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Development and validation of a prognostic 15-gene signature for stratifying HER2+/ER+ breast cancer

BACKGROUND: Human epidermal growth receptor 2-positive (HER2+) breast cancer (BC) is a heterogeneous subgroup. Estrogen receptor (ER) status is emerging as a predictive marker within HER2+ BCs, with the HER2+/ER+ cases usually having better survival in the first 5 years after diagnosis but have high...

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Autores principales: Liu, Qian, Huang, Shujun, Desautels, Danielle, McManus, Kirk J., Murphy, Leigh, Hu, Pingzhao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Research Network of Computational and Structural Biotechnology 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10196919/
https://www.ncbi.nlm.nih.gov/pubmed/37216014
http://dx.doi.org/10.1016/j.csbj.2023.05.002
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author Liu, Qian
Huang, Shujun
Desautels, Danielle
McManus, Kirk J.
Murphy, Leigh
Hu, Pingzhao
author_facet Liu, Qian
Huang, Shujun
Desautels, Danielle
McManus, Kirk J.
Murphy, Leigh
Hu, Pingzhao
author_sort Liu, Qian
collection PubMed
description BACKGROUND: Human epidermal growth receptor 2-positive (HER2+) breast cancer (BC) is a heterogeneous subgroup. Estrogen receptor (ER) status is emerging as a predictive marker within HER2+ BCs, with the HER2+/ER+ cases usually having better survival in the first 5 years after diagnosis but have higher recurrence risk after 5 years compared to HER2+/ER-. This is possibly because sustained ER signaling in HER2+ BCs helps escape the HER2 blockade. Currently HER2+/ER+ BC is understudied and lacks biomarkers. Thus, a better understanding of the underlying molecular diversity is important to find new therapy targets for HER2+/ER+ BCs. METHODS: In this study, we performed unsupervised consensus clustering together with genome-wide Cox regression analyses on the gene expression data of 123 HER2+/ER+ BC from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) cohort to identify distinct HER2+/ER+ subgroups. A supervised eXtreme Gradient Boosting (XGBoost) classifier was then built in TCGA using the identified subgroups and validated in another two independent datasets (Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and Gene Expression Omnibus (GEO) (accession number GSE149283)). Computational characterization analyses were also performed on the predicted subgroups in different HER2+/ER+ BC cohorts. RESULTS: We identified two distinct HER2+/ER+ subgroups with different survival outcomes using the expression profiles of 549 survival-associated genes from the Cox regression analyses. Genome-wide gene expression differential analyses found 197 differentially expressed genes between the two identified subgroups, with 15 genes overlapping the 549 survival-associated genes. XGBoost classifier, using the expression values of the 15 genes, achieved a strong cross-validated performance (Area under the curve (AUC) = 0.85, Sensitivity = 0.76, specificity = 0.77) in predicting the subgroup labels. Further investigation partially confirmed the differences in survival, drug response, tumor-infiltrating lymphocytes, published gene signatures, and CRISPR-Cas9 knockout screened gene dependency scores between the two identified subgroups. CONCLUSION: This is the first study to stratify HER2+/ER+ tumors. Overall, the initial results from different cohorts showed there exist two distinct subgroups in HER2+/ER+ tumors, which can be distinguished by a 15-gene signature. Our findings could potentially guide the development of future precision therapies targeted on HER2+/ER+ BC.
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spelling pubmed-101969192023-05-20 Development and validation of a prognostic 15-gene signature for stratifying HER2+/ER+ breast cancer Liu, Qian Huang, Shujun Desautels, Danielle McManus, Kirk J. Murphy, Leigh Hu, Pingzhao Comput Struct Biotechnol J Research Article BACKGROUND: Human epidermal growth receptor 2-positive (HER2+) breast cancer (BC) is a heterogeneous subgroup. Estrogen receptor (ER) status is emerging as a predictive marker within HER2+ BCs, with the HER2+/ER+ cases usually having better survival in the first 5 years after diagnosis but have higher recurrence risk after 5 years compared to HER2+/ER-. This is possibly because sustained ER signaling in HER2+ BCs helps escape the HER2 blockade. Currently HER2+/ER+ BC is understudied and lacks biomarkers. Thus, a better understanding of the underlying molecular diversity is important to find new therapy targets for HER2+/ER+ BCs. METHODS: In this study, we performed unsupervised consensus clustering together with genome-wide Cox regression analyses on the gene expression data of 123 HER2+/ER+ BC from The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) cohort to identify distinct HER2+/ER+ subgroups. A supervised eXtreme Gradient Boosting (XGBoost) classifier was then built in TCGA using the identified subgroups and validated in another two independent datasets (Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and Gene Expression Omnibus (GEO) (accession number GSE149283)). Computational characterization analyses were also performed on the predicted subgroups in different HER2+/ER+ BC cohorts. RESULTS: We identified two distinct HER2+/ER+ subgroups with different survival outcomes using the expression profiles of 549 survival-associated genes from the Cox regression analyses. Genome-wide gene expression differential analyses found 197 differentially expressed genes between the two identified subgroups, with 15 genes overlapping the 549 survival-associated genes. XGBoost classifier, using the expression values of the 15 genes, achieved a strong cross-validated performance (Area under the curve (AUC) = 0.85, Sensitivity = 0.76, specificity = 0.77) in predicting the subgroup labels. Further investigation partially confirmed the differences in survival, drug response, tumor-infiltrating lymphocytes, published gene signatures, and CRISPR-Cas9 knockout screened gene dependency scores between the two identified subgroups. CONCLUSION: This is the first study to stratify HER2+/ER+ tumors. Overall, the initial results from different cohorts showed there exist two distinct subgroups in HER2+/ER+ tumors, which can be distinguished by a 15-gene signature. Our findings could potentially guide the development of future precision therapies targeted on HER2+/ER+ BC. Research Network of Computational and Structural Biotechnology 2023-05-04 /pmc/articles/PMC10196919/ /pubmed/37216014 http://dx.doi.org/10.1016/j.csbj.2023.05.002 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Research Article
Liu, Qian
Huang, Shujun
Desautels, Danielle
McManus, Kirk J.
Murphy, Leigh
Hu, Pingzhao
Development and validation of a prognostic 15-gene signature for stratifying HER2+/ER+ breast cancer
title Development and validation of a prognostic 15-gene signature for stratifying HER2+/ER+ breast cancer
title_full Development and validation of a prognostic 15-gene signature for stratifying HER2+/ER+ breast cancer
title_fullStr Development and validation of a prognostic 15-gene signature for stratifying HER2+/ER+ breast cancer
title_full_unstemmed Development and validation of a prognostic 15-gene signature for stratifying HER2+/ER+ breast cancer
title_short Development and validation of a prognostic 15-gene signature for stratifying HER2+/ER+ breast cancer
title_sort development and validation of a prognostic 15-gene signature for stratifying her2+/er+ breast cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10196919/
https://www.ncbi.nlm.nih.gov/pubmed/37216014
http://dx.doi.org/10.1016/j.csbj.2023.05.002
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