More specifically, CIN refers to the increase in rate of addition or loss of entire chromosomes or sections of them.
[2] Some inherited genetic predispositions to cancer are the result of mutations in machinery that responds to and repairs DNA double-stranded breaks.
If repair enzymes do not catch this recombination event, the cell may contain non-reciprocal translocation where parts of non-homologous chromosomes are joined together.
The result is a pair of DNAs with broken ends that can attach to other broken-ended DNA segments creating additional translocation and continue the cycle of chromosome breakage and fusion.
As the cycle continues, more chromosome translocations result, leading to the amplification or loss of large DNA fragments.
Telomere shortening and p53 expression is a key mechanism to prevent uncontrolled replication and tumor development because even cells that excessively proliferate will eventually be inhibited.
When tumor cells have a mutation in p53 that results in a non-functional protein, telomeres can continue to shorten and proliferate, and the eroded segments are susceptible to chromosomal rearrangements through recombination and breakage-fusion-bridge cycles.
Telomere loss can be lethal for many cells, but in the few that are able to restore the expression of telomerase can bring about a “stable” yet tumorigenic chromosome structure.
Telomere degeneration thereby explains the transient period of extreme chromosomal instability observed in many emerging tumors.
[11] In experiments on mice where both telomerase and p53 were knocked out, they developed carcinomas with significant chromosomal instability similar to tumors seen in humans.
Genes on the other hand, refer only to the DNA sequence (hereditary unit) and it is not necessary that they will be expressed once epigenetic factors are taken into account.
Disorders such as chromosome instability can be inherited via genes, or acquired later in life due to environmental exposure.
[16] The chromosome theory of cancer is a long-standing idea originated from the work of Theodor Boveri, a German biologist, in the early 20th century.
[19] CIN is a more pervasive mechanism in cancer genetic instability than simple accumulation of point mutations.
However, the period of rapid change is transient as tumor cells generally reach an equilibrium abnormal chromosome content and number.
The DNA damage response during interphase of the cell cycle (G1, S and G2 phases) helps protect the genome against structural and numerical cancer chromosome instability.
[28] While some argue the canonical theory of oncogene activation and tumor suppressor gene inactivation, such as Robert Weinberg, some have argued that CIN may play a major role in the origin of cancer cells, since CIN confers a mutator phenotype[29] that enables a cell to accumulate large number of mutations at the same time.
Advances in technology, such as next-generation sequencing, are enabling researchers to study chromosomal abnormalities in cancer cells with greater detail and precision.
[32] For example, BRCA1, BRCA2 and BC-deficient cells have a sensitivity to poly(ADP-ribose) polymerase (PARP) which helps repair single-stranded breaks.
These micronuclei, which reside outside of the main nucleus have defective envelopes and often rupture exposing their genomic DNA content to the cytoplasm.
Often used to diagnose CIN is cytogenetics flow cytometry, Comparative genomic hybridization and Polymerase Chain Reaction.
[38][39][40] In Comparative genomic hybridization, since the DNA is extracted from large cell populations it is likely that several gains and losses will be identified.