Journal
CLINICAL GENITOURINARY CANCER
Volume 16, Issue 4, Pages 266-273Publisher
CIG MEDIA GROUP, LP
DOI: 10.1016/j.clgc.2018.01.013
Keywords
Biomarker; rs1642742; rs1678607; Sarcomatoid dedifferentiation; SNP
Categories
Funding
- Kom op tegen Kanker (Stand Up to Cancer)
- Flemish cancer society
- Fondation Martine Midy (Paris, France)
- Fonds voor Wetenschappelijk Onderzoek Vlaanderen (Belgium)
- Pfizer
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We assessed whether 3 single nucleotide polymorphisms (SNPs) in the VHL gene are associated with outcome in metastatic clear-cell renal-cell carcinoma patients treated with first-line vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) by genotyping 199 patients. After multivariable analysis, 2 SNPs in close linkage disequilibrium, rs1642742 and rs1642743, remained independent predictors of poor overall survival after initiation of VEGFR-TKI. They are also associated with higher levels of sarcomatoid dedifferentiation. 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 Fishe's exact test, and PFS and OS with Kaplan-Meier analysis and multivariable Cox regression. Secondary end points were association with VHL promoter 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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