Molecular Characterization of Clear Cell Renal Cell Carcinoma Reveals Prognostic Significance of Epithelial-mesenchymal Transition Gene Expression Signature.

There is an ongoing need to develop prognostic biomarkers to improve the management of clear cell renal cell carcinoma (ccRCC).

To leverage enriched pathways in ccRCC to improve risk-stratification.

We retrospectively identified two complementary discovery cohorts of patients with ccRCC who underwent (1) radical nephrectomy (RNx) with inferior vena cava tumor thrombectomy (patients = 5, samples = 24) and (2) RNx for localized disease and developed recurrence versus no recurrence (n = 36). Patients with localized ccRCC (M0) in The Cancer Genome Atlas (TCGA, n = 386) were used for validation.

A differential expression gene (DEG) analysis was performed on targeted RNA next-generation sequencing data from both discovery cohorts. Using TCGA for validation, Kaplan-Meier survival analysis and multivariable Cox proportional hazard testing were utilized to investigate the prognostic impact of DEGs, cell cycle proliferation (CCP), and a novel epithelial-mesenchymal transition (EMT) score on progression-free (PFS) and disease-specific (DSS) survival.

In the discovery cohorts, we observed overexpression of WT1 and CCP genes in the tumor thrombus versus the primary tumor, as well as in patients with recurrence versus those without recurrence. A hallmark pathway analysis demonstrated enrichment of the EMT- and CCP-related pathways in patients with high WT1 expression in the TCGA (validation) ccRCC cohort. CCP and EMT scores were derived in the validation cohort, which was stratified into four risk groups using Youden Index cut points: CCPlow/EMTlow, CCPlow/EMThigh, CCPhigh/EMTlow, and CCPhigh/EMThigh. The CCPhigh/EMThigh risk group was associated with the worst PFS and DSS (both p < 0.001). In a multivariable analysis, CCPhigh/EMThigh was independently associated with poor PFS and DSS (hazard ratio = 4.6 and 10.3, respectively; p < 0.001).

We demonstrate the synergistic prognostic impact of EMT in tumors with a high CCP score. Our novel EMT score has the potential to improve risk stratification and provide potential novel therapeutic targets.

Genes involved in epithelial-mesenchymal transition provides important prognostic information for patients with clear cell renal cell carcinoma.

European urology oncology. 2021 Nov 25 [Epub ahead of print]

Srinivas Nallandhighal, Randy Vince, Razeen Karim, Skylar Groves, Judith Stangl-Kremser, Christopher Russell, Kevin Hu, Trinh Pham, Andi K Cani, Chia-Jen Liu, Alexander Zaslavsky, Rohit Mehra, Marcin Cieslik, Todd M Morgan, Ganesh S Palapattu, Aaron M Udager, Simpa S Salami

Department of Urology, Michigan Medicine, Ann Arbor, MI, USA., Department of Urology, Michigan Medicine, Ann Arbor, MI, USA; Norfolk State University, Norfolk, VA, USA., Department of Urology, Michigan Medicine, Ann Arbor, MI, USA; Department of Urology, Medical University of Vienna, Vienna, Austria., Michigan Center for Translational Pathology, Michigan Medicine, Ann Arbor, MI, USA; Molecular and Cellular Pathology Graduate Program, University of Michigan, Ann Arbor, MI, USA., Michigan Center for Translational Pathology, Michigan Medicine, Ann Arbor, MI, USA; Department of Pathology, Michigan Medicine, Ann Arbor, MI, USA., Department of Urology, Michigan Medicine, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA., Michigan Center for Translational Pathology, Michigan Medicine, Ann Arbor, MI, USA; Department of Pathology, Michigan Medicine, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA., Department of Urology, Michigan Medicine, Ann Arbor, MI, USA; Department of Urology, Medical University of Vienna, Vienna, Austria; University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA., Michigan Center for Translational Pathology, Michigan Medicine, Ann Arbor, MI, USA; Department of Pathology, Michigan Medicine, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. Electronic address: ., Department of Urology, Michigan Medicine, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, Michigan Medicine, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. Electronic address: .

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