Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER Signaling
Mutations in the estrogen receptor gene (<i>ESR1</i>), its transcriptional regulators, and the mitogen-activated protein kinase (MAPK) pathway are enriched in patients with endocrine-resistant metastatic breast cancer (MBC). Here, we integrated whole genome sequencing with RNA sequencing...
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MDPI AG
2023-09-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/15/17/4416 |
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| author | Lindsay Angus Marcel Smid Saskia M. Wilting Manouk K. Bos Neeltje Steeghs Inge R. H. M. Konings Vivianne C. G. Tjan-Heijnen Johanna M. G. H. van Riel Agnes J. van de Wouw CPCT Consortium Edwin Cuppen Martijn P. Lolkema Agnes Jager Stefan Sleijfer John W. M. Martens |
| author_facet | Lindsay Angus Marcel Smid Saskia M. Wilting Manouk K. Bos Neeltje Steeghs Inge R. H. M. Konings Vivianne C. G. Tjan-Heijnen Johanna M. G. H. van Riel Agnes J. van de Wouw CPCT Consortium Edwin Cuppen Martijn P. Lolkema Agnes Jager Stefan Sleijfer John W. M. Martens |
| author_sort | Lindsay Angus |
| collection | DOAJ |
| description | Mutations in the estrogen receptor gene (<i>ESR1</i>), its transcriptional regulators, and the mitogen-activated protein kinase (MAPK) pathway are enriched in patients with endocrine-resistant metastatic breast cancer (MBC). Here, we integrated whole genome sequencing with RNA sequencing data from the same samples of 101 ER-positive/HER2-negative MBC patients who underwent a tumor biopsy prior to the start of a new line of treatment for MBC (CPCT-02 study, NCT01855477) to analyze the downstream effects of DNA alterations previously linked to endocrine resistance, thereby gaining a better understanding of the associated mechanisms. Hierarchical clustering was performed using expression of <i>ESR1</i> target genes. Genomic alterations at the DNA level, gene expression levels, and last administered therapy were compared between the identified clusters. Hierarchical clustering revealed two distinct clusters, one of which was characterized by increased expression of <i>ESR1</i> and its target genes. Samples in this cluster were significantly enriched for mutations in <i>ESR1</i> and amplifications in <i>FGFR1</i> and <i>TSPYL.</i> Patients in the other cluster showed relatively lower expression levels of <i>ESR1</i> and its target genes, comparable to ER-negative samples, and more often received endocrine therapy as their last treatment before biopsy. Genes in the MAPK-pathway, including <i>NF1</i>, and <i>ESR1</i> transcriptional regulators were evenly distributed. In conclusion, RNA sequencing identified a subgroup of patients with clear expression of <i>ESR1</i> and its downstream targets, probably still benefiting from ER-targeting agents. The lower ER expression in the other subgroup might be partially explained by ER activity still being blocked by recently administered endocrine treatment, indicating that biopsy timing relative to endocrine treatment needs to be considered when interpreting transcriptomic data. |
| first_indexed | 2024-03-10T23:25:22Z |
| format | Article |
| id | doaj.art-20cce45044e24c7984aa2046e7d671d0 |
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| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T23:25:22Z |
| publishDate | 2023-09-01 |
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| series | Cancers |
| spelling | doaj.art-20cce45044e24c7984aa2046e7d671d02023-11-19T07:57:27ZengMDPI AGCancers2072-66942023-09-011517441610.3390/cancers15174416Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER SignalingLindsay Angus0Marcel Smid1Saskia M. Wilting2Manouk K. Bos3Neeltje Steeghs4Inge R. H. M. Konings5Vivianne C. G. Tjan-Heijnen6Johanna M. G. H. van Riel7Agnes J. van de Wouw8CPCT Consortium9Edwin Cuppen10Martijn P. Lolkema11Agnes Jager12Stefan Sleijfer13John W. M. Martens14Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Cancer, Dr. Molewaterplein 40, 3015 GD Rotterdam, The NetherlandsDepartment of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Cancer, Dr. Molewaterplein 40, 3015 GD Rotterdam, The NetherlandsDepartment of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Cancer, Dr. Molewaterplein 40, 3015 GD Rotterdam, The NetherlandsDepartment of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Cancer, Dr. Molewaterplein 40, 3015 GD Rotterdam, The NetherlandsDepartment of Medical