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

Publication ,  Journal Article
Li, M; Mulkey, F; Jiang, C; O'Neil, BH; Schneider, BP; Shen, F; Friedman, PN; Momozawa, Y; Kubo, M; Niedzwiecki, D; Hochster, HS; Lenz, H-J ...
Published in: Clin Cancer Res
October 1, 2018

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.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

October 1, 2018

Volume

24

Issue

19

Start / End Page

4734 / 4744

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor A
  • Oncology & Carcinogenesis
  • Neovascularization, Pathologic
  • Neoplasms
  • Middle Aged
  • Male
  • Hypertension
  • Humans
  • Human Umbilical Vein Endothelial Cells
  • HSP90 Heat-Shock Proteins
 

Citation

APA
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MLA
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Li, M., Mulkey, F., Jiang, C., O’Neil, B. H., Schneider, B. P., Shen, F., … Kroetz, D. L. (2018). Identification of a Genomic Region between SLC29A1 and HSP90AB1 Associated with Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance). Clin Cancer Res, 24(19), 4734–4744. https://doi.org/10.1158/1078-0432.CCR-17-1523
Li, Megan, Flora Mulkey, Chen Jiang, Bert H. O’Neil, Bryan P. Schneider, Fei Shen, Paula N. Friedman, et al. “Identification of a Genomic Region between SLC29A1 and HSP90AB1 Associated with Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance).Clin Cancer Res 24, no. 19 (October 1, 2018): 4734–44. https://doi.org/10.1158/1078-0432.CCR-17-1523.
Li M, Mulkey F, Jiang C, O’Neil BH, Schneider BP, Shen F, et al. Identification of a Genomic Region between SLC29A1 and HSP90AB1 Associated with Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance). Clin Cancer Res. 2018 Oct 1;24(19):4734–44.
Li, Megan, et al. “Identification of a Genomic Region between SLC29A1 and HSP90AB1 Associated with Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance).Clin Cancer Res, vol. 24, no. 19, Oct. 2018, pp. 4734–44. Pubmed, doi:10.1158/1078-0432.CCR-17-1523.
Li M, Mulkey F, Jiang C, O’Neil BH, Schneider BP, Shen F, Friedman PN, Momozawa Y, Kubo M, Niedzwiecki D, Hochster HS, Lenz H-J, Atkins JN, Rugo HS, Halabi S, Kelly WK, McLeod HL, Innocenti F, Ratain MJ, Venook AP, Owzar K, Kroetz DL. Identification of a Genomic Region between SLC29A1 and HSP90AB1 Associated with Risk of Bevacizumab-Induced Hypertension: CALGB 80405 (Alliance). Clin Cancer Res. 2018 Oct 1;24(19):4734–4744.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

October 1, 2018

Volume

24

Issue

19

Start / End Page

4734 / 4744

Location

United States

Related Subject Headings

  • Vascular Endothelial Growth Factor A
  • Oncology & Carcinogenesis
  • Neovascularization, Pathologic
  • Neoplasms
  • Middle Aged
  • Male
  • Hypertension
  • Humans
  • Human Umbilical Vein Endothelial Cells
  • HSP90 Heat-Shock Proteins