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Clin Cancer Res. 2018 Oct 1;24(19):4734-4744. doi: 10.1158/1078-0432.CCR-17-1523. Epub 2018 Jun 5.

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

Author information

1
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California.
2
Alliance Statistics and Data Center, Duke University, Durham, North Carolina.
3
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
4
Department of Medicine, University of Chicago Comprehensive Cancer, Chicago, Illinois.
5
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
6
Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut.
7
Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
8
Southeast Clinical Oncology Research Consortium, Winston-Salem, North Carolina.
9
Department of Medicine, University of California San Francisco, San Francisco, California.
10
Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
11
DeBartolo Family Personalized Medicine Institute, Moffitt Cancer Center, Tampa, Florida.
12
Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
13
Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina.
14
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California. deanna.kroetz@ucsf.edu.

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+ hypertension (P = 0.01; OR, 2.4) and systolic blood pressure >180 mm Hg (P = 0.02; OR, 2.1). rs834576 was associated with early grade 3+ hypertension in CALGB 40502 (P = 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. Clin Cancer Res; 24(19); 4734-44. ©2018 AACR.

PMID:
29871907
PMCID:
PMC6168379
[Available on 2019-10-01]
DOI:
10.1158/1078-0432.CCR-17-1523

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