Genomic Fabrics of the Excretory System’s Functional Pathways Remodeled in Clear Cell Renal Cell Carcinoma

Abstract

Clear cell renal cell carcinoma (ccRCC) is the most frequent form of kidney cancer. Metastatic stages of ccRCC reduce the five-year survival rate to 15%. In this report, we analyze the ccRCC-induced remodeling of the five KEGG-constructed excretory functional pathways in a surgically removed right kidney and its metastasis in the chest wall from the perspective of the Genomic Fabric Paradigm (GFP). The GFP characterizes every single gene in each region by these independent variables: the average expression level (AVE), relative expression variability (REV), and expression correlation (COR) with each other gene. While the traditional approach is limited to only AVE analysis, the novel REV analysis identifies the genes whose correct expression level is critical for cell survival and proliferation. The COR analysis determines the real gene networks responsible for functional pathways. The analyses covered the pathways for aldosterone-regulated sodium reabsorption, collecting duct acid secretion, endocrine and other factor-regulated sodium reabsorption, proximal tubule bicarbonate reclamation, and vasopressin-regulated water reabsorption. The present study confirms the conclusion of our previously published articles on prostate and kidney cancers that even equally graded cancer nodules from the same tumor have different transcriptomic topologies. Therefore, the personalization of anti-cancer therapy should go beyond the individual, to his/her major cancer nodules.

Papillary Thyroid Cancer Remodels the Genetic Information Processing Pathways

“…Adding the independent REV and CORs characteristics to the AVE of each individual genes increased the information obtained from our gene expression experiments on thyroid cancer samples by almost 75 hundred times [49,52]. The independence of the three characteristics, presented here for 30 DNA replication genes in all four types of samples, was confirmed for several other gene sets profiled on surgically removed tumors from the kidney [26,56], prostate [87,93], and thyroid [25]. Altogether, AVEs, REVs, and CORs of all genes characterize the transcriptome as complete, as the numbers (AVE) of electronic devices of each type, their wiring (COR), and applied limits to the voltage fluctuations (REV) characterize a supercomputer.…”

“…What happens to a particular gene is not important, since its regulation is not only different from person to person, but even among histo-pathologically distinct regions of the same tissue, as shown in many publications (e.g., [91,92]). We have also proved the transcriptomic heterogeneity by profiling prostate [87,93] and kidney [26,56] tumors. Regardless of what happens to individual genes, what is important is the alteration of the functional pathway as a whole and the consequences for the proliferation of the cancer cells and invasion of other tissues.…”

“…The microarray data were filtered (eliminated all spots with foreground fluorescence less than twice in the background in one microarray), normalized (to the median of valid spots), and analyzed using our standard GFP algorithms (presented in [56]). In addition to the primary characteristics of adequately profiled individual genes in each condition of AVE, REV, and COR (Appendix A), we also considered the derived characteristics of Relative Expression Control (REC) and Coordination Degree (COORD) (Appendix B).…”

Low-Salt Diet Regulates the Metabolic and Signal Transduction Genomic Fabrics, and Remodels the Cardiac Normal and Chronic Pathological Pathways

“…In turn, COR analysis determines the most probable gene networking in functional pathways. It is based on the Principle of Transcriptomic Stoichiometry [ 76 , 77 ] that requires the networked genes to be coordinately expressed to ensure the efficiency of the functional pathway. Among much other interesting information, Figure 1 premieres the glycolysis/glucogenesis expression coordination partners of Slc8a1 , a key gene for calcium homeostasis whose inactivation limits the damages caused by myocardial infarction [ 78 ] and the dependence on diet of the partnership.…”

Advanced Molecular Solutions for Cancer Therapy—The Good, the Bad, and the Ugly of the Biomarker Paradigm

“…Intra-tumor genetic and transcriptomic heterogeneity was reported by many groups (e.g., [ 24 , 25 , 26 , 27 , 28 ]). In our gene expression studies (e.g., [ 29 , 30 ]), we found large differences even between equally graded cancer nodules from the same tumor. So, what do “genetic etiology” and “transcriptomic signature” (both deduced by comparing the average cancer patient with the average healthy counterpart) stand for when genes from different locations within the same tumor exhibit different mutations and expression regulations?…”