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

Veerla, Srinivas LU orcid ; Hohmann, Lennart LU orcid ; Nacer, Deborah F. LU orcid ; Vallon-Christersson, Johan LU orcid and Staaf, Johan LU orcid (2023) AACR Special Conference in Cancer Research: Advances in Breast Cancer Research
Abstract
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 populationrepresentative 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.... (More)
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 populationrepresentative 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. (Less)
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type
Contribution to conference
publication status
published
subject
conference name
AACR Special Conference in Cancer Research: Advances in Breast Cancer Research
conference location
San Diego, CA, United States
conference dates
2023-10-19 - 2023-10-22
language
English
LU publication?
yes
id
018b97d8-3eb3-4612-836e-58408ad492c0
date added to LUP
2024-02-12 13:25:06
date last changed
2024-02-14 14:37:35
@misc{018b97d8-3eb3-4612-836e-58408ad492c0,
  abstract     = {{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 populationrepresentative 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<br/>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.}},
  author       = {{Veerla, Srinivas and Hohmann, Lennart and Nacer, Deborah F. and Vallon-Christersson, Johan and Staaf, Johan}},
  language     = {{eng}},
  title        = {{Perturbation and stability of PAM50 subtyping in population-based primary invasive breast cancer}},
  year         = {{2023}},
}