Abstract
Breast cancer is highly heterogeneous. The subtypes defined using immunohistochemistry markers and gene expression profilings (GEP) are related but not equivalent, with inter-connections under investigated. Our previous study revealed a set of differentially expressed genes (diff-genes), containing 1015 mRNAs and 69 miRNAs, which characterize the immunohistochemistry-defined breast tumor subtypes at the GEP level. However, they may convey redundant information due to the large amount of genes included. By reducing the dimension of the diff-genes, we identified 119 mRNAs and 20 miRNAs best explaining breast tumor heterogeneity with the most succinct number of genes found using hierarchical clustering and nearest-to-center principle. The final signature panel contains 119 mRNAs, whose superiority over diff-genes was replicated in two independent public datasets. The comparison of our signature with two pioneering signatures, the Sorlie’s signature and PAM50, suggests a novel marker, FOXA1, in breast cancer classification. Subtype-specific feature genes are reported to characterize each immunohistochemistry-defined subgroup. Pathway and network analysis reveal the critical roles of Notch signalings in [ER+|PR+]HER2− and cell cycle in [ER+|PR+]HER2+ tumors. Our study reveals the primary differences among the four immunohistochemistry-defined breast tumors at the mRNA and miRNA levels, and proposes a novel signature for breast tumor subtyping given GEP data.
Highlights
By reducing the dimensionality of the differentially expressed genes among IHC-defined subtypes presented in[4], we report a 119-gene signature that captures the characteristics of these subtypes with improved accuracy and reduced number of genes
The feature genes of each subtype, including both mRNAs and miRNAs, are presented, which explain the heterogeneity of the four basic IHC-defined subtypes
Comparison of our signature with the Sorlie’s signature and PAM50 suggests the crucial roles played by FOXA1 in breast cancer classification
Summary
Our previous study revealed a set of differentially expressed genes (diff-genes), containing 1015 mRNAs and 69 miRNAs, which characterize the immunohistochemistry-defined breast tumor subtypes at the GEP level. They may convey redundant information due to the large amount of genes included. Our study reveals the core differences explaining the heterogeneity of the four basic subtypes defined using ER, PR and HER2 status at the mRNA and miRNA expression levels It bridges the gap between IHC and GEP in differentiating breast tumor subtypes and could be used for subtyping of such tumors given gene expression data
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