Abstract | PURPOSE: EXPERIMENTAL DESIGN: 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.
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Authors | Diether Lambrechts, Matthieu Moisse, Paul Delmar, David W Miles, Natasha Leighl, Bernard Escudier, Eric Van Cutsem, Aruna T Bansal, Peter Carmeliet, Stefan J Scherer, Sanne de Haas, Celine Pallaud |
Journal | Angiogenesis
(Angiogenesis)
Vol. 17
Issue 3
Pg. 685-94
(Jul 2014)
ISSN: 1573-7209 [Electronic] Germany |
PMID | 24558090
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Monoclonal, Humanized
- Genetic Markers
- Placebos
- Vascular Endothelial Growth Factor A
- Bevacizumab
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Topics |
- Antibodies, Monoclonal, Humanized
(adverse effects)
- Bevacizumab
- Demography
- Endpoint Determination
- Female
- Genetic Markers
- Genetic Predisposition to Disease
- Humans
- Hypertension
(chemically induced, epidemiology, genetics)
- Incidence
- Male
- Middle Aged
- Placebos
- Polymorphism, Single Nucleotide
(genetics)
- Signal Transduction
(genetics)
- Treatment Outcome
- Vascular Endothelial Growth Factor A
(genetics)
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