Angiotensinogen promoter methylation predicts bevacizumab treatment response of patients with recurrent glioblastoma
Patients with recurrent glioblastoma achieving response to bevacizumab combined with chemotherapy have clinical improvement and prolonged survival. High gene expression of angiotensinogen (AGT) is associated with a poor bevacizumab response. Because AGT expression is epigenetically regulated, we aim...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-05-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12660 |
| _version_ | 1818485874755633152 |
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| author | Thomas Urup Linn Gillberg Katja Kaastrup Maya Jeje Schuang Lü Signe Regner Michaelsen Vibeke Andrée Larsen Ib Jarle Christensen Helle Broholm Ulrik Lassen Kirsten Grønbæk Hans Skovgaard Poulsen |
| author_facet | Thomas Urup Linn Gillberg Katja Kaastrup Maya Jeje Schuang Lü Signe Regner Michaelsen Vibeke Andrée Larsen Ib Jarle Christensen Helle Broholm Ulrik Lassen Kirsten Grønbæk Hans Skovgaard Poulsen |
| author_sort | Thomas Urup |
| collection | DOAJ |
| description | Patients with recurrent glioblastoma achieving response to bevacizumab combined with chemotherapy have clinical improvement and prolonged survival. High gene expression of angiotensinogen (AGT) is associated with a poor bevacizumab response. Because AGT expression is epigenetically regulated, we aimed to investigate whether AGT promoter methylation in tumor tissue predicts response to bevacizumab combination therapy in patients with recurrent glioblastoma. The study included 159 patients with recurrent glioblastoma, treated with bevacizumab combination treatment (training cohort, n = 77; validation cohort, n = 82). All patients could be evaluated for treatment response and biomarkers. DNA methylation of 4 CpG sites in the AGT promoter was measured using pyrosequencing. A model for nonresponse was established using logistic regression analysis. In the training cohort, lower methylation of each of the four CpG sites in the AGT promoter was significantly associated with nonresponse (all P < 0.05). Moreover, the mean methylation level of all four CpG sites was associated with an increased likelihood of not achieving response to bevacizumab combination therapy (twofold decrease: odds ratio = 3.01; 95% confidence interval: 1.41–6.44; P = 0.004). We developed a model for nonresponse in the training cohort, where a threshold of mean AGT promoter methylation levels was set to below 12%. The model could predict bevacizumab nonresponse with 96% specificity. Importantly, this predictor was also significantly associated with nonresponse in the validation cohort (P = 0.037). Taken together, our findings suggest that low AGT promoter methylation in tumor tissue predicts nonresponse to bevacizumab combination treatment in patients with recurrent glioblastoma. We have, thus, established and successfully validated a predictor for nonresponse that can be used to identify patients who will not benefit from bevacizumab combination therapy. |
| first_indexed | 2024-12-10T16:14:53Z |
| format | Article |
| id | doaj.art-a869f372b7954f5c8bf9715dcc5ecaf3 |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-12-10T16:14:53Z |
| publishDate | 2020-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-a869f372b7954f5c8bf9715dcc5ecaf32022-12-22T01:41:59ZengWileyMolecular Oncology1574-78911878-02612020-05-0114596497310.1002/1878-0261.12660Angiotensinogen promoter methylation predicts bevacizumab treatment response of patients with recurrent glioblastomaThomas Urup0Linn Gillberg1Katja Kaastrup2Maya Jeje Schuang Lü3Signe Regner Michaelsen4Vibeke Andrée Larsen5Ib Jarle Christensen6Helle Broholm7Ulrik Lassen8Kirsten Grønbæk9Hans Skovgaard Poulsen10Department of Radiation Biology Centre for Cancer and Organ Diseases Rigshospitalet Copenhagen DenmarkDepartment of Hematology Centre for Cancer and Organ Diseases Rigshospitalet Copenhagen DenmarkDepartment of Hematology Centre for Cancer and Organ Diseases Rigshospitalet Copenhagen DenmarkDepartment of Radiation Biology Centre for Cancer and Organ Diseases Rigshospitalet Copenhagen DenmarkDepartment of