GLassonet: Identifying Discriminative Gene Sets Among Molecular Subtypes of Breast Cancer.

Abstract

Breast cancer is a heterogeneous disease caused by various alterations in the genome or transcriptome. Molecular subtypes of breast cancer have been reported, but useful biomarkers remain to be identified to uncover underlying biological mechanisms and guide clinical decisions. Towards biomarker discovery, several studies focus on genomic alterations that provide differences, while few works concern transcriptomic characterizations that mediate tumor progression. Rather than using differential expression (DE) or weighted network analysis, we propose a feature selection method, dubbed GLassonet, to identify discriminative biomarkers from transcriptome-wide expression profiles by embedding the relationship graph of high-dimensional expressions into the Lassonet model. GLassonet comprises a nonlinear neural network for identifying cancer subtypes, a skipping fully connected layer for canceling the connections of hidden layers from input features to output categories, and a graph enhancement for preserving the discriminative graph into the selected subspace. First, an iterative optimization algorithm learns model parameters on the TCGA breast cancer dataset to investigate the classification performance. Then, we probe the distribution patterns of GLassonet-selected gene sets across the cancer subtypes and compare them to gene sets outputted from the state-of-the-art. More profoundly, we conduct the overall survival analysis on three GLassonet-selected new marker genes, i.e., SOX10, TPX2, and TUBA1C, to investigate their expression changes and assess their prognostic impacts. Finally, we perform the enrichment analysis to discover the functional associations of the GLassonet-selected genes with GO terms and KEGG pathways. Experimental results show that GLassonet has a powerful ability to select the discriminative genes, which improve cancer subtype classification performance and provide potential biomarkers for cancer personalized therapy.