Use of integrated multi-omics profiling in renal cell carcinoma to identify molecular subtypes and associated clinical outcomes and therapeutic vulnerabilities.

588 Background: Although histologically defined subtypes exist, renal cell carcinoma (RCC) is a heterogenous disease, resulting in various treatment outcomes and prognosis. Here, we conducted comprehensive profiling of RCC with histopathologic, proteomic, phosphoproteomic, genomic, and transcriptomic analyses on tumor and paired adjacent normal tissues from 113 patients. Methods: Tumor and matched normal tissues were subjected to proteomic and phosphoproteomic analysis (N=113), whole exome sequencing (N=74), and whole transcriptomic sequencing (N=70). Results: RCC tumors are molecularly distinct from corresponding normal tissues, revealing the loss of tissue identity and de-differentiation. Various hallmarks of cancer were differentially observed at the individual patient level, highlighting the intertumoral heterogeneity of RCC. Proteomic subtyping classifies RCC tumors into four subtypes (C1-4) with distinct phosphoproteomic, genomic, and transcriptomic characteristics with prognostic and predictive implications. Among these subtypes, C1-3 were almost composed of clear cell RCC (ccRCC; 96.8%), whereas C4 was composed of non-clear cell RCC (nccRCC) or other types of cancer (100.0%). Among each subtype, C1 (N=37) exhibits the strongest angiogenesis signaling pathway activation with favorable prognosis after surgical resection. C2 (N=39) was characterized with enrichment in DNA repair pathways along with genetic alteration in BAP1 (24.0%). C3 (N=19) was characterized by chromosome 7q amplification and associated with enrichment in inflammatory response with dismal prognosis along with therapeutic resistance to tyrosine kinase inhibitors and/or immunotherapy. C4 (N=18) was exclusively enriched with nccRCC with active mitochondrial and oxidation phosphorylation. VHL had significant trans -acting effects on various protein and phosphoprotein substrates, whereas PBRM1 and SETD2 had differential cis - and trans -acting profiles. Based on the in silico and in vitro exploration, we also identified CDK5, located on chromosome 7q and highly upregulated in C3 subtype, as a valuable target which can be modulated by small molecule inhibitors. Conclusions: This study reports a large-scale multi-omics-based approach of RCC, providing insights into biologic underpinning and evidence for rational treatment selection as well as linking the multiomics-derived phenotypes to clinical outcomes of RCC.