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

Abstract

<b>Purpose:</b> 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.<b>Experimental Design:</b> 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.<b>Results:</b> Four common variants in independent linkage disequilibrium blocks between <i>SLC29A1</i> and <i>HSP90AB1</i> were among the top associations. Validation in larger bevacizumab-treated cohorts supported association between rs9381299 with early grade 3+ hypertension (<i>P</i> = 0.01; OR, 2.4) and systolic blood pressure >180 mm Hg (<i>P</i> = 0.02; OR, 2.1). rs834576 was associated with early grade 3+ hypertension in CALGB 40502 (<i>P</i> = 0.03; OR, 2.9). These SNP regions are enriched for regulatory elements that may potentially increase gene expression. <i>In vitro</i> overexpression of SLC29A1 in human endothelial cells disrupted adenosine signaling and reduced nitric oxide levels that were further lowered upon bevacizumab exposure.<b>Conclusions:</b> The genomic region between <i>SLC29A1</i> and <i>HSP90AB1</i> and its role in regulating adenosine signaling are key targets for further investigation into the pathogenesis of bevacizumab-induced hypertension. <i>Clin Cancer Res; 24(19); 4734-44. ©2018 AACR</i>.