Epigenetic determinants of an immune-evasive phenotype in HER2-low triple-negative breast cancer
Abstract Identifying molecular drivers in triple-negative breast cancer (TNBC) is crucial. While HER2-low expression predicts response to novel antibody-drug conjugates, its biological influence on TNBC biology is unknown. We performed a comprehensive multi-omics analysis, integrating genomic, epige...
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| Format: | Article |
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Nature Portfolio
2025-08-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-025-01023-3 |
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| author | Andrés F. Bedoya-López Sookyung Ahn Miquel Ensenyat-Mendez Javier I. J. Orozco Sandra Iñiguez-Muñoz Pere Llinàs-Arias Samantha M. Thomas Jennifer L. Baker Peggy S. Sullivan Jitin Makker Julie B. Steele Sunil M. Kurian Diego M. Marzese Maggie L. DiNome |
| author_facet | Andrés F. Bedoya-López Sookyung Ahn Miquel Ensenyat-Mendez Javier I. J. Orozco Sandra Iñiguez-Muñoz Pere Llinàs-Arias Samantha M. Thomas Jennifer L. Baker Peggy S. Sullivan Jitin Makker Julie B. Steele Sunil M. Kurian Diego M. Marzese Maggie L. DiNome |
| author_sort | Andrés F. Bedoya-López |
| collection | DOAJ |
| description | Abstract Identifying molecular drivers in triple-negative breast cancer (TNBC) is crucial. While HER2-low expression predicts response to novel antibody-drug conjugates, its biological influence on TNBC biology is unknown. We performed a comprehensive multi-omics analysis, integrating genomic, epigenomic, transcriptomic, and proteomic profiling to characterize HER2-low TNBC. We generated genome-wide DNA methylation profiles from a multi-institutional cohort and integrated our data with three independent cohorts (TCGA, SCAN-B, I-SPY2). TNBC cases were categorized as HER2-zero (IHC 0) or HER2-low TNBC (IHC 1+/2+, ISH non-amplified). Among 506 patients (HER2-low, n = 288; HER2-zero, n = 218), HER2-low TNBC exhibited significantly lower tumor mutational burden (P = 0.02). Epigenetic analysis identified 5287 differentially methylated sites, with consistent hypermethylation of HLA genes in HER2-low tumors. Transcriptomic analyses revealed significant downregulation of genes enriched in immune response pathways (e.g., leukocyte activation, T-cell signaling) in HER2-low TNBC (adjusted P < 0.001). Immune cell deconvolution showed reduced immune cell infiltration in the HER2-low tumor microenvironment (P = 0.002). Higher expression of five immune-related genes, downregulated in HER2-low, correlated with improved relapse-free (HR = 0.52; P < 0.001) and overall survival (HR = 0.36; P < 0.001). HER2-low TNBC tumors display distinct molecular features compared to HER2-zero, imparting an immune-evasive phenotype. These findings provide critical insights into the unique biology of HER2-low TNBC, warranting further clinical investigation. |
| format | Article |
| id | doaj-art-40d6e8a2add1475b8000e46b73a35d24 |
| institution | DOAJ |
| issn | 2397-768X |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj-art-40d6e8a2add1475b8000e46b73a35d242025-08-20T03:07:20ZengNature Portfolionpj Precision Oncology2397-768X2025-08-019111210.1038/s41698-025-01023-3Epigenetic determinants of an immune-evasive phenotype in HER2-low triple-negative breast cancerAndrés F. Bedoya-López0Sookyung Ahn1Miquel Ensenyat-Mendez2Javier I. J. Orozco3Sandra Iñiguez-Muñoz4Pere Llinàs-Arias5Samantha M. Thomas6Jennifer L. Baker7Peggy S. Sullivan8Jitin Makker9Julie B. Steele10Sunil M. Kurian11Diego M. Marzese12Maggie L. DiNome13Cancer Epigenetics Laboratory, Health Research Institute of the Balearic Islands (IdISBa)Department of Surgery, Duke University School of MedicineDepartment