Multi-Omic Regulation of the PAM50 Gene Signature in Breast Cancer Molecular Subtypes.

Breast cancer is a disease that exhibits heterogeneity that goes from the genomic to the clinical levels. This heterogeneity is thought to be captured (at least partially) by the so-called breast cancer molecular subtypes. These molecular subtypes were initially defined based on the unsupervised clustering of gene expression and its correlate with histological, morphological, phenotypic and clinical features already known. Later, a 50-gene signature, PAM50, was defined in order to identify the biological subtype of a given sample within the clinical setting. The PAM50 signature was obtained by the use of unsupervised statistical methods, and therefore no limitation was set on the biological relevance (or lack of) of the selected genes beyond its predictive capacity. An open question that remains is what are the regulatory elements that drive the various expression behaviors of this set of genes in the different molecular subtypes. This question becomes more relevant as the measurement of more biological layers of regulation becomes accessible. In this work, we analyzed the gene expression regulation of the 50 genes in the PAM50 signature, in terms of (a) gene co-expression, (b) transcription factors, (c) micro-RNAs, and (d) methylation. Using data from the Cancer Genome Atlas (TCGA) for the Luminal A and B, Basal, and HER2-enriched molecular subtypes as well as normal tumor adjacent tissue, we identified predictors for gene expression through the use of an elastic net model. We compare and contrast the sets of identified regulators for the gene signature in each molecular subtype, and systematically compare them to current literature. We also identified a unique set of predictors for the expression of genes in the PAM50 signature associated with each of the molecular subtypes. Most selected predictors are exclusive for a PAM50 gene and predictors are not shared across subtypes. There are only 13 coding transcripts and 2 miRNAs selected for the four subtypes.