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.

Verbiest, Annelies;Lambrechts, Diether;Van Brussel, Thomas;Couchy, Gabrielle;Beuselinck, Benoit;et.al.
(2018) Clinical Genitourinary Cancer — Vol. 16, n° 4, p. 266-273 (2018)

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Authors
  • Verbiest, Annelies
    Author
  • Lambrechts, Diether
    Author
  • Van Brussel, Thomas
    Author
  • Couchy, Gabrielle
    Author
  • Machiels, Jean-PascalUCLouvain
    Author
  • Beuselinck, Benoit
    Author
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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.
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Verbiest, A., Lambrechts, D., Van Brussel, T., Couchy, G., Wozniak, A., Méjean, A., Lerut, E., Oudard, S., Verkarre, V., Job, S., de Reynies, A., Machiels, J.-P., Patard, J.-J., Zucman-Rossi, J., & Beuselinck, B. (2018). 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. Clinical Genitourinary Cancer, 16(4), 266-273. https://doi.org/10.1016/j.clgc.2018.01.013 (Original work published 2018)