Chromosome instability

Chromosomal instability (CIN) is a type of genomic instability in which chromosomes are unstable, such that either whole chromosomes or parts of chromosomes are duplicated or deleted. 

CIN refers to the increase in rate of addition or loss of entire chromosomes or sections of them.

The unequal distribution of DNA to daughter cells upon mitosis results in a failure to maintain the correct number of chromosomes leading to aneuploidy  or then incorrect number of chromosomes.

The daughter cells do not have the same number of chromosomes as the cell they originated from, and chromosomal instability is the most common form of genetic instability and cause of aneuploidy.

CIN is a commonly occurs in solid and hematological malignancies, especially colorectal cancer.

CIN is characterised by an increased rate of chromosomal errors.

The number of cell divisions undergone by a cell population is related to the rate of chromosomal change.

Chromosomal instability assay measures whole chromosome change rates, and  the partial chromosomal changes such as deletions, insertions, inversion and amplifications to also take into account segmental aneuploidies.

Numerical CIN is a high rate of either gain or loss of whole chromosomes that causes aneuploidy. 

Normal cells make errors in chromosome segregation in 1% of cell divisions, whereas cells with CIN make these errors approximately 20% of cell divisions. 

CIN has a high rate of errors is definitive of CIN.

CIN causes widely variable and heterogeneous chromosomal aberrations.

When CIN is not the causal factor of chromosomal alterations it is often more clonal in nature.

Structural CI: rather than whole chromosomes, fragments of chromosomes may be duplicated or deleted. 

The arrangement of parts of chromosomes as translocations and amplifications or deletions within a chromosome may also occur in structural CIN.

A loss in the repair systems for DNA double-stranded breaks and eroded telomeres can allow chromosomal rearrangements that generate loss, amplification and/or exchange of chromosome segments.

Some inherited genetic predispositions to cancer are as a result of mutations in machinery that responds to and repairs DNA double-stranded breaks: 

ataxia telangiectasia – which is a mutation in the damage response kinase ATM, BRCA1 or MRN complex mutations that play a role in responding to DNA damage. 

When DNA repair is impaired the cell can also lose the ability to induce cell-cycle arrest or apoptosis. 

The cell can replicate or segregate incorrect chromosomes.

Faulty rearrangements can occur when homologous recombination fails to accurately repair double-stranded breaks. 

Broken DNA segments from one chromosome can combine with similar sequences on a non-homologous chromosome. 

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. 

Non-homologous end joining can also join two different chromosomes together that had broken ends. 

Non-reciprocal translocations are dangerous due to the the possibility of producing a dicentric chromosome – a chromosome with two centromeres. 

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. 

Telomeres – which are a protective cap at the end of DNA molecules – normally shorten in each replication cycle. 

Once 25-50 divisions pass, the telomeres can be completely lost, inducing p53 to either permanently arrest the cell or induce apoptosis. 

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.

Telomere degeneration, however, can also induce tumorigenesis in other cells, due to the difference in the presence of a functional p53 damage response. 

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 tumorigenic chromosome structure. 

Telomere degeneration thereby explains the transient period of extreme chromosomal instability observed in many emerging tumors.

In mice where both telomerase and p53 were knocked out, they developed carcinomas with significant chromosomal instability similar to tumors seen in humans.

Spindle assembly checkpoints normally delays cell division until all of the chromosomes are accurately attached to the spindle fibers at the kinetochore: errors may lead to lags on the mitotic spindle and not segregate, leading to aneuploidy and chromosome instability.

Chromosome instability often results in aneuploidy.

Aneuploidy can occur due to loss of a whole chromosome, gain of a whole chromosome or rearrangement of partial chromosomes known as gross chromosomal rearrangements (GCR). 

Most cancer cells are aneuploid, meaning that they have an abnormal number of chromosomes which often have significant structural abnormalities such as chromosomal translocations, where sections of one chromosome are exchanged or attached onto another. 

Changes in ploidy can alter expression of proto-oncogenes or tumor suppressor genes.

Segmental aneuploidy can occur due to deletions, amplifications or translocations, which arise from breaks in DNA, while loss and gain of whole chromosomes is often due to errors during mitosis.

