Prognostic Value of the VHL, HIF-1α, and VEGF Signaling Pathway and Associated MAPK (ERK1/2 and ERK5) Pathways in Clear-Cell Renal Cell Carcinoma. A Long-Term Study

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Micro-AbstractWe analyzed the status of the pathway von Hippel-Lindau (VHL)→hypoxia-inducible factor 1-α (HIF-1α)→vascular endothelial growth factor as well as 2 mitogen-activated protein kinase-associated pathways (extracellular signal-regulated kinase [ERK]1/2 and ERK5), in 50 patients with clear-cell renal cell carcinoma to determine its prognostic value.VHLmutation and methylation were analyzed, and expression was studied using Western blot and immunohistochemistry analyses. Patients with no VHL or HIF-1α expression and ERK5 overexpression had a worse course of disease.VHLstatus had no prognostic value. In the Cox analysis, only Tumor, Node, Metastases stage and Fuhrman nuclear grade remained in the model. Clinical and pathologic data continue to be essential in prognostic biomarker panels.Background:The prognostic value of molecular markers in renal cell carcinoma has been investigated in several studies. Although their value is still not confirmed, various proteins are important. We describe the effect on long-term survival of the status of the von Hippel-Lindau (VHL) hypoxia-inducible factor 1-α (HIF1-α) signaling pathway as well as associated mitogen-activated protein kinase (extracellular signal-regulated kinase [ERK]1/2 and ERK5).Patients and Methods:A prospective, longitudinal cohort study was conducted with 50 patients diagnosed with clear-cell renal cell carcinoma to analyze VHL mutations and hypermethylation as well as VHL, HIF1-α, vascular endothelial growth factor (VEGF), ERK1/2, and ERK5 protein expression. Overall survival (OS), disease-specific survival (DSS), and progression- or recurrence-free survival (PFS) were analyzed using the Kaplan–Meier method. Mantel–Haenszel was used for comparisons, and Cox proportional risk models were also constructed.Results:Follow-up was 66.9 months. There were 23 (46.0%) deaths, of which 17 (73.9%) were caused by the tumor. Mean periods were 85.6 months for OS and 94.3 months for DSS. A total of 22 (44.0%) patients showed progression (PFS, 78.1 months). VHL expression (P = .045) and > 10% of HIF1-α expression (P = .034) were associated with greater OS. DSS was greater in patients without VHL methylation (P = .012), with > 10% HIF1-α expression (P = .037), or with ERK5 protein underexpression. Greater PFS was associated with absence of VHL methylation (P = .045), presence of VHL expression (P < .0001), HIF1-α expression > 10% (P = .04), and ERK5 protein underexpression (P = .011). The presence of VHL mutation and/or methylation and VEGF expression had no prognostic value. Fuhrman nuclear grade and Tumor, Node, Metastases (TNM) stage were the only variables that remained in the Cox model.Conclusion:The HIF1-α and ERK5 pathway has prognostic value. Patients with no VHL or HIF1-α expression and ERK5 overexpression had a worse course of disease. VHL or VEGF status had no prognostic value. Only TNM stage and Fuhrman nuclear grade remained in the Cox model and, therefore, are still essential in prognostic biomarker panels.

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