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Perturbation and stability of PAM50 subtyping in population-based primary invasive breast cancer

PAM50 gene expression subtypes represent a cornerstone in the molecular classification of breast cancer and are included in risk prediction models to guide therapy. We aimed to illustrate the impact of included genes and biological processes on subtyping while considering a tumor’s underlying clinic...

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Autores principales: Veerla, Srinivas, Hohmann, Lennart, Nacer, Deborah F., Vallon-Christersson, Johan, Staaf, Johan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10587090/
https://www.ncbi.nlm.nih.gov/pubmed/37857634
http://dx.doi.org/10.1038/s41523-023-00589-0
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author Veerla, Srinivas
Hohmann, Lennart
Nacer, Deborah F.
Vallon-Christersson, Johan
Staaf, Johan
author_facet Veerla, Srinivas
Hohmann, Lennart
Nacer, Deborah F.
Vallon-Christersson, Johan
Staaf, Johan
author_sort Veerla, Srinivas
collection PubMed
description PAM50 gene expression subtypes represent a cornerstone in the molecular classification of breast cancer and are included in risk prediction models to guide therapy. We aimed to illustrate the impact of included genes and biological processes on subtyping while considering a tumor’s underlying clinical subgroup defined by ER, PR, and HER2 status. To do this we used a population-representative and clinically annotated early-stage breast tumor cohort of 6233 samples profiled by RNA sequencing and applied a perturbation strategy of excluding co-expressed genes (gene sets). We demonstrate how PAM50 nearest-centroid classification depends on biological processes present across, but also within, ER/PR/HER2 subgroups and PAM50 subtypes themselves. Our analysis highlights several key aspects of PAM50 classification. Firstly, we demonstrate the tight connection between a tumor’s nearest and second-nearest PAM50 centroid. Additionally, we show that the second-best subtype is associated with overall survival in ER-positive, HER2-negative, and node-negative disease. We also note that ERBB2 expression has little impact on PAM50 classification in HER2-positive disease regardless of ER status and that the Basal subtype is highly stable in contrast to the Normal subtype. Improved consciousness of the commonly used PAM50 subtyping scheme will aid in our understanding and interpretation of breast tumors that have seemingly conflicting PAM50 classification when compared to clinical biomarkers. Finally, our study adds further support in challenging the common misconception that PAM50 subtypes are distinct classes by illustrating that PAM50 subtypes in tumors represent a continuum with prognostic implications.
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spelling pubmed-105870902023-10-21 Perturbation and stability of PAM50 subtyping in population-based primary invasive breast cancer Veerla, Srinivas Hohmann, Lennart Nacer, Deborah F. Vallon-Christersson, Johan Staaf, Johan NPJ Breast Cancer Article PAM50 gene expression subtypes represent a cornerstone in the molecular classification of breast cancer and are included in risk prediction models to guide therapy. We aimed to illustrate the impact of included genes and biological processes on subtyping while considering a tumor’s underlying clinical subgroup defined by ER, PR, and HER2 status. To do this we used a population-representative and clinically annotated early-stage breast tumor cohort of 6233 samples profiled by RNA sequencing and applied a perturbation strategy of excluding co-expressed genes (gene sets). We demonstrate how PAM50 nearest-centroid classification depends on biological processes present across, but also within, ER/PR/HER2 subgroups and PAM50 subtypes themselves. Our analysis highlights several key aspects of PAM50 classification. Firstly, we demonstrate the tight connection between a tumor’s nearest and second-nearest PAM50 centroid. Additionally, we show that the second-best subtype is associated with overall survival in ER-positive, HER2-negative, and node-negative disease. We also note that ERBB2 expression has little impact on PAM50 classification in HER2-positive disease regardless of ER status and that the Basal subtype is highly stable in contrast to the Normal subtype. Improved consciousness of the commonly used PAM50 subtyping scheme will aid in our understanding and interpretation of breast tumors that have seemingly conflicting PAM50 classification when compared to clinical biomarkers. Finally, our study adds further support in challenging the common misconception that PAM50 subtypes are distinct classes by illustrating that PAM50 subtypes in tumors represent a continuum with prognostic implications. Nature Publishing Group UK 2023-10-19 /pmc/articles/PMC10587090/ /pubmed/37857634 http://dx.doi.org/10.1038/s41523-023-00589-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Veerla, Srinivas
Hohmann, Lennart
Nacer, Deborah F.
Vallon-Christersson, Johan
Staaf, Johan
Perturbation and stability of PAM50 subtyping in population-based primary invasive breast cancer
title Perturbation and stability of PAM50 subtyping in population-based primary invasive breast cancer
title_full Perturbation and stability of PAM50 subtyping in population-based primary invasive breast cancer
title_fullStr Perturbation and stability of PAM50 subtyping in population-based primary invasive breast cancer
title_full_unstemmed Perturbation and stability of PAM50 subtyping in population-based primary invasive breast cancer
title_short Perturbation and stability of PAM50 subtyping in population-based primary invasive breast cancer
title_sort perturbation and stability of pam50 subtyping in population-based primary invasive breast cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10587090/
https://www.ncbi.nlm.nih.gov/pubmed/37857634
http://dx.doi.org/10.1038/s41523-023-00589-0
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