Abstract 5217: Genome instability in renal tumors

Abstract

Abstract Genome instability (GI), a recognized cancer hallmark, encompasses CNV burden, tumor mutational burden (TMB), and microsatellite instability and is variably associated with several clinical/prognostic features in solid tumors. GI and intratumor mutational heterogeneity in clear cell renal cell carcinoma (ccRCC) were associated with poor prognosis in a large multi-site sequencing study. As 10-15% of renal tumors exhibit copy number burden associated GI, the development of proteogenomic biomarkers to identify this subset of tumors will be of high clinical value. In our in-depth analysis of CPTAC renal cancer cohorts namely, ccRCC discovery and rare RCC, we first estimated absolute copy number using CNVEX TPO analysis pipeline. Copy number burden-based genome instability was estimated by calculating whole genome instability index (wGII) from DNA sequencing data, in addition to the estimation of genome ploidy and purity of the tumors. Genome instability was associated with survival outcomes in both ccRCC and rare RCC (Ref. 1 and 2). Differential proteogenomic analysis identified IGF2BP3, IGF2BP1, PYCR1 RNA and protein, to be upregulated among high wGII tumors. High wGII tumors showed upregulation of cell proliferation and other cell cycle/proliferation concepts in gene set enrichment analysis. Interestingly, transcriptional module analysis revealed transcription factors and target genes specifically upregulated in GI cases and this pattern showed certain degree of overlap to 9p loss ccRCC tumors (another molecular ccRCC subset that is also associated with poor prognosis). Differential expression analysis also identified, kinases, phosphosites and co-regulated kinase-substrates that are dysregulated in genome instable renal tumors. IGF2BP3 immunohistochemistry staining showed specific overexpression in high wGII tumors and the high positivity was observed exclusivity in the tumor cells. Prognostic biomarkers IGF2BP3, IGF2BP1, PYCR1, and UCHL1 show great promise to be developed as clinical prognostic assays and warrants additional characterization. Citation Format: Hanbyul Cho, Ginny X. Li, Rahul Mannan, Noshad Hosseini, Yi Hsiao, Yuping Zhang, Aniket Dagar, Chandan Kumar-Sinha, Marcin P. Cieslik, Saravana M. Dhanasekaran, Alexey I. Nesvizhskii, Arul M. Chinnaiyan, Clinical Proteomic Tumor Analysis Consortium. Genome instability in renal tumors [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 5217.