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
Autor: | Gabrielle Couchy, Evelyne Lerut, Virginie Verkarre, Sylvie Job, Jean-Pascal Machiels, Benoit Beuselinck, Jessica Zucman-Rossi, Aurélien de Reyniès, Thomas Van Brussel, Jean-Jacques Patard, Annelies Verbiest, Stéphane Oudard, Diether Lambrechts, Arnaud Mejean, Agnieszka Wozniak |
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Rok vydání: | 2018 |
Předmět: |
Adult
Male 0301 basic medicine Oncology medicine.medical_specialty Linkage disequilibrium Pharmacogenomic Variants Urology Loss of Heterozygosity Single-nucleotide polymorphism urologic and male genital diseases Polymorphism Single Nucleotide Linkage Disequilibrium Loss of heterozygosity 03 medical and health sciences 0302 clinical medicine Internal medicine Genotype medicine Carcinoma Humans Promoter Regions Genetic Carcinoma Renal Cell Protein Kinase Inhibitors Aged Aged 80 and over business.industry Proportional hazards model Cell Dedifferentiation DNA Methylation Middle Aged medicine.disease Survival Analysis Kidney Neoplasms female genital diseases and pregnancy complications Exact test Clear cell renal cell carcinoma Treatment Outcome 030104 developmental biology Von Hippel-Lindau Tumor Suppressor Protein 030220 oncology & carcinogenesis Female business |
Zdroj: | Clinical Genitourinary Cancer. 16:266-273 |
ISSN: | 1558-7673 |
Popis: | 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. |
Databáze: | OpenAIRE |
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