@article{228fda8a0ca2494f8d0622a34b8202e5,
title = "Identification of a genomic region between SLC29A1 and HsP90AB1 associated with risk of bevacizumab-induced hypertension: CALGB 80405 (Alliance)",
abstract = "Purpose: 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. Experimental Design: 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. Results: Four common variants in independent linkage disequilibrium blocks between SLC29A1 and HSP90AB1 were among the top associations. Validation in larger bevacizumab-treated cohorts supported association between rs9381299 with early grade 3{\th} hypertension (P ¼ 0.01; OR, 2.4) and systolic blood pressure >180 mm Hg (P ¼ 0.02; OR, 2.1). rs834576 was associated with early grade 3{\th} hypertension in CALGB 40502 (P ¼ 0.03; OR, 2.9). These SNP regions are enriched for regulatory elements that may potentially increase gene expression. In vitro overexpression of SLC29A1 in human endothelial cells disrupted adenosine signaling and reduced nitric oxide levels that were further lowered upon bevacizumab exposure. Conclusions: The genomic region between SLC29A1 and HSP90AB1 and its role in regulating adenosine signaling are key targets for further investigation into the pathogenesis of bevacizumab-induced hypertension.",
author = "Megan Li and Flora Mulkey and Chen Jiang and O'Neil, {Bert H.} and Schneider, {Bryan P.} and Fei Shen and Friedman, {Paula N.} and Yukihide Momozawa and Michiaki Kubo and Donna Niedzwiecki and Hochster, {Howard S.} and Lenz, {Heinz Josef} and Atkins, {James N.} and Rugo, {Hope S.} and Susan Halabi and Kelly, {William Kevin} and McLeod, {Howard L.} and Federico Innocenti and Ratain, {Mark J.} and Venook, {Alan P.} and Kouros Owzar and Kroetz, {Deanna L.}",
note = "Funding Information: B.H. O'Neil is a consultant/advisory board member for Amgen and Genen-tech. H.S. Hochster is a consultant/advisory board member for Bristol-Myers Squibb and Roche. H.-J. Lenz reports receiving commercial research grants from and is a consultant/advisory board member for Bristol-Myers Squibb, EMD, and Genentech. M.J. Ratain is a consultant/advisory board member for Genentech. A. Venook is a consultant/advisory board member for Genentech/Roche. D. Kroetz reports receiving commercial research grants from and is a consultant/advisory board member for Genentech. No potential conflicts of interest were disclosed by the other authors. Funding Information: Research reported in this publication was supported by the NCI of the NIH under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), U10CA041287, U10CA045808, U10CA047559, U10CA047577, U24CA114725, U10CA138561, U10CA180836, U10CA180838, UG1CA189858, CA180830 (to H.-J. Lenz), CA180826 (to H.S. Hochster), CA180797, CA189828, Alliance Clinical Trial Foundation (to D.L. Kroetz and A.P. Venook), and the Pharmacogenomics Development Fund to NIH award number P30CA082103 (to D.L. Kroetz). M. Li was supported in part by NIH grants T32GM007175 and F31GM113350. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.",
year = "2018",
month = oct,
day = "1",
doi = "10.1158/1078-0432.CCR-17-1523",
language = "English",
volume = "24",
pages = "4734--4744",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "19",
}