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Updated: Jun 7, 2026
Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Association of epidermal growth factor receptor activating mutations with low ERCC1 gene expression in non-small cell
David R Gandara1, Peter Grimminger, Philip C Mack
1Division of Hematology/Oncology, University of California Davis Cancer Center, Sacramento, California 95817, USA. david.gandara@ucdmc.ucdavis.edu
Introduction:
Patients with non-small cell lung cancer (NSCLC) with cancers harboring activating mutations in the epidermal growth factor receptor (EGFR) show improved efficacy from EGFR tyrosine kinase inhibitors. Some clinical studies also suggest enhanced efficacy of platinum-based chemotherapy in patients with EGFR-mutant cancers. We investigated the relationship of EGFR mutation status and DNA repair capacity, as exemplified by excision repair cross-complementing 1 (ERCC1) gene expression, as a potential explanation for this observation.
Methods:
Microdissected formalin-fixed paraffin-embedded tumors from 1207 patients with NSCLC were analyzed by real-time polymerase chain reaction for mRNA expression levels of ERCC1 and for EGFR mutation status by an allele-specific polymerase chain reaction assay.
Results:
NSCLC subtype was adenocarcinoma (AC) in 712 patients, squamous in 175, and not otherwise specified or other in 320. EGFR activating mutations were detected in 183/1207 patients (15.2%). Median ERCC1 expression overall was 1.82 (range, 0.22-27.31) and was histology related: AC, median = 1.68 (0.22-11.33) and squamous, median = 2.42 (0.51-14.28) (p < 0.001). Using a previously defined reference level of <1.7, ERCC1 expression was categorized as low in 556 of 1207 patients (46.1%). The presence of EGFR mutations was highly associated with ERCC1 expression (p < 0.001). This association was retained when adjusting for AC histologic subtype (p = 0.001).
Conclusions:
NSCLC specimens harboring EGFR activating mutations are more likely to express low ERCC1 mRNA levels. Whether these findings translate into enhanced clinical efficacy of EGFR-mutant cancers to platinum-based chemotherapy remains to be determined.
Insights
Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations often show lower excision repair cross-complementing 1 (ERCC1) expression. This suggests a link between EGFR status and DNA repair capacity in NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Activating mutations in the epidermal growth factor receptor (EGFR) are common in non-small cell lung cancer (NSCLC).
- EGFR tyrosine kinase inhibitors demonstrate efficacy in EGFR-mutant NSCLC.
- Platinum-based chemotherapy may also be more effective in EGFR-mutant NSCLC.
Purpose of the Study:
- To investigate the relationship between EGFR mutation status and DNA repair capacity, specifically excision repair cross-complementing 1 (ERCC1) gene expression, in NSCLC.
- To explore a potential explanation for enhanced chemotherapy efficacy in EGFR-mutant NSCLC.
Main Methods:
- Analyzed microdissected NSCLC tumors from 1207 patients.
- Measured ERCC1 mRNA expression levels using real-time polymerase chain reaction.
- Determined EGFR mutation status via allele-specific polymerase chain reaction assay.
Main Results:
- EGFR activating mutations were detected in 15.2% of patients.
- ERCC1 expression levels varied by histology, with higher expression in squamous cell carcinoma than adenocarcinoma.
- A significant association was found between the presence of EGFR mutations and lower ERCC1 expression (p < 0.001).
Conclusions:
- NSCLC with activating EGFR mutations are more likely to exhibit low ERCC1 mRNA expression.
- The clinical significance of this association for platinum-based chemotherapy efficacy in EGFR-mutant NSCLC requires further investigation.
