Introduction: Epidermal growth factor receptor (EGFR) is a widely activated oncogene associated with several types of cancer. We identified a novel aberrant EGFR splice variant (EGFR-20-CTF) with specific expression in patients with clear cell renal cell carcinoma (ccRCC). The purpose of this study was to correlate EGFR-20-CTF expression with response to immunotherapy.
Methods: The tumors of 88 patients with ccRCC underwent RNA sequencing and characterization of EGFR-20-CTF. Nineteen patients had received immunotherapy. Patients were divided into 3 tertiles based on levels of EGFR-20-CTF expression. The time from first immunotherapy treatment to death was measured for each patient. Log-rank tests were used to compare survival between groups. Gene set enrichment analysis (GSEA) was also performed.
Results: EGFR-20-CTF was identified in 76.1% of ccRCC tumors. Patients with the highest levels of EFR-20-CTF expression had significantly worse survival at 48 months compared to patients with low EGFR-20-CTF (p = 0.036). The average survival in patients with high EGFR-20-CTF expression was < 16 months. GSEA showed that EGFR-20-CTF correlated with a significant decrease in expression of gene sets related to immune response including the HALLMARK inflammatory response, IL-2 signaling, and INF gamma response (all FDR q-val < 0.001).
Conclusions: EGFR-20-CTF occurs frequently in patients with ccRCC and is enriched in patients who had a poor response to immunotherapy. The presence of the EGFR-20-CTF was associated with a global decrease in expression of several gene sets related to immune response, which could account for the decreased response to immunotherapy observed in these patients. This previously unrecognized splice variant presents a possible marker of resistance and will need prospective validation. Source of
Funding: Urology Care Foundation Research Scholar Award Program; Society for Urologic Oncology