DNA methylation changes in response to neoadjuvant chemotherapy are associated with breast cancer survival
Abstract Background Locally advanced breast cancer is a heterogeneous disease with respect to response to neoadjuvant chemotherapy (NACT) and survival. It is currently not possible to accurately predict who will benefit from the specific types of NACT. DNA methylation is an epigenetic mechanism know...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-06-01
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| Series: | Breast Cancer Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13058-022-01537-9 |
| _version_ | 1811235652834951168 |
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| author | Christine Aaserød Pedersen Maria Dung Cao Thomas Fleischer Morten B. Rye Stian Knappskog Hans Petter Eikesdal Per Eystein Lønning Jörg Tost Vessela N. Kristensen May-Britt Tessem Guro F. Giskeødegård Tone F. Bathen |
| author_facet | Christine Aaserød Pedersen Maria Dung Cao Thomas Fleischer Morten B. Rye Stian Knappskog Hans Petter Eikesdal Per Eystein Lønning Jörg Tost Vessela N. Kristensen May-Britt Tessem Guro F. Giskeødegård Tone F. Bathen |
| author_sort | Christine Aaserød Pedersen |
| collection | DOAJ |
| description | Abstract Background Locally advanced breast cancer is a heterogeneous disease with respect to response to neoadjuvant chemotherapy (NACT) and survival. It is currently not possible to accurately predict who will benefit from the specific types of NACT. DNA methylation is an epigenetic mechanism known to play an important role in regulating gene expression and may serve as a biomarker for treatment response and survival. We investigated the potential role of DNA methylation as a prognostic marker for long-term survival (> 5 years) after NACT in breast cancer. Methods DNA methylation profiles of pre-treatment (n = 55) and post-treatment (n = 75) biopsies from 83 women with locally advanced breast cancer were investigated using the Illumina HumanMethylation450 BeadChip. The patients received neoadjuvant treatment with epirubicin and/or paclitaxel. Linear mixed models were used to associate DNA methylation to treatment response and survival based on clinical response to NACT (partial response or stable disease) and 5-year survival, respectively. LASSO regression was performed to identify a risk score based on the statistically significant methylation sites and Kaplan–Meier curve analysis was used to estimate survival probabilities using ten years of survival follow-up data. The risk score developed in our discovery cohort was validated in an independent validation cohort consisting of paired pre-treatment and post-treatment biopsies from 85 women with locally advanced breast cancer. Patients included in the validation cohort were treated with either doxorubicin or 5-FU and mitomycin NACT. Results DNA methylation patterns changed from before to after NACT in 5-year survivors, while no significant changes were observed in non-survivors or related to treatment response. DNA methylation changes included an overall loss of methylation at CpG islands and gain of methylation in non-CpG islands, and these changes affected genes linked to transcription factor activity, cell adhesion and immune functions. A risk score was developed based on four methylation sites which successfully predicted long-term survival in our cohort (p = 0.0034) and in an independent validation cohort (p = 0.049). Conclusion Our results demonstrate that DNA methylation patterns in breast tumors change in response to NACT. These changes in DNA methylation show potential as prognostic biomarkers for breast cancer survival. |
| first_indexed | 2024-04-12T11:55:38Z |
| format | Article |
| id | doaj.art-1e0f5801a9e14e8d979b6ce43580972f |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-04-12T11:55:38Z |
| publishDate | 2022-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-1e0f5801a9e14e8d979b6ce43580972f2022-12-22T03:34:01ZengBMCBreast Cancer Research1465-542X2022-06-0124111410.1186/s13058-022-01537-9DNA methylation changes in response to neoadjuvant chemotherapy are associated with breast cancer survivalChristine Aaserød Pedersen0Maria Dung Cao1Thomas Fleischer2Morten B. Rye3Stian Knappskog4Hans Petter Eikesdal5Per Eystein Lønning6Jörg Tost7Vessela N. Kristensen8May-Britt Tessem9Guro F. Giskeødegård10Tone F. Bathen11Department of Circulation and Medical Imaging, NTNU - Norwegian University of Science and TechnologyDepartment of Circulation and Medical Imaging, NTNU - Norwegian University of Science and TechnologyDepartment of Cancer Genetics, Institute for Cancer Research, Oslo University HospitalClinic of Surgery, St. Olavs Hospital, Trondheim University HospitalK.G. Jebsen Centre for Genome-Directed Cancer Therapy, Department