Chromosomes consist of the DNA sequence, and the proteins (such as histones) that are responsible for its packaging into chromosomes. 

With chromosome instability, epigenetic changes can also come into play. 

Genes on the other hand, refer only to the DNA sequence, the hereditary unit, and it is not necessary that they will be expressed once epigenetic factors are taken into account. 

Chromosome instability can be inherited via genes, or acquired later in life due to environmental exposure. 

Chromosome Instability can be acquired is by exposure to ionizing radiation, as it is known to cause DNA damage, which can cause errors in cell replication, which may result in chromosomal instability. 

Chromosomal instability can in turn cause cancer. 

Chromosomal instability syndromes: Bloom syndrome, ataxia telangiectasia and Fanconi anaemia are inherited and are considered to be genetic diseases. 

These disorders are associated with tumor genesis, but often have a distinctive phenotype.

 The genes that control chromosome instability are known as chromosome instability genes and they control pathways such as mitosis, DNA replication, repair and modification,  transcription, and process nuclear transport.

CIN is a more pervasive mechanism in cancer genetic instability than simple accumulation of point mutations. 

The degree of chromosomal instability varies between cancer types. 

In cancers where mismatch repair mechanisms are defective – like some colon and breast cancers, their chromosomes are relatively stable.

Rapid chromosomal instability is thought to be caused by telomere erosion.

The research associated with chromosomal instability is associated with solid tumors.

Studies suggest that chromosome instability can either promote or suppress tumor progression.

A small rate of chromosomal instability leads to tumor progression, while a large rate of chromosomal instability is often lethal to cancer.

Alarge rate of chromosomal instability is detrimental to the survival mechanisms of the cell, and the cancer cell cannot replicate and dies with apoptosis.

The relationship between chromosomal instability and cancer, assists with diagnosis of malignant vs. benign tumors.

The level of chromosome instability is influenced both by DNA damage during the cell cycle and DNA damage response in repairing damage. 

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. However untimely activation of the DNA damage response once cells have committed to the mitosis stage of the cell cycle appears to undermine genome integrity and induce chromosome segregation errors.

The majority of solid malignant tumors are characterized by chromosomal instability, and have gain or loss of whole chromosomes or fractions of chromosomes.

The majority of colorectal and other solid cancers have chromosomal instability (CIN).

Chromosomal instability can be responsible for the development of solid cancers. 

Genetic alterations in a tumor do not necessarily indicate that the tumor is genetically unstable, as genomic instability refers to various instability phenotypes, including the chromosome instability phenotype 

CIN may play a major role in the origin of cancer cells, since CIN confers a mutator phenotype that enables a cell to accumulate large number of mutations at the same time. 

Some studies show that CIN is associated with poor patient outcomes and drug resistance, while others studies actually find that people respond better with high CIN tumors.

CIN can be exploited to generate lethal interactions in tumor cells: ER negative breast cancer patients with the most extreme CIN have the best prognosis, with similar results for ovarian, gastric and non-small cell lung cancers. 

Therapeutic strategies to exacerbate CIN specifically in tumor cells to induce cell death are being implemented.

BRCA1, BRCA2 cells have a sensitivity to poly(ADP-ribose) polymerase (PARP) which helps repair single-stranded breaks. 

PARP tumor suppressing drugs could selectively inhibit BRCA tumors and cause catastrophic effects to breast cancer cells. 

Chromosomal instability has been identified as a genomic driver of metastasis, as chromosome segregation errors during mitosis lead to the formation of structures called micronuclei. 

Micronuclei, which reside outside of the main nucleus have defective envelopes and often rupture exposing their genomic DNA content to the cytoplasm.

Exposure of double-stranded DNA to the cytosol activates anti-viral pathways.

This pathway is normally involved in cellular immune defenses against viral infections. 

CIN drives metastasis through chronic inflammation stemming in a cancer cell-intrinsic manner.

Chromosomal instability can be diagnosed at the cellular level. 

Used to diagnose CIN: cytogenetics flow cytometry, comparative genomic hybridization, polymerase chain reaction, karyotyping, and fluorescence in situ hybridization (FISH) are other techniques that can be used.

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