Oncology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The NetherlandsDepartment of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The NetherlandsCenter for Personalized Cancer Treatment, 6500 HB Nijmegen, The NetherlandsDepartment of Internal Medicine, Elisabeth-TweeSteden Hospital, 5022 GC Tilburg, The NetherlandsDepartment of Medical Oncology, VieCuri Medical Center, 5912 BL Venlo, The NetherlandsCenter for Personalized Cancer Treatment, 6500 HB Nijmegen, The NetherlandsCenter for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, 3584 CX Utrecht, The NetherlandsDepartment of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Cancer, Dr. Molewaterplein 40, 3015 GD Rotterdam, The NetherlandsDepartment of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Cancer, Dr. Molewaterplein 40, 3015 GD Rotterdam, The NetherlandsDepartment of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Cancer, Dr. Molewaterplein 40, 3015 GD Rotterdam, The NetherlandsDepartment of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Cancer, Dr. Molewaterplein 40, 3015 GD Rotterdam, The NetherlandsMutations in the estrogen receptor gene (<i>ESR1</i>), its transcriptional regulators, and the mitogen-activated protein kinase (MAPK) pathway are enriched in patients with endocrine-resistant metastatic breast cancer (MBC). Here, we integrated whole genome sequencing with RNA sequencing data from the same samples of 101 ER-positive/HER2-negative MBC patients who underwent a tumor biopsy prior to the start of a new line of treatment for MBC (CPCT-02 study, NCT01855477) to analyze the downstream effects of DNA alterations previously linked to endocrine resistance, thereby gaining a better understanding of the associated mechanisms. Hierarchical clustering was performed using expression of <i>ESR1</i> target genes. Genomic alterations at the DNA level, gene expression levels, and last administered therapy were compared between the identified clusters. Hierarchical clustering revealed two distinct clusters, one of which was characterized by increased expression of <i>ESR1</i> and its target genes. Samples in this cluster were significantly enriched for mutations in <i>ESR1</i> and amplifications in <i>FGFR1</i> and <i>TSPYL.</i> Patients in the other cluster showed relatively lower expression levels of <i>ESR1</i> and its target genes, comparable to ER-negative samples, and more often received endocrine therapy as their last treatment before biopsy. Genes in the MAPK-pathway, including <i>NF1</i>, and <i>ESR1</i> transcriptional regulators were evenly distributed. In conclusion, RNA sequencing identified a subgroup of patients with clear expression of <i>ESR1</i> and its downstream targets, probably still benefiting from ER-targeting agents. The lower ER expression in the other subgroup might be partially explained by ER activity still being blocked by recently administered endocrine treatment, indicating that biopsy timing relative to endocrine treatment needs to be considered when interpreting transcriptomic data.https://www.mdpi.com/2072-6694/15/17/4416breast cancerwhole genome sequencingRNA sequencingendocrine resistance |
| spellingShingle | Lindsay Angus Marcel Smid Saskia M. Wilting Manouk K. Bos Neeltje Steeghs Inge R. H. M. Konings Vivianne C. G. Tjan-Heijnen Johanna M. G. H. van Riel Agnes J. van de Wouw CPCT Consortium Edwin Cuppen Martijn P. Lolkema Agnes Jager Stefan Sleijfer John W. M. Martens Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER Signaling Cancers breast cancer whole genome sequencing RNA sequencing endocrine resistance |
| title | Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER Signaling |
| title_full | Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER Signaling |
| title_fullStr | Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER Signaling |
| title_full_unstemmed | Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER Signaling |
| title_short | Genomic Alterations Associated with Estrogen Receptor Pathway Activity in Metastatic Breast Cancer Have a Differential Impact on Downstream ER Signaling |
| title_sort | genomic alterations associated with estrogen receptor pathway activity in metastatic breast cancer have a differential impact on downstream er signaling |
| topic | breast cancer whole genome sequencing RNA sequencing endocrine resistance |
| url | https://www.mdpi.com/2072-6694/15/17/4416 |
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