A Three-Gene Model to Robustly Identify Breast Cancer Molecular Subtypes

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A Three-Gene Model to Robustly Identify Breast Cancer Molecular Subtypes

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Title: A Three-Gene Model to Robustly Identify Breast Cancer Molecular Subtypes
Author: Haibe-Kains, B; Desmedt, C.; Loi, S.; Culhane, Aedin; Bontempi, G.; Quackenbush, John; Sotiriou, C.

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Citation: Haibe-Kains, B., C. Desmedt, S. Loi, A. C. Culhane, G. Bontempi, J. Quackenbush, and C. Sotiriou. 2012. “A Three-Gene Model to Robustly Identify Breast Cancer Molecular Subtypes.” JNCI Journal of the National Cancer Institute 104 (4) (January 18): 311–325. doi:10.1093/jnci/djr545.
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Abstract: Background - Single sample predictors (SSPs) and Subtype classification models (SCMs) are gene expression–based classifiers used to identify the four primary molecular subtypes of breast cancer (basal-like, HER2-enriched, luminal A, and luminal B). SSPs use hierarchical clustering, followed by nearest centroid classification, based on large sets of tumor-intrinsic genes. SCMs use a mixture of Gaussian distributions based on sets of genes with expression specifically correlated with three key breast cancer genes (estrogen receptor [ER], HER2, and aurora kinase A [AURKA]). The aim of this study was to compare the robustness, classification concordance, and prognostic value of these classifiers with those of a simplified three-gene SCM in a large compendium of microarray datasets.
Methods - Thirty-six publicly available breast cancer datasets (n = 5715) were subjected to molecular subtyping using five published classifiers (three SSPs and two SCMs) and SCMGENE, the new three-gene (ER, HER2, and AURKA) SCM. We used the prediction strength statistic to estimate robustness of the classification models, defined as the capacity of a classifier to assign the same tumors to the same subtypes independently of the dataset used to fit it. We used Cohen k and Cramer V coefficients to assess concordance between the subtype classifiers and association with clinical variables, respectively. We used Kaplan–Meier survival curves and cross-validated partial likelihood to compare prognostic value of the resulting classifications. All statistical tests were two-sided.
Results - SCMs were statistically significantly more robust than SSPs, with SCMGENE being the most robust because of its simplicity. SCMGENE was statistically significantly concordant with published SCMs (k = 0.65–0.70) and SSPs (k = 0.34–0.59), statistically significantly associated with ER (V = 0.64), HER2 (V = 0.52) status, and histological grade (V = 0.55), and yielded similar strong prognostic value.
Conclusion - Our results suggest that adequate classification of the major and clinically relevant molecular subtypes of breast cancer can be robustly achieved with quantitative measurements of three key genes.
Published Version: doi:10.1093/jnci/djr545
Other Sources: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3283537/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:29004169
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