Identification of a variant in KDR associated with serum VEGFR2 and pharmacodynamics of Pazopanib.

Maitland ML, Xu CF, Cheng YC, Kistner-Griffin E, Ryan KA, Karrison TG, Das S, Torgerson D, Gamazon ER, Thomeas V, Levine MR, Wilson PA, Bing N, Liu Y, Cardon LR, Pandite LN, O'Connell JR, Cox NJ, Mitchell BD, Ratain MJ, Shuldiner AR
Clin Cancer Res. 2015 21 (2): 365-72

PMID: 25411163 · PMCID: PMC4323272 · DOI:10.1158/1078-0432.CCR-14-1683

PURPOSE - VEGF receptor (VEGFR) kinases are important drug targets in oncology that affect function of systemic endothelial cells. To discover genetic markers that affect VEGFR inhibitor pharmacodynamics, we performed a genome-wide association study of serum soluble vascular VEGFR2 concentrations [sVEGFR2], a pharmacodynamic biomarker for VEGFR2 inhibitors.

EXPERIMENTAL DESIGN - We conducted a genome-wide association study (GWAS) of [sVEGFR2] in 736 healthy Old Order Amish volunteers. Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [sVEGFR2] measurements, and in 121 patients with renal carcinoma with [sVEGFR2] measured before and during pazopanib therapy.

RESULTS - rs34231037 (C482R) in KDR, the gene encoding sVEGFR2 was found to be highly associated with [sVEGFR2], explaining 23% of the variance (P = 2.7 × 10(-37)). Association of rs34231037 with [sVEGFR2] was replicated in 128 patients with cancer with comparable effect size (P = 0.025). Furthermore, rs34231037 was a significant predictor of changes in [sVEGFR2] in response to pazopanib (P = 0.01).

CONCLUSION - Our findings suggest that genome-wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers. Genotyping for germline variants in KDR may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of VEGFR2 kinase inhibitors.

©2014 American Association for Cancer Research.

MeSH Terms (13)

Adolescent Angiogenesis Inhibitors Carcinoma, Renal Cell Female Genome-Wide Association Study Humans Kidney Neoplasms Male Polymorphism, Single Nucleotide Pyrimidines Sulfonamides Vascular Endothelial Growth Factor Receptor-2 Young Adult

Connections (2)

This publication is referenced by other Labnodes entities:

Links