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Angiotensinogen gene silencing predicts bevacizumab response in recurrent glioblastoma patients

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Background
Bevacizumab in combination with chemotherapy has shown activity in recurrent glioblastoma patients. Patients who achieve response to bevacizumab have improved survival as well as quality of life. Recently, we found that low gene expression of angiotensinogen (AGT) was a predictive factor for bevacizumab response in recurrent glioblastoma patients. Promoter methylation of AGT has been associated with AGT gene silencing. This study investigated if AGT promoter methylation in tumor tissue predicts response to bevacizumab combination therapy in recurrent glioblastoma patients.
Methods
The study included 82 recurrent glioblastoma patients treated with bevacizumab combination therapy whom were both RANO response and biomarker evaluable. DNA methylation of 7 CpG sites in the AGT promoter was measured using pyrosequencing. AGT gene expression in tumor tissue was measured by NanoString analysis.
For each CpG site, methylation was associated with angiotensinogen gene expression using Spearman correlations and to treatment response using Mann-Whitney U test and logistic regression analysis.
Results
Preliminary results on 58 of 82 patients analyzed: AGT promoter methylation was inversely associated with AGT gene expression on Position 1 (P=0.049) and borderline significant on Position 2 (P=0.074). Compared to non-responding patients, responders expressed significantly higher methylation levels of Position 1 (P=0.015), 2 (P=0.013) and 3 (P=0.045). Position 4-7 were not associated with AGT gene expression or response. By univariate analysis, increased methylation of the AGT promoter region were predictive for bevacizumab response on Position 1 (2-fold increase: OR=1.81; 95%CI: 1.02-3.23; P=0.043) and on Position 2 (2-fold increase: OR=2.08; 95%CI: 1.04-4.17; P=0.040).
Conclusion
Increased methylation of two AGT promoter regions is associated with AGT gene silencing and is predictive for bevacizumab response in recurrent glioblastoma patients. If validated, this method can be used to identify patients who will or will not benefit from bevacizumab combination therapy.
Updated results will be presented.
Original languageEnglish
Publication date2018
DOIs
Publication statusPublished - 2018
EventASCO 2018 - Chicago
Duration: 1 Jun 20185 Jun 2018

Conference

ConferenceASCO 2018
CityChicago
Period01/06/201805/06/2018

Event

ASCO 2018

01/06/201805/06/2018

Chicago

Event: Conference

ID: 56702276