Spectrum of EGFR aberrations and potential clinical implications: insights from integrative pan‐cancer analysis

Abstract

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. Results 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. 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.

Analytic validation and clinical utilization of the comprehensive genomic profiling test, GEM ExTra®

“…Of the 65 KRAS-mutant tumors 57 (87.6%) harbored a G12A/C/D/R/S/V mutation. Although the tumor samples received for sequencing encompass a wide spectrum of pre-, and post-treatment primary and metastatic tumors with complex histopathology, GEM ExTra assay findings generally correlated with previously reported driver gene frequencies including but not limited to CDKN2A alterations in melanoma [ 34 ], EGFR in lung and CNS tumors [ 35 ], PIK3CA hotspot in breast and endometrial tumors [ 36 ], and PTEN loss of function alterations in endometrial tumors [ 37 ], suggesting the clinical utility of the GEM ExTra assay in the detection and reporting of clinically relevant somatic alterations in a wide spectrum of sample types. Hotspot alterations in clinically relevant cancer drivers were consistently identified across cancer types suggesting their pan-cancer significance [ 38 , 39 ] ( Figure 4B ).…”

EGFR in head and neck squamous cell carcinoma: exploring possibilities of novel drug combinations

“…This is due to the fact that EGFR is overexpressed in over 90% of head and neck tumors (2) and the association translates to shorter survival for patients (3)(4)(5). HNSCCs have significantly increased EGFR expression, high frequency of EGFR amplification, and low rates of single nucleotide variations (SNV)/indels (6).…”

Proteomics identifies EGF‐like domain multiple 7 as a potential therapeutic target for epidermal growth factor receptor‐positive glioma

“…Our proteomic data also demonstrated elevated expression of proteins in the PI3K-Akt pathway in EGFR-positive patients, such as phosphatidylinositol 3-kinase (PI3K), ERK, MEK, PKM2, and so on. At protein levels, molecular networks such as angiogenesis, degradation, proliferation, survival, and apoptosis were observed in the proteomic profiles of the EGFR-positive glioma patients [21][22][23][24]. Interestingly, we also identified some unreported overexpressed proteins in both cultured cells and patient samples, including EGFL7, Ca +2 -dependent kinase (CaMK), casitas B-lineage lymphoma (CBL), H2A histone family member X (H2AX), epidermal growth factor receptor substrate 15 (ESP15), and non-catalytic region of tyrosine kinase (NCK), highlighting potential treatment targets in glioma.…”