Genetic predisposition to bevacizumab-induced hypertension Journal Article
| Authors: | Frey, M. K.; Dao, F.; Olvera, N.; Konner, J. A.; Dickler, M. N.; Levine, D. A. |
| Article Title: | Genetic predisposition to bevacizumab-induced hypertension |
| Abstract: | Objective Bevacizumab, a monoclonal antibody to VEGF, has shown efficacy in ovarian, cervical and endometrial cancer in addition to several other solid tumors. Serious side effects include hypertension, proteinuria, bowel perforation, and thrombosis. We tested the hypothesis that genetic variation in hypertension-associated genes is associated with bevacizumab-induced hypertension (BIH). Methods Patients with solid tumors treated with bevacizumab in combination with other therapy were identified from six clinical trials. Haplotype-tagging (ht) SNPs for 10 candidate genes associated with hypertension were identified through the International Hapmap Project. Germline DNA was genotyped for 103 htSNPs using mass spectrometry. Bevacizumab toxicities were identified from clinical trial reports. Haplotypes were reconstructed from diploid genotyping data and frequencies were compared using standard two-sided statistical tests. Results The study included 114 patients with breast, lung, ovarian, or other cancers, of whom 38 developed BIH. WNK1, KLKB1, and GRK4 were found to contain single loci associated with BIH. Haplotype analysis of WNK1, KLKB1, and GRK4 identified risk haplotypes in each gene associated with grade 3/4 BIH. A composite risk model was created based on these haplotypes. Patients with the highest risk score were the most likely to develop grade 3/4 BIH (OR = 6.45; P = 0.005; 95%CI, 1.86–22.39). Conclusions We concluded that genetic variation in WNK1, KLKB1, and GRK4 may be associated with BIH. These genes are biologically plausible mediators due to their role in blood pressure control, regulating sodium homeostasis and vascular tone. This preliminary risk model performed better than population-based risk models and when further validated may help risk-stratify patients for BIH prior to initiating therapy. © 2017 Elsevier Inc. |
| Keywords: | adult; controlled study; aged; major clinical study; single nucleotide polymorphism; bevacizumab; hypertension; mass spectrometry; ovary cancer; breast cancer; genetic association; genotype; genetic variation; haplotype; kallikrein; genetic risk; genetic predisposition; proteinuria; non small cell lung cancer; haplotype map; human; male; female; priority journal; article; solid malignant neoplasm; grk4; klkb1; wnk1; g protein coupled receptor kinase 4; protein kinase wnk1; bih gene |
| Journal Title: | Gynecologic Oncology |
| Volume: | 147 |
| Issue: | 3 |
| ISSN: | 0090-8258 |
| Publisher: | Elsevier Inc. |
| Date Published: | 2017-12-01 |
| Start Page: | 621 |
| End Page: | 625 |
| Language: | English |
| DOI: | 10.1016/j.ygyno.2017.09.017 |
| PROVIDER: | scopus |
| PUBMED: | 28969913 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 4 December 2017 -- Source: Scopus |
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