Powerful quantifiers for cancer transcriptomics

Abstract

Every day, investigators find a new link between a form of cancer and a particular alteration in the sequence or/and expression level of a key gene, awarding this gene the title of “biomarker”. The clinician may choose from numerous available panels to assess the type of cancer based on the mutation or expression regulation (“transcriptomic signature”) of “driver” genes. However, cancer is not a “one-gene show” and, together with the alleged biomarker, hundreds other genes are found as mutated or/and regulated in cancer samples. Regardless of the platform, a well-designed transcriptomic study produces three independent features for each gene: Average expression level, expression variability and coordination with expression of each other gene. While the average expression level is used in all studies to identify what genes were up-/down-regulated or turn on/off, the other two features are unfairly ignored. We use all three features to quantify the transcriptomic change during the progression of the disease and recovery in response to a treatment. Data from our published microarray experiments on cancer nodules and surrounding normal tissue from surgically removed tumors prove that the transcriptomic topologies are not only different in histopathologically distinct regions of a tumor but also dynamic and unique for each human being. We show also that the most influential genes in cancer nodules [the Gene Master Regulators (GMRs)] are significantly less influential in the normal tissue. As such, “smart” manipulation of the cancer GMRs expression may selectively kill cancer cells with little consequences on the normal ones. Therefore, we strongly recommend a really personalized approach of cancer medicine and present the experimental procedure and the mathematical algorithm to identify the most legitimate targets (GMRs) for gene therapy.

Keywords: Cancer biomarkers, Cancer nodule, Gene therapy, Kidney cancer, Prostate cancer, RNA gene, Thyroid cancer

Core Tip: The Genomic Fabric Paradigm was developed as a holistic alternative to the biomarker approach of cancer transcriptomics. The genomic fabric of a functional pathway is the transcriptome associated with the most interconnected and stably expressed gene network responsible for that pathway. We present the associated analytical tools to characterize the topology, remodeling during cancer progression and in response to a therapy, and interplay of the genomic fabrics and identify the most legitimate targets in cancer gene therapy. The analyses are illustrated with examples from our transcriptomic studies on human cancer tissues and cell lines.