A Traceable Cancer Model: DNA Damage, Fragile Site-SMGs, Mitotic Slippage, 4n-Genome-Reduction to Fitness-Gained, Initiating, 2n First Cells

We have known since 1976 that cancer evolves clonally from one initiated normal human cell, the first cell. Today we see that this fact has been overshadowed from federal funding choice of the mutation theory (MT), which not yet has shown tumorigenesis-initiation in normal human cells. Our suggested, death signaled, stress model from time delayed S-period (replication slowness), causing repair instability from under-replicated lesions in repetitive DNAs, herein has the objective of revealing, significant literature support from a mini-review. We reasoned that early versus late S-period stress would have different outcomes: early the slowness affecting mitotic slippage with diploid re-replication to 4n cells whereas late-S, with milder stress effect, producing diploid cells. In cancer burden, near-half is diploid, but tetraploid solid tumors have the attention. The initial 4n cells were special with orderly genomic reductive division to diploid first cells with measurable fitness-gain from hours-reduced total cell cycle time. Experimental data from Coxsakie-B3 virus infected normal fibroblasts, reiterated 4n cell production from death-signaled recovery-cells with progressive cell-phenotypic changes to polygonal and roundness cell-shapes, indistinguishable from diagnostic/prognostic cancer morphology. The 4n cells showed a self-inflicted 90° turn of the 4n nucleus before division, affecting a perpendicular orientation of the fitness-gained first cells relative to neighboring cells. In an illustrated cell cycle drawing with early and late S-period stress, it became clear that coding genes on borders of repair unstable satellite, repetitive DNA regions, could become mutated. We found these mutations to be tumor SMGs (significantly mutated genes). Evidential material was presented for loss of function genetics driving tumorigenesis to a parasitic lifestyle.

Genomic Instability in Cancer I: DNA-Repair Triggering Primitive Hereditary 4n-Skewed, Amitotic Division-System, the Culprit in EMT/MET/Metaplasia Cancer-Concepts

The objective was to gain proof of genome damage-repair induced mitotic slippage process (MSP) to 4n-diplochromosome skewed division-system, earlier suggested to have “cancer-deciding” consequences. Our damage-model showed two succeeding phases: molecular mutations for initiation of fitness-gained cells, and large chromosomal changes to aneuploidy from inherited DNA-breakage-repair inaccuracies. The mutations were gained while DNA-repair and DNA-replication, co-existed in the route to tetraploidy, a phenomenon also expressed for some existing unicellular organisms. These organisms also showed genome reductive, amitotic, meioticlike division, and was the origin of human genome conserved, self-inflicted 90° reorientation of the 4n nucleus relative to the cytoskeleton axis. In the in vitro DNA-damage model, this remarkable 4n-event deciding “flat-upright” cell-growth characteristics showed several consequences, for example, cancer-important, E-cadherin-β-catenin cell-to-cell adherence destruction, which gave diploid progeny cells, mobility freedom from cell contact inhibition, likely in renewal tissues. This 4n-skewed division-system with inheritance in progeny cells for repeat occurrences as mentioned for flat-up-right growth patterns is similar to claimed concepts of metaplasia-EMT/MET embryogenesis events in cancer evolution. A scrutiny of this literature, proof-wise invalidated this embryological concept by tetraploid 8C cells occurring in MET events and, was noted for small cell occurrence, i.e., diploidy from 4n-8C reductive division, an also event for tumor relapse cells, derived from genome damaging therapy agents. Pre-cancer hyperplasia reported MSP, cadherincatenin destruction and 90° perpendicularity to basal cell membrane. The DNA-damage-repair model can weed-out therapy-agents triggering 4n-skewed division. Cancer-control, beginning-information, is likely from mutational identity of the 4n derived fitness-gained cells.