Cancer Genetic Network Inference Using Gaussian Graphical Models

Abstract

The Cancer Genome Atlas (TCGA) provides a rich resource that can be used to understand how genes interact in cancer cells and has collected RNA-Seq gene expression data for many types of human cancer. However, mining the data to uncover the hidden gene-interaction patterns remains a challenge. Gaussian graphical model (GGM) is often used to learn genetic networks because it defines an undirected graphical structure, revealing the conditional dependences of genes. In this study, we focus on inferring gene interactions in 15 specific types of human cancer using RNA-Seq expression data and GGM with graphical lasso. We take advantage of the corresponding Kyoto Encyclopedia of Genes and Genomes pathway maps to define the subsets of related genes. RNA-Seq expression levels of the subsets of genes in solid cancerous tumor and normal tissues were extracted from TCGA. The gene expression data sets were cleaned and formatted, and the genetic network corresponding to each cancer type was then inferred using GGM with graphical lasso. The inferred networks reveal stable conditional dependences among the genes at the expression level and confirm the essential roles played by the genes that encode proteins involved in the two key signaling pathway phosphoinositide 3-kinase (PI3K)/AKT/mTOR and Ras/Raf/MEK/ERK in human carcinogenesis. These stable dependences elucidate the expression level interactions among the genes that are implicated in many different human cancers. The inferred genetic networks were examined to further identify and characterize a collection of gene interactions that are unique to cancer. The cross-cancer genetic interactions revealed from our study provide another set of knowledge for cancer biologists to propose strong hypotheses, so further biological investigations can be conducted effectively.