Genome Instability Causes Cancer

Genome instability is an almost universal feature of cancer cells. The genome instability is probably necessary to enable a cell to accumulate enough mutations to develop to cancerous cell. There are two types of genome instability which are chromosomal instability (CIN) and microsatellite instability (MIN). As tumours usually show either CIN or MIN but not both, therefore the instability is not a chance feature but is the result of selection.

Chromosomal Instability (CIN)

Chromosomal Instability is the alterations in chromosome number in cancer cell genomes. Most of the chromosomal abnormalities seen in tumour cells occurred randomly.

i. Spindle checkpoint

The chromosomal abnormalities can occur at the spindle checkpoint. Tumour cells lose the spindle checkpoint. The spindle checkpoint plays a role to prevent chromosome segregation at mitosis until all chromosomes are correctly attached to the spindle fibers. APC gene is the only one known to be commonly mutated in cancer cell. It is involved in polyposis coli. APC encodes a very large multifunctional protein that is probably involved in a variety of cellular processes. In the colon CIN is observed even in very early adenomas, and APC^-/- cells have abnormal mitotic spindles that lead to chromosomal instability.

ii. DNA Replication with Damage DNA

Furthermore, structural chromosome abnormalities can be a by-product of attempts at DNA replication or mitosis with damage DNA. Tumour cells are able to pass through the cell cycle despite having DNA damage. Initially, cells are trying to constantly repair all types of damage to their DNA. The normal response to such damage is to stop the cell cycle until the damage is repaired, yet cancer cell is loss of that control. A multiprotein machine called the BASC (BRCA1-associated genome surveillance complex), is involved, together with a raft of other proteins. Most of the cell defects have bad repairing at double-strand breaks.

iii. Shorten of Telomeres

Besides, the normal cells may transform to tumour cells when the telomeres become too short to protect chromosome ends. On the other hand, the tumour cells that have gross chromosomal abnormalities, have acquired excessive telomerase to maintain the telomeres which protect chromosome end and the tumour cells become immortal. This will cause the excessive cell division.

Microsatellite Instability (MIN)

Microsatellite Instability involves changes in thousands of microsatellite sequences scattered throughout a cell genome. There are many defects of DNA repairing system that cause cancer-prone genetic disorders.

i. Nucleotide Excision Repair Defects

One of them is nucleotide excision repair defects. When there are single-strand breaks and crosslinks in DNA that has been damaged by ionizing radiation, UV light or chemical mutagens, this repairing system will be activated before the next round of replication. However, the defect of this repairing system will cause cancer. For example, the xeroderma pigmentosum (XP) patients are homozygous for inherited loss of function mutations, and are unable to repair DNA damage caused by UV light. They are exceedingly sensitive to sunlight and develop many tumours on exposed skin.

ii. Base Excision Repair Defects

Another defect repairing system that will cause cancer is base excision repair defects. For instance, colon cancer is caused by defects in the MYH repair enzyme.

iii. Double-strand Breaks Defects

Moreover, the defect of double-strand break repair causes cancer too. The double-strand breaks are repaired by homologous recombination or nonhomologous end joining. The defect of replication error repair also causes cancer like colon cancer.

Comparison between CIN and MIN

CIN	MIN
Loss of heterozygosity (LOH) and causing the loss of whole chromosome.	Loss of allele and not causing the loss of whole chromosome
No nucleotide sequence alteration.	Show nucleotide sequence alteration.
Effective mechanism for changing cellular genome in a way that favours evolution toward neoplasm.	Effective mechanism for changing cellular genome in a way that favours evolution toward neoplasm.

p53 and Apoptosis

Another major contributor to genomic instability is loss or mutation of TP53, the gene encoding the p53 transcription factor. This loss is probably the most common single genetic change in cancer. The p53 has been recognized as ‘the guardian of the genome. p53 is essential in controlling the apoptosis. If the damage of the cell is not repairable, apoptosis is triggered. Tumour cells that lack of p53 may continue to replicate damaged DNA and do not undergo apoptosis.

In conclusion, the genome instability is an important factor to enable a cell to accumulate the mutations to develop to cancerous cell. Without breakdown of the various mechanisms responsible for maintaining the integrity of the genome, it seems like the mutation rate would be too slow to allow tumour progression to reach completion. Cancer research will certainly give some contributions to make us more understand about the tumour progression.

Genome Instability Causes Cancer is a post from: Cytogenetics and Cancer Research