Latent Factor Analysis to Discover Pathway-Associated Putative Segmental Aneuploidies in Human Cancers

Abstract

Tumor microenvironmental stresses, such as hypoxia and lactic acidosis, play important roles in tumor progression. Although gene signatures reflecting the influence of these stresses are powerful approaches to link expression with phenotypes, they do not fully reflect the complexity of human cancers. Here, we describe the use of latent factor models to further dissect the stress gene signatures in a breast cancer expression dataset. The genes in these latent factors are coordinately expressed in tumors and depict distinct, interacting components of the biological processes. The genes in several latent factors are highly enriched in chromosomal locations. When these factors are analyzed in independent datasets with gene expression and array CGH data, the expression values of these factors are highly correlated with copy number alterations (CNAs) of the corresponding BAC clones in both the cell lines and tumors. Therefore, variation in the expression of these pathway-associated factors is at least partially caused by variation in gene dosage and CNAs among breast cancers. We have also found the expression of two latent factors without any chromosomal enrichment is highly associated with 12q CNA, likely an instance of “trans”-variations in which CNA leads to the variations in gene expression outside of the CNA region. In addition, we have found that factor 26 (1q CNA) is negatively correlated with HIF-1α protein and hypoxia pathways in breast tumors and cell lines. This agrees with, and for the first time links, known good prognosis associated with both a low hypoxia signature and the presence of CNA in this region. Taken together, these results suggest the possibility that tumor segmental aneuploidy makes significant contributions to variation in the lactic acidosis/hypoxia gene signatures in human cancers and demonstrate that latent factor analysis is a powerful means to uncover such a linkage.

Cystine addiction of triple-negative breast cancer associated with EMT augmented death signaling

“…The projection analysis of these signatures to a breast tumor dataset (GSE69031) was performed according to our previous reports 10, 31, 49 .…”

Alternative Fuels for Cancer Cells

“…An accumulation of extracellular lactate and low pH, often called lactic acidosis (LA), is one prominent microenvironmental stress found in most solid cancer tumors 43 . Many studies have shown that LA triggers transcriptional responses, somatic alterations and phenotypic alterations 3,4,44,45 . In addition, lactate can serve as a signaling molecule to trigger HIF-1α 46 , NF-κB 47 and stemness 48 pathways to alter the signaling events and oncogenic properties of cancer cells.…”

“…There is extensive cross-talk and reciprocal metabolite flow between these alternative fuels and the sensing and metabolic pathways of glucose metabolism. The importance of these pathways can be demonstrated by the DNA amplifications or significant up-regulation of many genes involved in the metabolic adaptations under stresses 44,45 . It is important to note that while lactate and acetate are well-appreciated fuels for yeast and bacteria, they were not considered viable metabolic fuels for human cells until recently.…”

Biological pathway selection through Bayesian integrative modeling

“…Our approach to this problem is to extend a factor model-based approach because of its practical application in genomic studies (Lucas et al, 2006(Lucas et al, , 2009(Lucas et al, , 2010Zheng and Lucas, 2012;Ray et al, 2014). The factor analysis framework allows dimension reduction and estimation of correlation structure in the context of high-dimensional gene expression data.…”