Abstract
Decades of research identified genomic similarities among prostate cancer patients and proposed general solutions for diagnostic and treatments. However, each human is a dynamic unique with never repeatable transcriptomic topology and no gene therapy is good for everybody. Therefore, we propose the Genomic Fabric Paradigm (GFP) as a personalized alternative to the biomarkers approach. Here, GFP is applied to three (one primary—“A”, and two secondary—“B” & “C”) cancer nodules and the surrounding normal tissue (“N”) from a surgically removed prostate tumor. GFP proved for the first time that, in addition to the expression levels, cancer alters also the cellular control of the gene expression fluctuations and remodels their networking. Substantial differences among the profiled regions were found in the pathways of P53-signaling, apoptosis, prostate cancer, block of differentiation, evading apoptosis, immortality, insensitivity to anti-growth signals, proliferation, resistance to chemotherapy, and sustained angiogenesis. ENTPD2, AP5M1 BAIAP2L1, and TOR1A were identified as the master regulators of the “A”, “B”, “C”, and “N” regions, and potential consequences of ENTPD2 manipulation were analyzed. The study shows that GFP can fully characterize the transcriptomic complexity of a heterogeneous prostate tumor and identify the most influential genes in each cancer nodule.
Highlights
According to the 29–31 March 2021 release of the Harmonized Cancer Datasets Genomic Data Commons Data Portal [1], 33,288 mutations in 20,237 genes were identified so far in 2355 cases of prostate cancer
We quantified the expressions of 14,908 unigenes in each of the 16 quarters of the three cancer nodules (“A”, “B”, “C”) and the surrounding normal tissue (“N”), isolated from a surgically removed metastatic prostate tumor
The use of Genomic Fabric Paradigm (GFP) translated the quantified 56,632 expression values (4 regions × 14,908 genes in one region) data into 1,778,077,160 transcriptomic characteristics of the profiled tumor (119,270 times larger than the number of expression levels of the individual genes considered by the traditional analysis)
Summary
According to the 29–31 March 2021 release of the Harmonized Cancer Datasets Genomic Data Commons Data Portal [1], 33,288 mutations in 20,237 genes were identified so far in 2355 cases of prostate cancer. The most frequently mutated genes in prostate cancer, TP53 (tumor protein p53) and TTN (titin) are among the most 10 frequently mutated genes in almost all other cancers. Together with the blamed mutation, millions of others occur in each individual, whose contributions to the cancer pathology are neglected without evidence that they are really negligible. Transcriptomic data from prostate tumors were compared to identify regulated genes (e.g., [4,5]) whose restoration might provide therapeutic solutions. Unrepeatable combinations of hundreds of other genes are regulated among patients, and their contributions are unjustifiably neglected
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