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An integrated omics...
An integrated omics approach highlights how epigenetic events can explain and predict response to neoadjuvant chemotherapy and bevacizumab in breast cancer
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- Fleischer, Thomas (författare)
- Oslo university hospital
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- Haugen, Mads Haugland (författare)
- Oslo university hospital
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- Ankill, Jørgen (författare)
- Oslo university hospital
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- Silwal-Pandit, Laxmi (författare)
- Oslo university hospital
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- Børresen-Dale, Anne Lise (författare)
- Oslo university hospital,University of Oslo
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- Hedenfalk, Ingrid (författare)
- Lund University,Lunds universitet,Bröst- och ovarialcancer,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Bröst/ovarialcancer,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Breast and Ovarian Cancer Genomics,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Breast/ovarian cancer,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine
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- Hatschek, Thomas (författare)
- Karolinska Institute,Karolinska University Hospital
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- Tost, Jörg (författare)
- CEA National Genotyping Center (CNG)
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- Engebraaten, Olav (författare)
- University of Oslo,Oslo university hospital
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- Kristensen, Vessela N. (författare)
- Oslo university hospital,University of Oslo
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(creator_code:org_t)
- 2024
- 2024
- Engelska.
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Ingår i: Molecular Oncology. - 1574-7891 .- 1878-0261.
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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http://kipublication...
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Abstract
Ämnesord
Stäng
- Treatment with the anti-angiogenic drug bevacizumab in addition to chemotherapy has shown efficacy for breast cancer in some clinical trials, but better biomarkers are needed to optimally select patients for treatment. Here, we present an omics approach where DNA methylation profiles are integrated with gene expression and results from proteomic data in breast cancer patients to predict response to therapy and pinpoint response-related epigenetic events. Fresh-frozen tumor biopsies taken before, during, and after treatment from human epidermal growth factor receptor 2 negative non-metastatic patients receiving neoadjuvant chemotherapy with or without bevacizumab were subjected to molecular profiling. Here, we report that DNA methylation at enhancer CpGs related to cell cycle regulation can predict response to chemotherapy and bevacizumab for the estrogen receptor positive subset of patients (AUC = 0.874), and we validated this observation in an independent patient cohort with a similar treatment regimen (AUC = 0.762). Combining the DNA methylation scores with the scores from a previously published protein signature resulted in a slight increase in the prediction performance (AUC = 0.784). We also show that tumors receiving the combination treatment underwent more extensive epigenetic alterations. Finally, we performed an integrative expression–methylation quantitative trait loci analysis on alterations in DNA methylation and gene expression levels, showing that the epigenetic alterations that occur during treatment are different between responders and non-responders and that these differences may be explained by the proliferation–epithelial-to-mesenchymal transition axis through the activity of grainyhead like transcription factor 2. Using tumor purity computed from copy number data, we developed a method for estimating cancer cell-specific methylation to confirm that the association to response reflects DNA methylation in cancer cells. Taken together, these results support the potential for clinical benefit of the addition of bevacizumab to chemotherapy when administered to the correct patients.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- bevacizumab
- breast cancer
- chemotherapy
- DNA methylation
- epigenetics
- multiomics
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Fleischer, Thoma ...
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Haugen, Mads Hau ...
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Ankill, Jørgen
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Silwal-Pandit, L ...
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Børresen-Dale, A ...
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Hedenfalk, Ingri ...
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visa fler...
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Hatschek, Thomas
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Tost, Jörg
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Engebraaten, Ola ...
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Kristensen, Vess ...
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