of Clinical Science, University of BergenK.G. Jebsen Centre for Genome-Directed Cancer Therapy, Department of Clinical Science, University of BergenK.G. Jebsen Centre for Genome-Directed Cancer Therapy, Department of Clinical Science, University of BergenLaboratory for Epigenetics and Environment, Centre National de Recherche en Génomique Humaine, CEA – Institut de Biologie François Jacob, Université Paris SaclayDepartment of Medical Genetics, Institute of Clinical Medicine, Oslo University HospitalDepartment of Circulation and Medical Imaging, NTNU - Norwegian University of Science and TechnologyClinic of Surgery, St. Olavs Hospital, Trondheim University HospitalDepartment of Circulation and Medical Imaging, NTNU - Norwegian University of Science and TechnologyAbstract Background Locally advanced breast cancer is a heterogeneous disease with respect to response to neoadjuvant chemotherapy (NACT) and survival. It is currently not possible to accurately predict who will benefit from the specific types of NACT. DNA methylation is an epigenetic mechanism known to play an important role in regulating gene expression and may serve as a biomarker for treatment response and survival. We investigated the potential role of DNA methylation as a prognostic marker for long-term survival (> 5 years) after NACT in breast cancer. Methods DNA methylation profiles of pre-treatment (n = 55) and post-treatment (n = 75) biopsies from 83 women with locally advanced breast cancer were investigated using the Illumina HumanMethylation450 BeadChip. The patients received neoadjuvant treatment with epirubicin and/or paclitaxel. Linear mixed models were used to associate DNA methylation to treatment response and survival based on clinical response to NACT (partial response or stable disease) and 5-year survival, respectively. LASSO regression was performed to identify a risk score based on the statistically significant methylation sites and Kaplan–Meier curve analysis was used to estimate survival probabilities using ten years of survival follow-up data. The risk score developed in our discovery cohort was validated in an independent validation cohort consisting of paired pre-treatment and post-treatment biopsies from 85 women with locally advanced breast cancer. Patients included in the validation cohort were treated with either doxorubicin or 5-FU and mitomycin NACT. Results DNA methylation patterns changed from before to after NACT in 5-year survivors, while no significant changes were observed in non-survivors or related to treatment response. DNA methylation changes included an overall loss of methylation at CpG islands and gain of methylation in non-CpG islands, and these changes affected genes linked to transcription factor activity, cell adhesion and immune functions. A risk score was developed based on four methylation sites which successfully predicted long-term survival in our cohort (p = 0.0034) and in an independent validation cohort (p = 0.049). Conclusion Our results demonstrate that DNA methylation patterns in breast tumors change in response to NACT. These changes in DNA methylation show potential as prognostic biomarkers for breast cancer survival.https://doi.org/10.1186/s13058-022-01537-9DNA methylationLocally advanced breast cancerSurvivalTreatment responseBreast cancerNeoadjuvant chemotherapy |
| spellingShingle | Christine Aaserød Pedersen Maria Dung Cao Thomas Fleischer Morten B. Rye Stian Knappskog Hans Petter Eikesdal Per Eystein Lønning Jörg Tost Vessela N. Kristensen May-Britt Tessem Guro F. Giskeødegård Tone F. Bathen DNA methylation changes in response to neoadjuvant chemotherapy are associated with breast cancer survival Breast Cancer Research DNA methylation Locally advanced breast cancer Survival Treatment response Breast cancer Neoadjuvant chemotherapy |
| title | DNA methylation changes in response to neoadjuvant chemotherapy are associated with breast cancer survival |
| title_full | DNA methylation changes in response to neoadjuvant chemotherapy are associated with breast cancer survival |
| title_fullStr | DNA methylation changes in response to neoadjuvant chemotherapy are associated with breast cancer survival |
| title_full_unstemmed | DNA methylation changes in response to neoadjuvant chemotherapy are associated with breast cancer survival |
| title_short | DNA methylation changes in response to neoadjuvant chemotherapy are associated with breast cancer survival |
| title_sort | dna methylation changes in response to neoadjuvant chemotherapy are associated with breast cancer survival |
| topic | DNA methylation Locally advanced breast cancer Survival Treatment response Breast cancer Neoadjuvant chemotherapy |
| url | https://doi.org/10.1186/s13058-022-01537-9 |
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