Cancer Prevention? Fundamental Genomic Alterations Are Present in Preneoplasia, Including Function of High Frequency Selected Mutations (HFSMs)

Walen, Kirsten H.

doi:10.4236/jct.2016.76044

Cited by 2 publications

(4 citation statements)

References 74 publications

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“…In a model on this oncogenic transformation event, it was calculated that three mutations, were sufficient to instigate the cancer-important change [6]. Whereas, we suggested [20] that two mutations (e.g., p16ink4a and Rb) occurring in accumulated, tetraploid 4n/4C/G1 cells in the senescent phase, could trigger S-period entry (G1 > S) with resultant cell cycling in the 3n-4n range [82] [83]. The absence of this type of 3n-4n cell cycling in the above immortalization, we suggest was precluded from the used methodology, perhaps specifically from shRNA, gene silencing.…”

Section: Distictions Between Initiation and Oncogenic Transformationmentioning

confidence: 91%

“…), because cell cycle time of 4n, diploid progeny cells, PtK-1 & 2, was measured from autoradiography of tritiated thymedine incorporation, and found to be about 3 hours shorter than for control, normal marsupial, Potoroo cells (2002 [55]. Autoradiographs of present human diplochromosomal cells [56] demonstrated non-randomness in chromatid replication process, and extensive, sister chromatid chiasmata from recombination repair-processes [20], emphasizing "break and repair" in this 4n-situation. Of note, is that reduced cell cycling time is in itself a proliferative advantage, which for the fitness gained 4n-derived diploid cells, may well have been in addition to mutations created by inaccurate repair [57]-the mutator phenotype [30].…”

Section: A Cellular Mechanism In Cancer Initiation and Evolutionmentioning

confidence: 99%

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

Walen¹

2018

JCT

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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-upright 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.

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Section: Distictions Between Initiation and Oncogenic Transformationmentioning

confidence: 91%

Section: A Cellular Mechanism In Cancer Initiation and Evolutionmentioning

confidence: 99%

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

Walen¹

2018

JCT

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“…In Barrett's esophagus from acid reflux disease causing areas of damaged epithelial cells and like-wise in ulcerative colitis, bacteria caused cell damage, the preneoplasias showed tetraploid-dization with division to 4n/4C/G1 accumulating cells, most peculiar [70] [71]. A suggested step for gain of S-phase entry of these cells is their gain of p53 and p16ink4a mutations plus in-activation of Rb (frequently negatively affected in cancers), which would lead to trip-tetraploid cell cycling, a feature observed for both diseases [14].…”

Section: Genomic Damage and Repairmentioning

confidence: 99%

“…It should be recognized that any unveiled genomic/CIN mechanism may have attached cellular behavioral consequences, which rather recently was called "dark matter" for genomic sequencing identification [12] [13]. However, such cell responses, to some degree revealed by microscopy (KW) [14], has also more recently been revealed by improvements in sequencing technology, showing chromosome and molecular anoma-lies (indels) as "copy number alterations across human cancers" (CNAs) [15].…”

Section: Introductionmentioning

confidence: 99%

Mitotic Slippage Process Concealed Cancer-Sought Chromosome Instability Mechanism (S-CIN)

Walen¹

2017

JCT

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Official (NIH) cancer investigation is on identification of inherited cancer genes in you and me for early interventions, and for use of such knowledge in therapy. In this review the emphasis is on the unknown cancer initiation, and on the question of a mechanism for inherited CIN (chromosomal instability). Evidence for fitness increased cells from the mitotic slippage process (in vivo/in vitro) originated from genome damaged diploid cells in G2/M, skipping mitosis to G1, which illegitimately permitted S-phase re-replication of the chromatid cohesed-2n cells to 4n-tetraploidy. During which, down-load of genome-wide cohesin occurred, producing 4-chromatid diplochromosomes, evolutionary conserved in repair of DNA. This type of 4n cells divided 2-step meiotic-like, leading to diploid aneuploid cells with increased fitness, and expression of gross chromosomal anomalies in proliferation. The diploid cohesed chromatids during re-replication would hinder replication of sticky heterochromatic regions, resulting in their under-replication, and known from Drosophila. The human chromosomes are longitudinally differentiated into satellite DNA regions, folic acid sensitive sites and the primary constriction (centromere); they are breakage sensitive regions and being heterochromatic. This strongly suggests, multiple, chromosomal regional under-replicationcites, translated to origin of slippage, S-CIN, a genome inherited destabilization mechanism. Logically, S-CIN would affect genes differentially depending on chromosome location, for example, the high frequency in cancers of mutated p53 on the small 17p-arm, which with centromere breakage would be preferentially lost in mitosis. This likely S-CIN mechanism in cancer evolution can be studied in vivo for APC mutated crypt cells with demonstrated mitotic slippage process.

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Cancer Prevention? Fundamental Genomic Alterations Are Present in Preneoplasia, Including Function of High Frequency Selected Mutations (HFSMs)

Cited by 2 publications

References 74 publications

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

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

Mitotic Slippage Process Concealed Cancer-Sought Chromosome Instability Mechanism (S-CIN)

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