Aberrant Epidermal Growth Factor Receptor RNA Splice Products Are Among the Most Frequent Somatic Alterations in Clear Cell Renal Cell Carcinoma and Are Associated with a Poor Response to Immunotherapy.

European urology focus 2021 Mar

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Accumulating evidence suggests that alternative RNA splicing has an important role in cancer development and progression by driving the expression of a diverse array of RNA and protein isoforms from a handful of genes. However, our understanding of the clinical significance of cancer-specific RNA splicing in renal cell carcinoma (RCC) is limited. To characterize and validate a novel oncogene RNA splicing event discovered in patients with RCC and to correlate expression with clinical outcomes. Using DNA and RNA sequencing, we identified a novel epidermal growth factor receptor (EGFR) splicing alteration (EGFR_pr20CTF) in RCC tumor tissue. We confirmed the frequency and specificity of the EGFR_pr20CTF variant by analyzing cohorts of patients from our institution (n = 699) and The Cancer Genome Atlas (TCGA; n = 832). Furthermore, we analyzed its expression in tumor tissue and a human kidney cancer cell line using reverse transcriptase-polymerase chain reaction. Variant expression was also correlated with survival and response to systemic therapy. EGFR_pr20CTF expression was identified in 71.7% (n = 71/99) of patients with RCC in our institutional cohort and in 56.7% (n = 279/492) of patients in the TCGA cohort. EGFR_pr20CTF was found to be specific to clear cell renal cell carcinoma (ccRCC), occurring in <0.2% of non-RCC tumors (n = 2/1091). High levels of EGFR_pr20CTF correlated with lower survival at 48 mo following immunotherapy (p = 0.036). The average survival in patients with high EGFR_pr20CTF expression was <16 mo. The EGFR_pr20CTF RNA splice variant occurs frequently, is specific to patients with advanced ccRCC, and is associated with a poor response to immunotherapy. Cancer-specific RNA alternative splicing may portend a poor prognosis in patients with advanced clear cell renal cell carcinoma. Further investigation will help clarify whether EGFR_pr20CTF can be used as a biomarker for this patient population. Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Citation

Saif Zaman, Ali Hajiran, George A Coba, Timothy Robinson, Thushara W Madanayake, Daniel T Segarra, Boris I Chobrutskiy, Theresa A Boyle, Jun-Min Zhou, Youngchul Kim, James J Mulé, Jamie K Teer, Brandon J Manley. Aberrant Epidermal Growth Factor Receptor RNA Splice Products Are Among the Most Frequent Somatic Alterations in Clear Cell Renal Cell Carcinoma and Are Associated with a Poor Response to Immunotherapy. European urology focus. 2021 Mar;7(2):373-380