Supplementary Methods, Figures S1-S2, Table S1-S2 from Identification of a Variant in KDR Associated with Serum VEGFR2 and Pharmacodynamics of Pazopanib

Maitland, Michael L.; Xu, Chun-Fang; Cheng, Yu-Ching; Kistner-Griffin, Emily; Ryan, Kathleen A.; Karrison, Theodore G.; Das, Soma; Torgerson, Dara; Gamazon, Eric R.; Thomeas, Vasiliki; Levine, Matthew R.; Wilson, Paul A.; Bing, Nan; Liu, Yuan; Cardon, Lon R.; Pandite, Lini N.; O'Connell, Jeffrey R.; Cox, Nancy J.; Mitchell, Braxton D.; Ratain, Mark J.; Shuldiner, Alan R.

doi:10.1158/1078-0432.22460669.v1

Supplementary Methods, Figures S1-S2, Table S1-S2 from Identification of a Variant in KDR Associated with Serum VEGFR2 and Pharmacodynamics of Pazopanib

journal contribution

posted on 2023-03-31, 19:05 authored by Michael L. Maitland, Chun-Fang Xu, Yu-Ching Cheng, Emily Kistner-Griffin, Kathleen A. Ryan, Theodore G. Karrison, Soma Das, Dara Torgerson, Eric R. Gamazon, Vasiliki Thomeas, Matthew R. Levine, Paul A. Wilson, Nan Bing, Yuan Liu, Lon R. Cardon, Lini N. Pandite, Jeffrey R. O'Connell, Nancy J. Cox, Braxton D. Mitchell, Mark J. Ratain, Alan R. Shuldiner

Materials and Methods Fig. S1. Linkage disequilibrium (LD) between rs725344 and SNPs from the IBC chip within KDR in the Old Order Amish. Fig. S2. Interspecies conservation of C482 in homologous sequences. Table S1. Candidate variants within the 4MB linkage peak tested in 128 cancer patients for association with [sVEGFR2]. Table S2. Polymorphisms within KDR strongly associated with serum concentrations of sVEGFR2 in the Amish.

History

ARTICLE ABSTRACT

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. Clin Cancer Res; 21(2); 365–72. ©2014 AACR.