ERBB2/HOXB13 co-amplification with interstitial loss of BRCA1 defines a unique subset of breast cancers
Abstract Background The HOXB13/IL17RB gene expression biomarker has been shown to predict response to adjuvant and extended endocrine therapy in patients with early-stage ER+ HER2- breast tumors. HOXB13 gene expression is the primary determinant driving the prognostic and endocrine treatment-predict...
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| Format: | Article |
| Language: | English |
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BMC
2024-12-01
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| Series: | Breast Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13058-024-01943-1 |
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| author | Irene Rin Mitsiades Maristela Onozato A. John Iafrate Daniel Hicks Doğa C. Gülhan Dennis C. Sgroi Esther Rheinbay |
| author_facet | Irene Rin Mitsiades Maristela Onozato A. John Iafrate Daniel Hicks Doğa C. Gülhan Dennis C. Sgroi Esther Rheinbay |
| author_sort | Irene Rin Mitsiades |
| collection | DOAJ |
| description | Abstract Background The HOXB13/IL17RB gene expression biomarker has been shown to predict response to adjuvant and extended endocrine therapy in patients with early-stage ER+ HER2- breast tumors. HOXB13 gene expression is the primary determinant driving the prognostic and endocrine treatment-predictive performance of the biomarker. Currently, there is limited data on HOXB13 expression in HER2+ and ER- breast cancers. Herein, we studied the expression of HOXB13 in large cohorts of HER2+ and ER- breast cancers. Methods We investigated gene expression, genomic copy number, mutational signatures, and clinical outcome data in the TGGA and METABRIC breast cancer cohorts. Genomic-based gene amplification data was validated with tri-colored fluorescence in situ hybridization. Results In the TCGA breast cancer cohort, HOXB13 gene expression was significantly higher in HER2+ versus HER2- breast cancers, and its expression was also significantly higher in the ER- versus ER+ breast cancers. HOXB13 is frequently co-gained or co-amplified with ERBB2. Joint copy gains of HOXB13 and ERBB2 occurred with low-level co-gains or high-level co-amplifications (co-amp), the latter of which is associated with an interstitial loss that includes the tumor suppressor BRCA1. ERBB2/HOXB13 co-amp tumors with interstitial BRCA1 loss exhibit a mutational signature associated with APOBEC deaminase activity and copy number signatures associated with chromothripsis and genomic instability. Among ERBB2-amplified tumors of different tissue origins, ERBB2/HOXB13 co-amp with a BRCA1 loss appeared to be enriched in breast cancer compared to other tumor types. Lastly, patients with ERBB2/HOXB13 co-amplified and BRCA1 lost tumors displayed a significantly shorter progression-free survival (PFS) than those with ERBB2-only amplifications. The difference in PFS was restricted to the ER- subset patients and this difference in PFS was not solely driven by HOXB13 gene expression. Conclusions HOXB13 is frequently co-gained with ERBB2 at both low-copy number level or as complex high-level amplification with relative BRCA1 loss. ERBB2/HOXB13 amplified, BRCA1-lost tumors are strongly enriched in breast cancer, and patients with such breast tumors experience a shortened PFS. |
| format | Article |
| id | doaj-art-91e44c3be2884b2c93e1252eb7d6e821 |
| institution | Kabale University |
| issn | 1465-542X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj-art-91e44c3be2884b2c93e1252eb7d6e8212024-12-22T12:56:51ZengBMCBreast Cancer Research1465-542X2024-12-0126111510.1186/s13058-024-01943-1ERBB2/HOXB13 co-amplification with interstitial loss of BRCA1 defines a unique subset of breast cancersIrene Rin Mitsiades0Maristela Onozato1A. John Iafrate2Daniel Hicks3Doğa C. Gülhan4Dennis C. Sgroi5Esther Rheinbay6Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer CenterVertex Pharmaceuticals, Preclinical Safety Assessment, PathologyKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer CenterKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer CenterKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer CenterKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer CenterKrantz Family Center for Cancer Research, Massachusetts General Hospital Cancer CenterAbstract Background The HOXB13/IL17RB gene expression biomarker has been shown to predict response to adjuvant and extended endocrine therapy in patients with early-stage ER+ HER2- breast tumors. HOXB13 gene expression is the primary determinant driving the prognostic and endocrine treatment-predictive performance of the biomarker. Currently, there is limited data on HOXB13 expression in HER2+ and ER- breast cancers. Herein, we studied the expression of HOXB13 in large cohorts of HER2+ and ER- breast cancers. Methods We investigated gene expression, genomic copy number, mutational signatures, and clinical outcome data in the TGGA and METABRIC breast cancer cohorts. Genomic-based gene amplification data was validated with tri-colored fluorescence in situ hybridization. Results In the TCGA breast cancer cohort, HOXB13 gene expression was significantly higher in HER2+ versus HER2- breast cancers, and its expression was also significantly higher in the ER- versus ER+ breast cancers. HOXB13 is frequently co-gained or co-amplified with ERBB2. Joint copy gains of HOXB13 and ERBB2 occurred with low-level co-gains or high-level co-amplifications (co-amp), the latter of which is associated with an interstitial loss that includes the tumor suppressor BRCA1. ERBB2/HOXB13 co-amp tumors with interstitial BRCA1 loss exhibit a mutational signature associated with APOBEC deaminase activity and copy number signatures associated with chromothripsis and genomic instability. Among ERBB2-amplified tumors of different tissue origins, ERBB2/HOXB13 co-amp with a BRCA1 loss appeared to be enriched in breast cancer compared to other tumor types. Lastly, patients with ERBB2/HOXB13 co-amplified and BRCA1 lost tumors displayed a significantly shorter progression-free survival (PFS) than those with ERBB2-only amplifications. The difference in PFS was restricted to the ER- subset patients and this difference in PFS was not solely driven by HOXB13 gene expression. Conclusions HOXB13 is frequently co-gained with ERBB2 at both low-copy number level or as complex high-level amplification with relative BRCA1 loss. ERBB2/HOXB13 amplified, BRCA1-lost tumors are strongly enriched in breast cancer, and patients with such breast tumors experience a shortened PFS.https://doi.org/10.1186/s13058-024-01943-1HOXB13ERBB2Co-amplificationBreast cancerBRCA1 |
| spellingShingle | Irene Rin Mitsiades Maristela Onozato A. John Iafrate Daniel Hicks Doğa C. Gülhan Dennis C. Sgroi Esther Rheinbay ERBB2/HOXB13 co-amplification with interstitial loss of BRCA1 defines a unique subset of breast cancers Breast Cancer Research HOXB13 ERBB2 Co-amplification Breast cancer BRCA1 |
| title | ERBB2/HOXB13 co-amplification with interstitial loss of BRCA1 defines a unique subset of breast cancers |
| title_full | ERBB2/HOXB13 co-amplification with interstitial loss of BRCA1 defines a unique subset of breast cancers |
| title_fullStr | ERBB2/HOXB13 co-amplification with interstitial loss of BRCA1 defines a unique subset of breast cancers |
| title_full_unstemmed | ERBB2/HOXB13 co-amplification with interstitial loss of BRCA1 defines a unique subset of breast cancers |
| title_short | ERBB2/HOXB13 co-amplification with interstitial loss of BRCA1 defines a unique subset of breast cancers |
| title_sort | erbb2 hoxb13 co amplification with interstitial loss of brca1 defines a unique subset of breast cancers |
| topic | HOXB13 ERBB2 Co-amplification Breast cancer BRCA1 |
| url | https://doi.org/10.1186/s13058-024-01943-1 |
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