The Gene Master Regulators (GMR) Approach Provides Legitimate Targets for Personalized, Time-Sensitive Cancer Gene Therapy

Abstract

The dynamic and never exactly repeatable tumor transcriptomic profile of people affected by the same form of cancer requires a personalized and time-sensitive approach of the gene therapy. The Gene Master Regulators (GMRs) were defined as genes whose highly controlled expression by the homeostatic mechanisms commands the cell phenotype by modulating major functional pathways through expression correlation with their genes. The Gene Commanding Height (GCH), a measure that combines the expression control and expression correlation with all other genes, is used to establish the gene hierarchy in each cell phenotype. We developed the experimental protocol, the mathematical algorithm and the computer software to identify the GMRs from transcriptomic data in surgically removed tumors, biopsies or blood from cancer patients. The GMR approach is illustrated with applications to our microarray data on human kidney, thyroid and prostate cancer samples, and on thyroid, prostate and blood cancer cell lines. We proved experimentally that each patient has his/her own GMRs, that cancer nuclei and surrounding normal tissue are governed by different GMRs, and that manipulating the expression has larger consequences for genes with higher GCH. Therefore, we launch the hypothesis that silencing the GMR may selectively kill the cancer cells from a tissue.

Oligodendrocytes Remodel the Genomic Fabrics of Functional Pathways in Astrocytes

“…However, experimental alteration of a gene is expected to have transcriptomic consequences in line with its GCH. We confirmed this hypothesis by stably lentiviral transfecting each of two different human thyroid cancer cell lines (papillary BCPAP and anaplastic 850C) with the same gene (DDX19B, NEMP1, PANK2, UBALD1) [50,51]. Interestingly, the top gene (highest GCH) in one condition scores very low in the other.…”

“…The Gene Commanding Height (GCH) score was introduced recently[50,51] to establish the gene hierarchy in each condition. It combines an estimate of the transcription control of that gene with a measure of its expression coordination with each other gene:…”

Pulmonary Hypertension Remodels the Genomic Fabrics of Major Functional Pathways

“…Transcriptomic analysis: A gene was considered as significantly regulated if the absolute foldchange exceeded the cut-off calculated for that gene [30]. The cut-off (CUT, Eq.…”

Optic Nerve Crush Activates the Genomic Fabrics of the Complement Cascade and Delta-Notch Signaling

“…1.5x) for all genes with a value that accounts for the combined contributions of the technical noise and biological expression variability of each gene independently [52]. This composite criterion, in which the cut-offs were computed with Bonferroni-type corrections applied to the redundancy groups [53][54], eliminates most of the false positives without increasing the number of false negatives (Eq. 2).…”

“…The profiles of two genes can be similar, opposite or neutral. Two genes were considered as having similar coordination profiles when there is significant overlap of their synergistically, antagonistically and independently expressed partners; genes were considered as having opposite coordination profiles when most of the synergistically expressed partners of one gene were antagonistically expressed partners for the other, and most of the independently expressed partners of one gene were synergistically or antagonistically expressed for the other [53][54].…”