of Surgery, Duke University School of MedicineSaint John’s Cancer Institute, Providence Saint John’s Health CenterCancer Epigenetics Laboratory, Health Research Institute of the Balearic Islands (IdISBa)Cancer Epigenetics Laboratory, Health Research Institute of the Balearic Islands (IdISBa)Department of Biostatistics & Bioinformatics, Duke University School of MedicineDepartment of Surgery, University of California Los AngelesDepartment of Pathology and Laboratory Medicine, University of California Los AngelesDepartment of Pathology and Laboratory Medicine, University of California Los AngelesDepartment of Pathology and Laboratory Medicine, Scripps Clinic Medical GroupScripps Clinic Biorepository and BioinformaticsCancer Epigenetics Laboratory, Health Research Institute of the Balearic Islands (IdISBa)Department of Surgery, Duke University School of MedicineAbstract Identifying molecular drivers in triple-negative breast cancer (TNBC) is crucial. While HER2-low expression predicts response to novel antibody-drug conjugates, its biological influence on TNBC biology is unknown. We performed a comprehensive multi-omics analysis, integrating genomic, epigenomic, transcriptomic, and proteomic profiling to characterize HER2-low TNBC. We generated genome-wide DNA methylation profiles from a multi-institutional cohort and integrated our data with three independent cohorts (TCGA, SCAN-B, I-SPY2). TNBC cases were categorized as HER2-zero (IHC 0) or HER2-low TNBC (IHC 1+/2+, ISH non-amplified). Among 506 patients (HER2-low, n = 288; HER2-zero, n = 218), HER2-low TNBC exhibited significantly lower tumor mutational burden (P = 0.02). Epigenetic analysis identified 5287 differentially methylated sites, with consistent hypermethylation of HLA genes in HER2-low tumors. Transcriptomic analyses revealed significant downregulation of genes enriched in immune response pathways (e.g., leukocyte activation, T-cell signaling) in HER2-low TNBC (adjusted P < 0.001). Immune cell deconvolution showed reduced immune cell infiltration in the HER2-low tumor microenvironment (P = 0.002). Higher expression of five immune-related genes, downregulated in HER2-low, correlated with improved relapse-free (HR = 0.52; P < 0.001) and overall survival (HR = 0.36; P < 0.001). HER2-low TNBC tumors display distinct molecular features compared to HER2-zero, imparting an immune-evasive phenotype. These findings provide critical insights into the unique biology of HER2-low TNBC, warranting further clinical investigation.https://doi.org/10.1038/s41698-025-01023-3 |
| spellingShingle | Andrés F. Bedoya-López Sookyung Ahn Miquel Ensenyat-Mendez Javier I. J. Orozco Sandra Iñiguez-Muñoz Pere Llinàs-Arias Samantha M. Thomas Jennifer L. Baker Peggy S. Sullivan Jitin Makker Julie B. Steele Sunil M. Kurian Diego M. Marzese Maggie L. DiNome Epigenetic determinants of an immune-evasive phenotype in HER2-low triple-negative breast cancer npj Precision Oncology |
| title | Epigenetic determinants of an immune-evasive phenotype in HER2-low triple-negative breast cancer |
| title_full | Epigenetic determinants of an immune-evasive phenotype in HER2-low triple-negative breast cancer |
| title_fullStr | Epigenetic determinants of an immune-evasive phenotype in HER2-low triple-negative breast cancer |
| title_full_unstemmed | Epigenetic determinants of an immune-evasive phenotype in HER2-low triple-negative breast cancer |
| title_short | Epigenetic determinants of an immune-evasive phenotype in HER2-low triple-negative breast cancer |
| title_sort | epigenetic determinants of an immune evasive phenotype in her2 low triple negative breast cancer |
| url | https://doi.org/10.1038/s41698-025-01023-3 |
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