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
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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