0.035) but not with patient prognosis. In conclusion, decreased EGFR protein expression was more frequent in HPV-OPC than in nHPV-OPC and was related to EGFR methylation, infection of HPV16, and the viral genome load of HPV16-E6. Clinicopathologically, it was related to the tumor histology of non-keratinizing SCC.
表皮生长因子受体（EGFR）通路在口咽癌（OPC）的肿瘤发生中很重要。然而，导致 OPC 中 EGFR 表达的分子机制尚不清楚。为了检测 OPC 中 EGFR 蛋白表达的相关因素和临床病理影响，我们使用 HPV16-E6 和 E7 的 qPCR 提取 HPV16 相关的 OPC 后，研究了 74 例 OPC 手术病例中 EGFR 的基因扩增/缺失、点突变（包括同义突变）、启动子甲基化以及人乳头瘤病毒 16 型（HPV16）-E5、-E6 和 -E7 的病毒基因组载量。包括 52 例 HPV 相关（HPV-OPC）和 22 例 HPV 不相关（nHPV-OPC）的病例。通过 EGFR mRNA 的 qPCR 验证，对 EGFR 表达的免疫组化（IHC）数据（高、弱和阴性）与患者的分子、病毒和临床病理数据进行了比较。所有 nHPV-OPC 病例的 EGFR-IHC 均为高表达，而 HPV-OPC 病例中分别有 21.2%、65.4%和 13.5%的病例表现为 EGFR-IHC-高、弱和阴性（p<0.01）。在 HPV-OPC 病例中，EGFR-IHC 弱/阴性状态与 EGFR 启动子甲基化有关（p=0.009），但与基因扩增/缺失或 EGFR 点突变无关，且在 HPV16-OPC 病例中更为常见（p=0.049）。在 HPV16-OPC 病例中，EGFR-IHC 弱/阴性与高 E6 表达有关。EGFR 蛋白丢失与非角化鳞状细胞癌（SCC）的肿瘤组织学有关（p=0.035），但与患者预后无关。总之，HPV-OPC 中 EGFR 蛋白表达降低的频率高于 nHPV-OPC，与 EGFR 甲基化、HPV16 感染和 HPV16-E6 的病毒基因组载量有关。临床病理上，它与非角化 SCC 的肿瘤组织学有关。
