Abstract
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.
Keywords
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Article info
Publication history
Published online: May 24, 2017
Accepted:
May 16,
2017
Received in revised form:
May 2,
2017
Received:
February 7,
2017
Footnotes
A.S.S.-S. and L.S.-O. contributed equally to this work.
Identification
Copyright
© 2017 Elsevier Inc. All rights reserved.
