PD01-09 PROTEOGENOMIC AND CLINICAL IMPLICATIONS OF RECURRENT SPLICE VARIANTS IN CLEAR CELL RENAL CELL CARCINOMA

Abstract

You have accessJournal of UrologyCME1 May 2022PD01-09 PROTEOGENOMIC AND CLINICAL IMPLICATIONS OF RECURRENT SPLICE VARIANTS IN CLEAR CELL RENAL CELL CARCINOMA Andrew Chang, Paul Stewart, Nicholas Chakiryan, Alex Soupir, Yijun Tian, Dongliang Du, Jamie Teer, Youngchul Kim, Philippe Spiess, Jad Chahoud, Yonghong Zhang, John Koomen, Anders Berglund, Timothy Robinson, Liang Wang, and Brandon Manley Andrew ChangAndrew Chang More articles by this author , Paul StewartPaul Stewart More articles by this author , Nicholas ChakiryanNicholas Chakiryan More articles by this author , Alex SoupirAlex Soupir More articles by this author , Yijun TianYijun Tian More articles by this author , Dongliang DuDongliang Du More articles by this author , Jamie TeerJamie Teer More articles by this author , Youngchul KimYoungchul Kim More articles by this author , Philippe SpiessPhilippe Spiess More articles by this author , Jad ChahoudJad Chahoud More articles by this author , Yonghong ZhangYonghong Zhang More articles by this author , John KoomenJohn Koomen More articles by this author , Anders BerglundAnders Berglund More articles by this author , Timothy RobinsonTimothy Robinson More articles by this author , Liang WangLiang Wang More articles by this author , and Brandon ManleyBrandon Manley More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002516.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Alternative mRNA splicing is recognized as a key driver of proteomic diversity. In cancer, this splicing process can be altered resulting in generation of aberrant splice variants (SvPs) that can contribute to tumor pathogenesis. However, our understanding of the significance of aberrant SvPs in clear cell renal cell carcinoma (ccRCC) is currently limited. Given the lack of actionable genomic mutations in ccRCC, aberrant SpVs may be the avenue to new pathogenic mechanisms and biomarkers. METHODS: We implemented a novel pipeline to screen for and select SpVs frequent in and relatively specific to ccRCC. We started with RNA-seq data from the Cancer Cell Line Encyclopedia to identify SpVs specific to ccRCC cell lines. These were screened across normal tissue in the Genotype-Tissue Expression Project and excluded if expressed. We analyzed bulk RNA-seq data of ccRCC primary tumors obtained from our institutional Total Cancer Care cohort (TCC; n=111), The Cancer Genome Atlas (TCGA; n=484) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC; n = 110) to analyze SpV expression in these samples. Using raw proteomics files from the CPTAC portal, proteins were identified and quantified using MaxQuant. Associations of SvP with protein expression were filtered by a Spearman correlation cutoff of +/-0.3. The Enrichr R library was used for pathway enrichment. Finally, we correlated SpV expression with overall (OS) and cancer-specific survival (CSS). Using LASSO Cox regression analysis, we derived a SpV-based risk score trained on OS from the TCGA cohort and validated on the TCC and CPTAC cohorts. RESULTS: Our pipeline selected 16 previously uncharacterized SpVs, including variants of suspected oncogenes and tumor suppressors. Proteogenomic analysis identified interesting biological associations. Among patients with high levels of EGFR SpV, we found significantly higher expression of the protein regulatory T cell marker CD70 (padj=0.03). MVK SvP was highly correlated with 25 proteins enriched for the mTOR pathway (padj=0.002). We derived a survival risk score based on expression of 5 SpVs (PDZD2, COBLL1, PTPN14, RNASET2, FGD1) in the TCGA cohort. This risk score remained significant on multivariate analysis (HR 1.4, p=0.002) adjusting for covariates including AJCC stage. This was validated on multivariate analysis in the TCC (HR 3.56, p<0.001) and CPTAC (HR 3.18, p=0.019) cohorts. CONCLUSIONS: Our novel pipeline selected 16 unique SpVs frequent in and relatively specific for ccRCC. Some are associated with proteins expressed in oncogenic pathways, suggesting a potential role in disease pathogenesis. Additionally, our SpV-based risk score is strongly associated with OS and CSS across multiple cohorts. This study provides a template for identifying and characterizing disease-specific aberrant SpVs to aid discovery of new mechanisms and biomarkers. Source of Funding: Kidney Cancer Association Young Investigator Award © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e33 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrew Chang More articles by this author Paul Stewart More articles by this author Nicholas Chakiryan More articles by this author Alex Soupir More articles by this author Yijun Tian More articles by this author Dongliang Du More articles by this author Jamie Teer More articles by this author Youngchul Kim More articles by this author Philippe Spiess More articles by this author Jad Chahoud More articles by this author Yonghong Zhang More articles by this author John Koomen More articles by this author Anders Berglund More articles by this author Timothy Robinson More articles by this author Liang Wang More articles by this author Brandon Manley More articles by this author Expand All Advertisement PDF DownloadLoading ...