Candidate methylation sites associated with endocrine therapy resistance in ER+/HER2- breast cancer
Abstract Background Estrogen receptor (ER) positive breast cancer is often effectively treated with drugs that inhibit ER signaling, i.e., tamoxifen (TAM) and aromatase inhibitors (AIs). However, 30% of ER+ breast cancer patients develop resistance to therapy leading to tumour recurrence. Changes in...
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doaj-05e1012ebaf343358c57d489aa9794d12020-11-25T02:40:26ZengBMCBMC Cancer1471-24072020-07-0120111510.1186/s12885-020-07100-zCandidate methylation sites associated with endocrine therapy resistance in ER+/HER2- breast cancerMaryam Soleimani Dodaran0Simone Borgoni1Emre Sofyalı2Pernette J. Verschure3Stefan Wiemann4Perry D. Moerland5Antoine H. C. van Kampen6Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Amsterdam Public Health research institute, Amsterdam UMC, University of AmsterdamDivision of Molecular Genome Analysis, German Cancer Research Center (DKFZ)Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ)Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of AmsterdamDivision of Molecular Genome Analysis, German Cancer Research Center (DKFZ)Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Amsterdam Public Health research institute, Amsterdam UMC, University of AmsterdamBioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Amsterdam Public Health research institute, Amsterdam UMC, University of AmsterdamAbstract Background Estrogen receptor (ER) positive breast cancer is often effectively treated with drugs that inhibit ER signaling, i.e., tamoxifen (TAM) and aromatase inhibitors (AIs). However, 30% of ER+ breast cancer patients develop resistance to therapy leading to tumour recurrence. Changes in the methylation profile have been implicated as one of the mechanisms through which therapy resistance develops. Therefore, we aimed to identify methylation loci associated with endocrine therapy resistance. Methods We used genome-wide DNA methylation profiles of primary ER+/HER2- tumours from The Cancer Genome Atlas in combination with curated data on survival and treatment to predict development of endocrine resistance. Association of individual DNA methylation markers with survival was assessed using Cox proportional hazards models in a cohort of ER+/HER2- tumours (N = 552) and two sub-cohorts corresponding to the endocrine treatment (AI or TAM) that patients received (N = 210 and N = 172, respectively). We also identified multivariable methylation signatures associated with survival using Cox proportional hazards models with elastic net regularization. Individual markers and multivariable signatures were compared with DNA methylation profiles generated in a time course experiment using the T47D ER+ breast cancer cell line treated with tamoxifen or deprived from estrogen. Results We identified 134, 5 and 1 CpGs for which DNA methylation is significantly associated with survival in the ER+/HER2-, TAM and AI cohorts respectively. Multi-locus signatures consisted of 203, 36 and 178 CpGs and showed a large overlap with the corresponding single-locus signatures. The methylation signatures were associated with survival independently of tumour stage, age, AI treatment, and luminal status. The single-locus signature for the TAM cohort was conserved among the loci that were differentially methylated in endocrine-resistant T47D cells. Similarly, multi-locus signatures for the ER+/HER2- and AI cohorts were conserved in endocrine-resistant T47D cells. Also at the gene set level, several sets related to endocrine therapy and resistance were enriched in both survival and T47D signatures. Conclusions We identified individual and multivariable DNA methylation markers associated with therapy resistance independently of luminal status. Our results suggest that these markers identified from primary tumours prior to endocrine treatment are associated with development of endocrine resistance.http://link.springer.com/article/10.1186/s12885-020-07100-zBreast cancerDNA methylationEndocrine therapyResistanceSurvivalT47D |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Maryam Soleimani Dodaran Simone Borgoni Emre Sofyalı Pernette J. Verschure Stefan Wiemann Perry D. Moerland Antoine H. C. van Kampen |
spellingShingle |
Maryam Soleimani Dodaran Simone Borgoni Emre Sofyalı Pernette J. Verschure Stefan Wiemann Perry D. Moerland Antoine H. C. van Kampen Candidate methylation sites associated with endocrine therapy resistance in ER+/HER2- breast cancer BMC Cancer Breast cancer DNA methylation Endocrine therapy Resistance Survival T47D |
author_facet |
Maryam Soleimani Dodaran Simone Borgoni Emre Sofyalı Pernette J. Verschure Stefan Wiemann Perry D. Moerland Antoine H. C. van Kampen |
author_sort |
Maryam Soleimani Dodaran |
title |
Candidate methylation sites associated with endocrine therapy resistance in ER+/HER2- breast cancer |
title_short |
Candidate methylation sites associated with endocrine therapy resistance in ER+/HER2- breast cancer |
title_full |
Candidate methylation sites associated with endocrine therapy resistance in ER+/HER2- breast cancer |
title_fullStr |
Candidate methylation sites associated with endocrine therapy resistance in ER+/HER2- breast cancer |
title_full_unstemmed |
Candidate methylation sites associated with endocrine therapy resistance in ER+/HER2- breast cancer |
title_sort |
candidate methylation sites associated with endocrine therapy resistance in er+/her2- breast cancer |
publisher |
BMC |
series |
BMC Cancer |
issn |
1471-2407 |
publishDate |
2020-07-01 |
description |
Abstract Background Estrogen receptor (ER) positive breast cancer is often effectively treated with drugs that inhibit ER signaling, i.e., tamoxifen (TAM) and aromatase inhibitors (AIs). However, 30% of ER+ breast cancer patients develop resistance to therapy leading to tumour recurrence. Changes in the methylation profile have been implicated as one of the mechanisms through which therapy resistance develops. Therefore, we aimed to identify methylation loci associated with endocrine therapy resistance. Methods We used genome-wide DNA methylation profiles of primary ER+/HER2- tumours from The Cancer Genome Atlas in combination with curated data on survival and treatment to predict development of endocrine resistance. Association of individual DNA methylation markers with survival was assessed using Cox proportional hazards models in a cohort of ER+/HER2- tumours (N = 552) and two sub-cohorts corresponding to the endocrine treatment (AI or TAM) that patients received (N = 210 and N = 172, respectively). We also identified multivariable methylation signatures associated with survival using Cox proportional hazards models with elastic net regularization. Individual markers and multivariable signatures were compared with DNA methylation profiles generated in a time course experiment using the T47D ER+ breast cancer cell line treated with tamoxifen or deprived from estrogen. Results We identified 134, 5 and 1 CpGs for which DNA methylation is significantly associated with survival in the ER+/HER2-, TAM and AI cohorts respectively. Multi-locus signatures consisted of 203, 36 and 178 CpGs and showed a large overlap with the corresponding single-locus signatures. The methylation signatures were associated with survival independently of tumour stage, age, AI treatment, and luminal status. The single-locus signature for the TAM cohort was conserved among the loci that were differentially methylated in endocrine-resistant T47D cells. Similarly, multi-locus signatures for the ER+/HER2- and AI cohorts were conserved in endocrine-resistant T47D cells. Also at the gene set level, several sets related to endocrine therapy and resistance were enriched in both survival and T47D signatures. Conclusions We identified individual and multivariable DNA methylation markers associated with therapy resistance independently of luminal status. Our results suggest that these markers identified from primary tumours prior to endocrine treatment are associated with development of endocrine resistance. |
topic |
Breast cancer DNA methylation Endocrine therapy Resistance Survival T47D |
url |
http://link.springer.com/article/10.1186/s12885-020-07100-z |
work_keys_str_mv |
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