Department of Pathology, School of Basic Medical Sciences, Third Hospital, Peking University Health Science Center, Beijing, 100191, P. R. China.
Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, 55905, USA.
Cancer Commun (Lond). 2020 Jan;40(1):43-59. doi: 10.1002/cac2.12005. Epub 2020 Feb 18.
Human epidermal growth factor receptor (EGFR) is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations. Although there are many reports for some individual cancers, comprehensive profiling of EGFR mutations, overexpression, amplification, DNA methylation, and their clinical associations across many different cancers simultaneously was not available. This study aimed to fill the gap and provide insights to the alteration spectrum of EGFR and its therapeutic and prognostic implications.
The Cancer Genome Atlas (TCGA) datasets for 32 cancer types involving 11,314 patients were analyzed for alterations (mutations and amplification/deletion), abnormal expression and DNA methylation in EGFR gene. Mutation frequency, genomic location distribution, functional impact, and clinical targeted therapy implication were compared among different cancer types, and their associations with patient survival were analyzed.
EGFR alteration frequency, mutation sites across functional domains, amplification, overexpression, and DNA methylation patterns differed greatly among different cancer types. The overall mutation frequency in all cancers combined was relatively low. Targetable mutations, mainly in lung cancer, were primarily found in the Pkinase_Tyr domain. Glioblastoma multiforme had the highest rate of alterations, but it was dominated by gene amplification and most mutations were in the Furin-like domain where targeted therapy was less effective. Low-grade glioma often had gene amplification and increased EGFR expression which was associated with poor outcome. Colon and pancreatic adenocarcinoma had very few EGFR mutations; however, high EGFR expression was significantly associated with short patient survival. Squamous cell carcinoma regardless of their sites (the head and neck, lung, or esophagus) exhibited similar characteristics with an alteration frequency of about 5.0%, was dominated by gene amplification, and had increased EGFR expression generally associated with short patient survival. DNA methylation was highly associated with EGFR expression and patient outcomes in some cancers.
EGFR aberration type, frequency, distribution in functional domains, and expression vary from cancer to cancer. While mutations in the Pkinase_Tyr domain are more important for treatment selection, increased expression from amplification or deregulation affects more tumor types and leads to worse outcome, which calls for new treatment strategies for these EGFR-driven tumors.
人类表皮生长因子受体（EGFR）是一种致癌基因，也是 EGFR 突变型肺癌精准治疗的首要靶点之一。尽管针对某些特定癌症已有许多相关报道，但对于 EGFR 突变、过表达、扩增、DNA 甲基化及其在多种不同癌症中的临床相关性，目前尚无全面的综合分析。本研究旨在填补这一空白，并深入了解 EGFR 的改变谱及其治疗和预后意义。
分析了涉及 11314 名患者的 32 种癌症的癌症基因组图谱（TCGA）数据集，以研究 EGFR 基因的改变（突变和扩增/缺失）、异常表达和 DNA 甲基化。比较了不同癌症类型之间的突变频率、基因组位置分布、功能影响以及临床靶向治疗意义，并分析了它们与患者生存的相关性。
不同癌症类型之间 EGFR 改变频率、功能域内的突变部位、扩增、过表达和 DNA 甲基化模式存在显著差异。所有癌症类型的总体突变频率相对较低。主要在肺癌中发现的可靶向突变主要发生在 Pkinase_Tyr 结构域。多形性胶质母细胞瘤的改变率最高，但主要为基因扩增，且大多数突变发生在靶向治疗效果较差的 Furin-like 结构域。低级别胶质瘤常发生基因扩增和 EGFR 表达增加，与预后不良相关。结直肠癌和胰腺腺癌的 EGFR 突变非常少；然而，高 EGFR 表达与患者的短期生存显著相关。无论部位如何（头颈部、肺部或食管），鳞状细胞癌都表现出相似的特征，改变频率约为 5.0%，主要为基因扩增，且普遍存在 EGFR 表达增加，通常与患者的短期生存不良相关。在某些癌症中，DNA 甲基化与 EGFR 表达和患者预后高度相关。
EGFR 改变类型、频率、功能域分布和表达因癌症类型而异。虽然 Pkinase_Tyr 结构域的突变对治疗选择更为重要，但扩增或失调引起的表达增加会影响更多的肿瘤类型，并导致更差的预后，这就需要为这些 EGFR 驱动的肿瘤制定新的治疗策略。
