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Published on: April 11, 2016
Spectrum of EGFR aberrations and potential clinical implications: insights from integrative pan-cancer analysis
Haijing Liu1,2, Bo Zhang1, Zhifu Sun2
1Department of Pathology, School of Basic Medical Sciences, Third Hospital, Peking University Health Science Center, Beijing, 100191, P. R. China.
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.
Insights
Human epidermal growth factor receptor (EGFR) alterations vary across cancers. While mutations are key for lung cancer therapy, increased EGFR expression in other cancers like glioblastoma and colon cancer is linked to poor outcomes, necessitating new treatment strategies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Human epidermal growth factor receptor (EGFR) is a critical oncogene and a primary target for precision therapy in lung cancer.
- Comprehensive profiling of EGFR alterations (mutations, expression, amplification, methylation) across diverse cancer types is lacking.
- This study addresses the need for a unified understanding of EGFR's role in various cancers.
Purpose of the Study:
- To comprehensively analyze the spectrum of EGFR alterations across 32 cancer types.
- To investigate the clinical associations of EGFR alterations with targeted therapy and patient survival.
- To provide insights into the therapeutic and prognostic implications of EGFR aberrations.
Main Methods:
- Utilized The Cancer Genome Atlas (TCGA) datasets from 11,314 patients across 32 cancer types.
- Analyzed EGFR gene alterations (mutations, amplification/deletion), abnormal expression, and DNA methylation.
- Compared mutation frequency, genomic location, functional impact, and survival associations among cancer types.
Main Results:
- EGFR alteration patterns, mutation sites, amplification, overexpression, and methylation varied significantly across cancer types.
- Targetable EGFR mutations were mainly in lung cancer's Pkinase_Tyr domain; glioblastoma showed high amplification but less effective mutations.
- Increased EGFR expression, often from amplification, correlated with poor outcomes in low-grade glioma, colon, pancreatic, and squamous cell carcinomas.
Conclusions:
- EGFR aberration type, frequency, and functional domain distribution differ across cancers.
- While Pkinase_Tyr domain mutations guide treatment, increased EGFR expression from amplification affects more tumor types and worsens outcomes.
- New therapeutic strategies are needed for EGFR-driven tumors, particularly those with amplified or deregulated EGFR expression.
