Abstract 4357: Examining the role of end-stage kidney as a potential intermediate stage in the development of renal cell carcinomas; understanding the pathogenesis allowing for early detection

Abstract

Abstract Introduction: Clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma (PRCC) are both thought to arise from the renal proximal tubules. End stage renal disease (ESRD) patients have an increased incidence of developing PRCC and CCRCC. Some studies showed a progenitor cell population that is inherently present in renal tubules, and is significantly increased after renal injury. The studies have also illustrated similarities between these progenitor cells and PRCC & CCRCC; hypothesizing that they are the cell of origin of these tumors. This trend was not observed in other renal cell carcinomas such as chromophobe renal cell carcinoma (chRCC). This study aims to further examine the possible role of ESRD in the development of PRCC and CCRCC to understand this initial step of renal cell carcinoma pathogenesis. Methods: A cohort of n = 39 PRCC, 25 CCRCC, 63 normal, 10 end-stage and 18 chRCC cases were selected. RNA sequencing was performed and differential-gene-expression analysis was conducted between normal, ESRD and tumor using DESeq2 software. Pathway analysis was performed using GSEA. Genes from oncogenic pathways that have been studied to be involved in renal cancer development were selected to perform consensus clustering analysis on Genepattern. Results: Oncogenic and developmental pathways enriched in ESRD are consistently overlapping with that of CCRCC and PRCC tumors. 50% of end-stage developmental pathways are found in both CCRCC and PRCC but only 4.5% in chRCC. 62.4% and 46.4% of end-stage oncogenic pathways are found in CCRCC and PRCC respectively but only 16% in chRCC. Clustering analysis showed ESRD cases clustered together with CCRCC and PRCC groups and not with chRCC. Overall, the ESRD cases exhibited a gene expression profile more closely resembling that of CCRCC and PRCC than chRCC. Conclusion: Our findings support the hypothesis that ESRD provides a favorable environment for tumor growth promoting pathogenesis of both PRCC and CCRCC. The enrichment of the same developmental pathways in both ESRD and the tumors suggests that the progenitor cell population in the renal tubules, mentioned above, could be the origin of both PRCC and CCRCC lesions. Further analysis would allow the uncovering of the pathways that lead to tumor progression from these cells of origin, and can be used to determine biomarkers for early detection of CCRCC and PRCC. This is of particular benefit for those with increased risk as the ESRD patients. Citation Format: Mingyuan Wan, Vincent Castillo, Rola Saleeb. Examining the role of end-stage kidney as a potential intermediate stage in the development of renal cell carcinomas; understanding the pathogenesis allowing for early detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4357.