Abstract 2632: Increased recurrence and clinical grade in renal cell carcinomas associated with novel EGFR splice variants
Authors: Coba George A. , Zaman Saif , Teer Jamie K. , Robinson Timothy , Li Roger , Zhang Jingsong , Knepper Todd C. , Spiess Philippe E. , Sexton Wade , Smith Matthew A. , Fishman Mayer N. , Pow-Sang Julio M. , Poch Michael A. , Gilbert Scott M. , Magliocco Anthony M. , Boyle Theresa A. , Manley Brandon J. 
Published: August 2019

Abstract
Background: It is well established that alterations of epidermal growth factor receptor (EGFR) are associated with the development and progression of epithelial tumors across several cancer types. Alternative splicing and alterations of EGFR splice sites can cause translational changes and EGFR alterations have historically demonstrated associations with clinical and therapeutic outcomes in lung cancer.
Objectives: To evaluate the prevalence and clinical significance of recently identified novel ΔEGFR-TKF splice variant in 102 renal cell carcinoma (RCC) tumors
Methods: The majority of the RCC samples were RNA sequenced through the Orien AVATAR™ pipeline, and 7 additional cases were analyzed through Moffitt STAR™. Moffitt STAR™ and AVATAR™ are next generation targeted sequencing assay that include both DNA and RNA analyses. Frequency tables were generated using the data collected. The Grehan-Breslow-Wilcoxon test was used to compare recurrence free survival (RFS) due to the higher weight given to survival difference at earlier time points. The rationale being that the majority of recurrence events occurred earlier than 25 months in EGFR ≥5% cases and 50 months in the EGFR &lt;5% cases compared to the follow-up times of 75 months and 125 months in the study cohort.
Results: We identified a EGFR gene splice variant, predominantly c.2470-188_c.2470-2, between exons 20 and 21 in RCCs subjected to the sequencing assay. Of 1075 solid tumors analyzed, the presence of the EGFR gene splice variant was observed, in any amount, within 74 of 102 RCC cases (72.5%), with the only exceptions being one multiple myeloma and sarcoma case. Using an EGFR slice variant cutoff of ≥5%, 33 of 102 (32.4%) RCC were chosen to be further investigated. Upon further analysis, 32 EGFR slice variant tumors were clear cell RCC, while 1 was papillary type II RCC. Thirty cases involving ≥5% slice variants were clinically staged revealed 6 T1, 8 T2, and 16 T3/4 cases compared to tumors with &lt;5% of the splice variants which were staged 28 T1, 10 T2, 21 T3/4, and 8 Tx (p=.011). The RFS curve trended to worse outcomes for patients with ≥5% EGFR splice variants compared to &lt;5% EGFR splice variants (p=.0315). All variants were identified at the RNA level without obvious corresponding DNA alterations. There was an average of 106 unique reads (average of 7.7% of all reads) for these cases supporting this variant.
Conclusion: EGFR splice variants in RCC are a relatively frequent and specific molecular alteration. This novel splice variant may prove to be significant as a druggable target or as part of a kidney cancer screening protocol.
Citation Format: George A. Coba, Saif Zaman, Jamie K. Teer, Timothy Robinson, Roger Li, Jingsong Zhang, Todd C. Knepper, Philippe E. Spiess, Wade Sexton, Matthew A. Smith, Mayer N. Fishman, Julio M. Pow-Sang, Michael A. Poch, Scott M. Gilbert, Anthony M. Magliocco, Theresa A. Boyle, Brandon J. Manley. Increased recurrence and clinical grade in renal cell carcinomas associated with novel EGFR splice variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2632.