Spectrum of EGFR aberrations and potential clinical implications: insights from integrative pan-cancer analysis
Spectrum of EGFR aberrations and potential clinical implications: insights from integrative pan-cancer analysis
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DOI：
10.1002/cac2.12005
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发表时间：
2020-02-18
影响因子：
16.2
通讯作者：
Sun, Zhifu
中科院分区：
文献类型：
--
作者：
Liu, Haijing;Zhang, Bo;Sun, Zhifu
背景人表皮生长因子受体（EGFR）是一种致癌基因，是EGFR突变肺癌精确治疗的首选靶点之一。尽管有许多关于某些癌症的报告，但EGFR突变、过表达、扩增、DNA甲基化及其在许多不同癌症中的临床关联的综合分析尚不可用。本研究旨在填补这一差距，并为EGFR基因的改变谱及其治疗和预后意义提供新的见解。方法收集32种癌症类型共11,314例患者的癌症基因组图谱（Cancer Genome Atlas，TCGA）数据，分析EGFR基因的改变（突变和扩增/缺失）、异常表达和DNA甲基化。突变频率，基因组的位置分布，功能的影响，和临床靶向治疗的意义进行了比较，不同的癌症类型之间，和他们的协会与患者的生存率进行了analysed.ResultsEGFR的改变频率，突变位点跨功能域，扩增，过表达，和DNA甲基化模式不同的癌症类型之间有很大的差异。所有癌症的总体突变频率相对较低。靶向突变主要发生在Pkinase_Tyr结构域，主要发生在肺癌中。多形性胶质母细胞瘤的变异率最高，但主要是基因扩增，大多数突变发生在靶向治疗效果较差的弗林蛋白酶样结构域。低级别胶质瘤常存在基因扩增和EGFR表达增加，与预后不良相关。结肠癌和胰腺癌的EGFR突变很少;然而，EGFR高表达与患者生存期短显著相关。鳞状细胞癌无论其部位（头颈部、肺或食管）均表现出相似的特征，变异频率约为5.0%，以基因扩增为主，EGFR表达增加，通常与患者生存期短相关。DNA甲基化与EGFR表达和患者预后在某些cancer.Conclusions EGFR畸变的类型，频率，分布在功能域，和表达不同的癌症。虽然Pkinase_Tyr结构域中的突变对于治疗选择更重要，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结果，这需要针对这些EGFR驱动的肿瘤的新治疗策略。
Background 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.Methods 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.ResultsEGFR 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.Conclusions 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.