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 language | English |
|---|---|
| Pages (from-to) | 4734-4744 |
| Number of pages | 11 |
| Journal | Clinical Cancer Research |
| Volume | 24 |
| Issue number | 19 |
| DOIs | |
| Publication status | Published - 01-10-2018 |
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All Science Journal Classification (ASJC) codes
- Oncology
- Cancer Research
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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 journal › Article
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.
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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 -