Radiation Biology Centre for Cancer and Organ Diseases Rigshospitalet Copenhagen DenmarkDepartment of Radiology Center of Diagnostic Investigation Rigshospitalet Copenhagen DenmarkDepartment of Gastroenterology Hvidovre Hospital Hvidovre DenmarkDepartment of Neuropathology Center of Diagnostic Investigation Rigshospitalet Copenhagen DenmarkDepartment of Radiation Biology Centre for Cancer and Organ Diseases Rigshospitalet Copenhagen DenmarkDepartment of Hematology Centre for Cancer and Organ Diseases Rigshospitalet Copenhagen DenmarkDepartment of Radiation Biology Centre for Cancer and Organ Diseases Rigshospitalet Copenhagen DenmarkPatients with recurrent glioblastoma achieving response to bevacizumab combined with chemotherapy have clinical improvement and prolonged survival. High gene expression of angiotensinogen (AGT) is associated with a poor bevacizumab response. Because AGT expression is epigenetically regulated, we aimed to investigate whether AGT promoter methylation in tumor tissue predicts response to bevacizumab combination therapy in patients with recurrent glioblastoma. The study included 159 patients with recurrent glioblastoma, treated with bevacizumab combination treatment (training cohort, n = 77; validation cohort, n = 82). All patients could be evaluated for treatment response and biomarkers. DNA methylation of 4 CpG sites in the AGT promoter was measured using pyrosequencing. A model for nonresponse was established using logistic regression analysis. In the training cohort, lower methylation of each of the four CpG sites in the AGT promoter was significantly associated with nonresponse (all P < 0.05). Moreover, the mean methylation level of all four CpG sites was associated with an increased likelihood of not achieving response to bevacizumab combination therapy (twofold decrease: odds ratio = 3.01; 95% confidence interval: 1.41–6.44; P = 0.004). We developed a model for nonresponse in the training cohort, where a threshold of mean AGT promoter methylation levels was set to below 12%. The model could predict bevacizumab nonresponse with 96% specificity. Importantly, this predictor was also significantly associated with nonresponse in the validation cohort (P = 0.037). Taken together, our findings suggest that low AGT promoter methylation in tumor tissue predicts nonresponse to bevacizumab combination treatment in patients with recurrent glioblastoma. We have, thus, established and successfully validated a predictor for nonresponse that can be used to identify patients who will not benefit from bevacizumab combination therapy.https://doi.org/10.1002/1878-0261.12660bevacizumabDNA methylationglioblastomalocal renin–angiotensin systempredictive biomarker |
| spellingShingle | Thomas Urup Linn Gillberg Katja Kaastrup Maya Jeje Schuang Lü Signe Regner Michaelsen Vibeke Andrée Larsen Ib Jarle Christensen Helle Broholm Ulrik Lassen Kirsten Grønbæk Hans Skovgaard Poulsen Angiotensinogen promoter methylation predicts bevacizumab treatment response of patients with recurrent glioblastoma Molecular Oncology bevacizumab DNA methylation glioblastoma local renin–angiotensin system predictive biomarker |
| title | Angiotensinogen promoter methylation predicts bevacizumab treatment response of patients with recurrent glioblastoma |
| title_full | Angiotensinogen promoter methylation predicts bevacizumab treatment response of patients with recurrent glioblastoma |
| title_fullStr | Angiotensinogen promoter methylation predicts bevacizumab treatment response of patients with recurrent glioblastoma |
| title_full_unstemmed | Angiotensinogen promoter methylation predicts bevacizumab treatment response of patients with recurrent glioblastoma |
| title_short | Angiotensinogen promoter methylation predicts bevacizumab treatment response of patients with recurrent glioblastoma |
| title_sort | angiotensinogen promoter methylation predicts bevacizumab treatment response of patients with recurrent glioblastoma |
| topic | bevacizumab DNA methylation glioblastoma local renin–angiotensin system predictive biomarker |
| url | https://doi.org/10.1002/1878-0261.12660 |
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