Genomic characterization of the HER2-enriched intrinsic molecular subtype in primary ER-positive HER2-negative breast cancer
Abstract ER-positive/HER2-negative (ERpHER2n) breast cancer classified as PAM50 HER2-enriched (ERpHER2n-HER2E) represents a small high-risk patient subgroup. In this study, we investigate genomic, transcriptomic, and clinical features of ERpHER2n-HER2E breast tumors using two primary ERpHER2n cohort...
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Nature Portfolio
2025-03-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57419-z |
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| author | Lennart Hohmann Kristin Sigurjonsdottir Ana Bosch Campos Deborah F. Nacer Srinivas Veerla Frida Rosengren Poojaswini Thimmaraya Reddy Jari Häkkinen Nicklas Nordborg Johan Vallon-Christersson Yasin Memari Daniella Black Ramsay Bowden Helen R. Davies Åke Borg Serena Nik-Zainal Johan Staaf |
| author_facet | Lennart Hohmann Kristin Sigurjonsdottir Ana Bosch Campos Deborah F. Nacer Srinivas Veerla Frida Rosengren Poojaswini Thimmaraya Reddy Jari Häkkinen Nicklas Nordborg Johan Vallon-Christersson Yasin Memari Daniella Black Ramsay Bowden Helen R. Davies Åke Borg Serena Nik-Zainal Johan Staaf |
| author_sort | Lennart Hohmann |
| collection | DOAJ |
| description | Abstract ER-positive/HER2-negative (ERpHER2n) breast cancer classified as PAM50 HER2-enriched (ERpHER2n-HER2E) represents a small high-risk patient subgroup. In this study, we investigate genomic, transcriptomic, and clinical features of ERpHER2n-HER2E breast tumors using two primary ERpHER2n cohorts comprising a total of 5640 patients. We show that ERpHER2n-HER2E tumors exhibit aggressive clinical features and poorer clinical outcomes compared to Luminal A and Luminal B tumors. Furthermore, ERpHER2n-HER2E breast cancer does not consist of misclassified or HER2-low cases, has little impact of ERBB2, is highly proliferative and less ER dependent than other luminal subtypes. It is not an obvious biological entity but is nevertheless associated with potentially targetable molecular features, notably a high immune response and high FGFR4 expression. Strikingly, molecular features that define the HER2E subtype in luminal disease are also consistent in HER2-positive disease, including an epigenetic mechanism for high FGFR4 expression in breast cancer. |
| format | Article |
| id | doaj-art-c15ba9a90b574a5fae4010c3ed404c4e |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-c15ba9a90b574a5fae4010c3ed404c4e2025-08-20T03:05:43ZengNature PortfolioNature Communications2041-17232025-03-0116111710.1038/s41467-025-57419-zGenomic characterization of the HER2-enriched intrinsic molecular subtype in primary ER-positive HER2-negative breast cancerLennart Hohmann0Kristin Sigurjonsdottir1Ana Bosch Campos2Deborah F. Nacer3Srinivas Veerla4Frida Rosengren5Poojaswini Thimmaraya Reddy6Jari Häkkinen7Nicklas Nordborg8Johan Vallon-Christersson9Yasin Memari10Daniella Black11Ramsay Bowden12Helen R. Davies13Åke Borg14Serena Nik-Zainal15Johan Staaf16Division of Oncology, Department of Clinical Sciences Lund, Lund UniversityDivision of Oncology, Department of Clinical Sciences Lund, Lund UniversityDivision of Oncology, Department of Clinical Sciences Lund, Lund UniversityDivision of Oncology, Department of Clinical Sciences Lund, Lund UniversityDivision of Oncology, Department of Clinical Sciences Lund, Lund UniversityDivision of Oncology, Department of Clinical Sciences Lund, Lund UniversityDivision of Translational Cancer Research, Department of Laboratory Medicine, Lund UniversityDivision of Oncology, Department of Clinical Sciences Lund, Lund UniversityDivision of Oncology, Department of Clinical Sciences Lund, Lund UniversityDivision of Oncology, Department of Clinical Sciences Lund, Lund UniversityAcademic Department of Medical Genetics, School of Clinical Medicine & Early Cancer Institute, University of CambridgeAcademic Department of Medical Genetics, School of Clinical Medicine & Early Cancer Institute, University of CambridgeAcademic Department of Medical Genetics, School of Clinical Medicine & Early Cancer Institute, University of CambridgeAcademic Department of Medical Genetics, School of Clinical Medicine & Early Cancer Institute, University of CambridgeDivision of Oncology, Department of Clinical Sciences Lund, Lund UniversityAcademic Department of Medical Genetics, School of Clinical Medicine & Early Cancer Institute, University of CambridgeDivision of Oncology, Department of Clinical Sciences Lund, Lund UniversityAbstract ER-positive/HER2-negative (ERpHER2n) breast cancer classified as PAM50 HER2-enriched (ERpHER2n-HER2E) represents a small high-risk patient subgroup. In this study, we investigate genomic, transcriptomic, and clinical features of ERpHER2n-HER2E breast tumors using two primary ERpHER2n cohorts comprising a total of 5640 patients. We show that ERpHER2n-HER2E tumors exhibit aggressive clinical features and poorer clinical outcomes compared to Luminal A and Luminal B tumors. Furthermore, ERpHER2n-HER2E breast cancer does not consist of misclassified or HER2-low cases, has little impact of ERBB2, is highly proliferative and less ER dependent than other luminal subtypes. It is not an obvious biological entity but is nevertheless associated with potentially targetable molecular features, notably a high immune response and high FGFR4 expression. Strikingly, molecular features that define the HER2E subtype in luminal disease are also consistent in HER2-positive disease, including an epigenetic mechanism for high FGFR4 expression in breast cancer.https://doi.org/10.1038/s41467-025-57419-z |
| spellingShingle | Lennart Hohmann Kristin Sigurjonsdottir Ana Bosch Campos Deborah F. Nacer Srinivas Veerla Frida Rosengren Poojaswini Thimmaraya Reddy Jari Häkkinen Nicklas Nordborg Johan Vallon-Christersson Yasin Memari Daniella Black Ramsay Bowden Helen R. Davies Åke Borg Serena Nik-Zainal Johan Staaf Genomic characterization of the HER2-enriched intrinsic molecular subtype in primary ER-positive HER2-negative breast cancer Nature Communications |
| title | Genomic characterization of the HER2-enriched intrinsic molecular subtype in primary ER-positive HER2-negative breast cancer |
| title_full | Genomic characterization of the HER2-enriched intrinsic molecular subtype in primary ER-positive HER2-negative breast cancer |
| title_fullStr | Genomic characterization of the HER2-enriched intrinsic molecular subtype in primary ER-positive HER2-negative breast cancer |
| title_full_unstemmed | Genomic characterization of the HER2-enriched intrinsic molecular subtype in primary ER-positive HER2-negative breast cancer |
| title_short | Genomic characterization of the HER2-enriched intrinsic molecular subtype in primary ER-positive HER2-negative breast cancer |
| title_sort | genomic characterization of the her2 enriched intrinsic molecular subtype in primary er positive her2 negative breast cancer |
| url | https://doi.org/10.1038/s41467-025-57419-z |
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