Polymorphisms in the Von Hippel-Lindau Gene Are Associated With Overall Survival in Metastatic Clear-Cell Renal-Cell Carcinoma Patients Treated With VEGFR Tyrosine Kinase Inhibitors

Annelies Verbiest; Diether Lambrechts; Thomas Van Brussel; Gabrielle Couchy; Agnieszka Wozniak; Arnaud Méjean; Evelyne Lerut; Stéphane Oudard; Virginie Verkarre; Sylvie Job; Aurélien de Reynies; Jean-Pascal Machiels; Jean-Jacques Patard; Jessica Zucman-Rossi; Benoit Beuselinck

doi:10.1016/j.clgc.2018.01.013

Polymorphisms in the Von Hippel-Lindau Gene Are Associated With Overall Survival in Metastatic Clear-Cell Renal-Cell Carcinoma Patients Treated With VEGFR Tyrosine Kinase Inhibitors

Clin Genitourin Cancer. 2018 Aug;16(4):266-273. doi: 10.1016/j.clgc.2018.01.013. Epub 2018 Feb 5.

Authors

Affiliations

¹ Laboratory of Experimental Oncology, Department of Oncology, University of Leuven, Leuven, Belgium; Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.
² Center for Cancer Biology, Flemish Institute for Biotechnology, Leuven, Belgium; Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
³ INSERM, UMR-1162, Functional Genomics of Solid Tumors, Institute of Hematology, Paris, France.
⁴ Laboratory of Experimental Oncology, Department of Oncology, University of Leuven, Leuven, Belgium.
⁵ Department of Urology, University Hospitalsof Central Paris, Paris, France.
⁶ Department of Pathology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.
⁷ Department of Medical Oncology, University Hospitalsof Central Paris, Paris, France.
⁸ Department of Pathology, University Hospitalsof Central Paris, Paris, France.
⁹ Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France.
¹⁰ Institut Roi Albert II, Service d'Oncologie Médicale, Cliniques universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale, Université Catholique de Louvain, Brussels, Belgium.
¹¹ Department of Urology, Hôpital Bicêtre, Paris, France.
¹² Laboratory of Experimental Oncology, Department of Oncology, University of Leuven, Leuven, Belgium; Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium. Electronic address: benoit.beuselinck@uzleuven.be.

PMID: 29503246
DOI: 10.1016/j.clgc.2018.01.013

Abstract

Background: Clear-cell renal-cell carcinoma (ccRCC) is characterized by loss of a functional Von Hippel-Lindau (VHL) protein. We investigated the potential of 3 single nucleotide polymorphisms (SNPs) in VHL as biomarkers in metastatic ccRCC (m-ccRCC) patients treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs).

Patients and methods: We genotyped 3 VHL SNPs in 199 m-ccRCC patients: rs1642742 T > C, rs1642743 A > G, and rs1678607 C > A. Primary end points were response rate (RR), progression-free survival (PFS), and overall survival (OS) after start of first-line TKI. RR was compared with Fisher's exact test, and PFS and OS with Kaplan-Meier analysis and multivariable Cox regression. Secondary end points were association with VHL promotor hypermethylation, VHL mutation status, VHL loss of heterozygosity, ≥ 25% sarcomatoid dedifferentiation, and expression of genes implicated in angiogenesis and immunoresponse (Fisher's exact test and unpaired t tests).

Results: The minor alleles of rs1642742 and rs1642743, known to be in close linkage disequilibrium, were associated with poor outcome, following a recessive pattern. For the rs1642742 CC versus TT/TC genotype, OS was 11 versus 26 months (hazard ratio = 2.3; 95% confidence interval, 1.2-6.6; P = .015). For the rs1642743 GG versus AA/AG genotype, OS was 15 versus 28 months (hazard ratio = 2.6; 95% confidence interval, 1.4-5.0; P = .004). After multivariable analysis, both remained linked with poor OS (P = .018 and P = .009, respectively). There was a trend toward shorter PFS and poorer RR. Both SNPs were associated with ≥ 25% sarcomatoid dedifferentiation (P = .037 and .006, respectively). No significant results were found for rs1678607.

Conclusion: rs1642742 and rs1642743 are candidate biomarkers for poor OS in m-ccRCC patients receiving first-line VEGFR-TKI. They are associated with higher levels of sarcomatoid dedifferentiation.

Keywords: Biomarker; SNP; Sarcomatoid dedifferentiation; rs1642742; rs1678607.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Carcinoma, Renal Cell / drug therapy*
Carcinoma, Renal Cell / genetics
Cell Dedifferentiation
DNA Methylation
Female
Humans
Kidney Neoplasms / drug therapy*
Kidney Neoplasms / genetics
Linkage Disequilibrium
Loss of Heterozygosity
Male
Middle Aged
Pharmacogenomic Variants
Polymorphism, Single Nucleotide*
Promoter Regions, Genetic
Protein Kinase Inhibitors / therapeutic use*
Survival Analysis
Treatment Outcome
Von Hippel-Lindau Tumor Suppressor Protein / genetics*

Substances

Protein Kinase Inhibitors
Von Hippel-Lindau Tumor Suppressor Protein
VHL protein, human