Genomic Instability in Cancer II: 4N-Skewed (90°) Reductive Division via Fragile Sites to Fitness Increase for Solid and Hematological Cancer Beginnings
The
objective herein was to connect the ontogeny process of diplochromosomal,
amitotic, 4n-skewed division-system, to cytogenetic deficiency lesions in
satellite, repetitive DNAs, especially in the chromosomal fragile sites, some
100 distributed over the genome. These latter studies had shown that chemical
induced replication-stress led to un-replicated lesions in these fragile sites,
which from inaccurate repair processes caused genomic instability. In the chain
of events of the ontogeny process to the special tetraploidy, it was proposed
that primary damaged human cells could undergo replication stress from
repair-process present during cell replication, a suggestion verified by X-ray
damaged cells producing the unstable fragile sites (see text). The cancer-importance
for therapy is recognition of cell cycle change for the 4n derivative
fitness-gained, diploid progeny cells. An open question is whether RB
controlling G1 to S-period is mutated at this suggested tumorigenesis initiating
phase, and if so, with what consequences for therapy. The fragile site studies
further showed that repair of repetitive DNAs could produce two types of
genomic changes: single gene mutations and CNVs, which were here shown to be chromosomally
located on “borders” to repairing satellite lesions. This genomic placement was
found to correspond to mutations identified in tumor sequencing (p53, Rb, MYC),
favoring a bad luck location for their cancer “mutational nature”. The CNVs in
cancers, are here seen as molecular
expressions of long-known cytogenetic HSRs and DMs also with demonstrated
origin from amplifications of single genes. Over-expression of oncogenes
was hinted of being from duplications, but Drosophila genetics demonstrated the opposite,gene inactivation. The reduced eye-size from dominant,
BAR-Ultra-Bar-eye phenotypes, was caused by duplications, inactivating the
genetic system for eye-size. The finding of CNVs showing “evasion” of the
immune systemsuggests, inactivation of immune-determining genetics.
Since mutated genes on borders to satellite DNAs are a fact in hematological cancers,
the 4n-skewed division-system is suggested to replace
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