title: Genetic markers of bevacizumab-induced hypertension.
abstract: OBJECTIVE
  There are currently no validated biomarkers predicting bevacizumab treatment outcome or toxicity. We combined biomarker data from six phase III trials of bevacizumab to assess whether genetic variation in vascular endothelial growth factor-A (VEGF-A) pathway or hypertension-related genes are associated with bevacizumab-induced hypertension.
  
  
  METHODS
  Germline DNA was available from 1,631 patients receiving bevacizumab-containing therapy for advanced solid tumors. Overall, 194 white patients had grade 1-4 bevacizumab-induced hypertension. In total, 236 single nucleotide polymorphisms (SNPs) located in VEGF-A, VEGF-A receptors (FLT1 and KDR), and other genes were selected using a SNP tagging approach and genotyped. A logistic regression on individual patient data was performed after adjustment for cancer type and five other covariates.
  
  
  RESULTS
  Ten SNPs were associated with bevacizumab-induced hypertension (P ≤ 0.05), but none surpassed the threshold adjusted for multiple testing (P < 0.0002). The most significant VEGF-A pathway SNP was rs1680695 in EGLN3 [allelic odds ratio (OR) 1.50 [95 % confidence interval (Cl) 1.09-2.07], P = 0.012]. Two additional SNPs, rs4444903 in EGF and rs2305949 in KDR, were associated with hypertension (allelic OR 1.57 [95 % CI 1.17-2.11], P = 0.0025; allelic OR 0.62 [95 % CI 0.42-0.93], P = 0.020, respectively) and closely linked to nearby functional variants. Consistent with previous reports, rs11064560 in WNK1 was also associated with bevacizumab-induced hypertension (OR 1.41 [95 % CI 1.04-1.92], P = 0.028).
  
  
  CONCLUSIONS
  The genes described in this large genetic analysis using pooled datasets warrant further functional investigation regarding their role in mediating bevacizumab-induced hypertension.
authors.affiliation: Vesalius Research Center, VIB, Campus Gasthuisberg, Herestraat 49, Box 912, 3000, Leuven, Belgium, Diether.Lambrechts@vib-kuleuven.be.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.forename: Matthieu
authors.initials: M
authors.lastname: Moisse
authors.forename: Paul
authors.initials: P
authors.lastname: Delmar
authors.forename: David W
authors.initials: DW
authors.lastname: Miles
authors.forename: Natasha
authors.initials: N
authors.lastname: Leighl
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Aruna T
authors.initials: AT
authors.lastname: Bansal
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Scherer
authors.forename: Sanne
authors.initials: S
authors.lastname: de Haas
authors.forename: Celine
authors.initials: C
authors.lastname: Pallaud
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects*; D000068258:Bevacizumab; D003710:Demography; D023381:Endpoint Determination; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000453:epidemiology / Q000235:genetics*; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010919:Placebos; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D005819:Genetic Markers; D010919:Placebos; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab