Identification of a Genomic Region between SLC29A1 and HSP90AB1 Associated with Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance)

• Published in: Clinical cancer research 2018-10, Vol.24 (19), p.4734-4744
• Main Authors: Li, Megan, Mulkey, Flora, Jiang, Chen, O'Neil, Bert H, Schneider, Bryan P, Shen, Fei, Friedman, Paula N, Momozawa, Yukihide, Kubo, Michiaki, Niedzwiecki, Donna, Hochster, Howard S, Lenz, Heinz-Josef, Atkins, James N, Rugo, Hope S, Halabi, Susan, Kelly, William Kevin, McLeod, Howard L, Innocenti, Federico, Ratain, Mark J, Venook, Alan P, Owzar, Kouros, Kroetz, Deanna L
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - adverse effects; Bevacizumab - administration & dosage; Bevacizumab - adverse effects; Clinical Trials as Topic; Equilibrative Nucleoside Transporter 1 - genetics; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; HSP90 Heat-Shock Proteins - genetics; Human Umbilical Vein Endothelial Cells; Humans; Hypertension - chemically induced; Hypertension - genetics; Hypertension - pathology; Male; Middle Aged; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - pathology; Vascular Endothelial Growth Factor A - antagonists & inhibitors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-17-1523

Bevacizumab is a VEGF-specific angiogenesis inhibitor indicated as an adjunct to chemotherapy for the treatment of multiple cancers. Hypertension is commonly observed during bevacizumab treatment, and high-grade toxicity can limit therapy or lead to cardiovascular complications. The factors that contribute to interindividual variability in blood pressure rise during bevacizumab treatment are not well understood. To identify genomic regions associated with bevacizumab-induced hypertension risk, sequencing of candidate genes and flanking regulatory regions was performed on 61 patients treated with bevacizumab (19 cases developed early-onset grade 3 hypertension and 42 controls had no reported hypertension in the first six cycles of treatment). SNP-based tests for common variant associations and gene-based tests for rare variant associations were performed in 174 candidate genes. Four common variants in independent linkage disequilibrium blocks between and were among the top associations. Validation in larger bevacizumab-treated cohorts supported association between rs9381299 with early grade 3+ hypertension ( = 0.01; OR, 2.4) and systolic blood pressure >180 mm Hg ( = 0.02; OR, 2.1). rs834576 was associated with early grade 3+ hypertension in CALGB 40502 ( = 0.03; OR, 2.9). These SNP regions are enriched for regulatory elements that may potentially increase gene expression. overexpression of SLC29A1 in human endothelial cells disrupted adenosine signaling and reduced nitric oxide levels that were further lowered upon bevacizumab exposure. The genomic region between and and its role in regulating adenosine signaling are key targets for further investigation into the pathogenesis of bevacizumab-induced hypertension. .