Identification of a genomic region between SLC29A1 and HsP90AB1 associated with risk of bevacizumab-induced hypertension: CALGB 80405 (Alliance)

Megan Li, Flora Mulkey, Chen Jiang, Bert H. O'Neil, Bryan P. Schneider, Fei Shen, Paula N. Friedman, Yukihide Momozawa, Michiaki Kubo, Donna Niedzwiecki, Howard S. Hochster, Heinz Josef Lenz, James N. Atkins, Hope S. Rugo, Susan Halabi, William Kevin Kelly, Howard L. McLeod, Federico Innocenti, Mark J. Ratain, Alan P. VenookKouros Owzar, Deanna L. Kroetz

Research output: Contribution to journalArticle

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 3þ 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 3þ 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.

Original languageEnglish
Pages (from-to)4734-4744
Number of pages11
JournalClinical Cancer Research
Volume24
Issue number19
DOIs
Publication statusPublished - 01-10-2018

Fingerprint

Hypertension
Nucleic Acid Regulatory Sequences
Blood Pressure
Adenosine
Single Nucleotide Polymorphism
Genes
Therapeutics
Angiogenesis Inhibitors
Bevacizumab
Linkage Disequilibrium
Vascular Endothelial Growth Factor A
Nitric Oxide
Research Design
Endothelial Cells
Gene Expression
Drug Therapy
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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. / Identification of a genomic region between SLC29A1 and HsP90AB1 associated with risk of bevacizumab-induced hypertension : CALGB 80405 (Alliance). In: Clinical Cancer Research. 2018 ; Vol. 24, No. 19. pp. 4734-4744.
@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.}",
year = "2018",
month = "10",
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",

}

Li, M, Mulkey, F, Jiang, C, O'Neil, BH, Schneider, BP, Shen, F, Friedman, PN, Momozawa, Y, Kubo, M, Niedzwiecki, D, Hochster, HS, Lenz, HJ, Atkins, JN, Rugo, HS, Halabi, S, Kelly, WK, McLeod, HL, Innocenti, F, Ratain, MJ, Venook, AP, Owzar, K & Kroetz, DL 2018, 'Identification of a genomic region between SLC29A1 and HsP90AB1 associated with risk of bevacizumab-induced hypertension: CALGB 80405 (Alliance)', Clinical Cancer Research, vol. 24, no. 19, pp. 4734-4744. https://doi.org/10.1158/1078-0432.CCR-17-1523

Identification of a genomic region between SLC29A1 and HsP90AB1 associated with risk of bevacizumab-induced hypertension : CALGB 80405 (Alliance). / 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.

In: Clinical Cancer Research, Vol. 24, No. 19, 01.10.2018, p. 4734-4744.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Identification of a genomic region between SLC29A1 and HsP90AB1 associated with risk of bevacizumab-induced hypertension

T2 - CALGB 80405 (Alliance)

AU - Li, Megan

AU - Mulkey, Flora

AU - Jiang, Chen

AU - O'Neil, Bert H.

AU - Schneider, Bryan P.

AU - Shen, Fei

AU - Friedman, Paula N.

AU - Momozawa, Yukihide

AU - Kubo, Michiaki

AU - Niedzwiecki, Donna

AU - Hochster, Howard S.

AU - Lenz, Heinz Josef

AU - Atkins, James N.

AU - Rugo, Hope S.

AU - Halabi, Susan

AU - Kelly, William Kevin

AU - McLeod, Howard L.

AU - Innocenti, Federico

AU - Ratain, Mark J.

AU - Venook, Alan P.

AU - Owzar, Kouros

AU - Kroetz, Deanna L.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - 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 3þ 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 3þ 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.

AB - 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 3þ 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 3þ 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.

UR - http://www.scopus.com/inward/record.url?scp=85054067794&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85054067794&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-17-1523

DO - 10.1158/1078-0432.CCR-17-1523

M3 - Article

C2 - 29871907

AN - SCOPUS:85054067794

VL - 24

SP - 4734

EP - 4744

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 19

ER -