Genomic Fabric Remodeling in Metastatic Clear Cell Renal Cell Carcinoma (ccRCC): A New Paradigm and Proposal for a Personalized Gene Therapy Approach

Abstract

Published transcriptomic data from surgically removed metastatic clear cell renal cell carcinoma (ccRCC) samples were re-analyzed from the Genomic Fabric Perspective that considers the transcriptome a multi-dimensional mathematical object, constrained by a dynamic set of expression correlations among genes. Every gene in the chest wall metastasis (MET), two primary tumors (PTA, PTB) and the surrounding normal tissue (NOR) of the right kidney was characterized by three independent measures: average expression level (AVE), relative expression variation (REV) and expression correlation (COR) with each other gene. AVE was used to determine the regulation of the genomic fabrics of ccRCC, apoptosis, chemokine and VEGF signaling pathways. REV quantified the alteration of the transcripts’ abundances control, while COR determined the remodeling of the transcriptomic networks of chemokine signaling and oxidative phosphorylation genes. The gene hierarchy was established in based on Gene Commanding Height and the Gene Master Regulators (GMR) TASOR (PTA), FAM27C (PTB) and ALG13 (MET) and DAPK3 (NOR) were identified in each profiled region. We predict that TASOR overexpression would block transcription in PTA but not in PTB, while slightly stimulating it in NOR. Silencing of ALG3 would slow-down the cell-cycle in all three cancer regions with practically no effect in NOR.

A Personalized Genomics Approach of the Prostate Cancer

“…As such, the GMRs command the cellular functional pathways, and their directed alteration might eliminate the cancer phenotype. Our analysis suggests that GMR targeting may enhance apoptosis (as in [ 79 ]), stop cell proliferation [ 37 ], significantly alter cell cycle [ 37 ], or force cancer cells to go back to the normal transcriptome as hypothesized in Section 3.11 . Unfortunately, we could not functionally validate these predictions on the profiled tumors.…”

“…In recent years, highly cited papers documented that tumors have not only heterogeneous histology but also heterogeneous gene expression profiles [ 34 , 35 , 36 ] as proved also by us in a case of clear cell renal cell carcinoma [ 37 ]. If this is true within one tumor, what justifies comparing the average gene expression profiles in large groups of phenotypically similar but distinct cancer patients with healthy counterparts as reported by thousands of papers?…”

“…Moreover, GFP establishes the gene hierarchy of that region based on their Gene Commanding Height [ 37 ]. The topgene, termed Gene Master Regulator (GMR), is the gene whose strictly controlled expression level regulates the major functional pathways by coordinating the expressions of most of their genes.…”

“…REV and COR are used to determine the Gene Commanding Height (GCH) [ 37 ]: where 〈 〉 = median, = average of the square values.…”

Transcriptomic uniqueness and commonality of the ion channels and transporters in the four heart chambers

“…We used GCH to identify the genes whose significat altered expression may selectively kill the cancer cells in a heterogeneous tumor 85 .…”