Genomic Instability - Causes and Impact

Introduction:

Genomic instability is a feature of cancer cells that causes defects in the DNA (deoxyribonucleic axcid). Changes in DNA can occur, such as mutations, chromosome rearrangements, microsatellites, and increased frequency of base pair mutations. Many pathways, such as DNA damage checkpoint, telomere maintenance, mitotic checkpoint, and DNA repair pathway, maintain genomic stability.

What Is Genomic Instability?

Genomic instability is a state of increased changes or defects in the DNA and genetics that occur during cell division. The defects can be mutations in genes that occur during the repair of damaged DNA. Other defects can be such as missing, broken, extra, or rearranged chromosomes. These genetic changes can also result in cancer; therefore, studying genomic instability will help in understanding certain diseases such as cancer, including its diagnosis, treatment, and prevention. Tumor cells are more genetically unstable than normal cells.

What Are the Genetic Changes That Can Occur?

To find out the genetic changes, a biomarker test is done to identify the alterations in the genes; it is also called tumor profiling or molecular profiling. There are various changes in genetics, which are:

• DNA Mutation: It is also called a genetic variant, which is a change in DNA code that occurs due to errors in the DNA during the multiplication of cells, exposure to mutagens such as UV (ultraviolet) light, certain chemicals, radioactive substances, or certain diseases or viral infections. Somatic mutations (alteration in DNA after fertilization or occurs during a person's life) or acquired mutations cannot be passed down, whereas germline mutation or inherited cancer (altered DNA which gets inherited from the egg or sperm) can be passed down. When the mutation affects a single nucleotide (replaced or missing) is called a point mutation. The types of mutation are:

  1. Missense Mutation: This mutation refers to a change in the single DNA base, which changes the amino acid sequence.

  2. Frameshift Mutation: This mutation refers to the addition or deletion of DNA bases.

  3. Nonsense Mutation: This mutation refers to the change in a single DNA base that forms a stop codon and stops the translation.

  4. LOH (Loss of Heterozygosity): It is a type of mutation where the genetic contribution from one of the parents is lost.

• Chromosomal Instability: This occurs when the large segments of DNA get copied, inserted, rearranged, translocated, inverted, or deleted. They can cause fusion genes, where two different genes join together. In the case of chronic myelogenous leukemias, blood cancer occurs due to the rearrangement of chromosomes.

• Epigenetic Changes (Epimutations): These are the alteration in the chemical structure of DNA and not in the DNA sequence. These changes occur due to exposure to chemicals, drugs, environmental factors such as tobacco, smoke, diet, cadmium (a metal), Epstein-Barr virus, and age.

• Increased Frequency of Base Pair Mutations: These types of mutations are found in cancers that are hereditary and are a result of loss of genomic integrity maintenance genes. For example, in the case of hereditary MYH-associated polyposis (development of multiple adenomatous colon polyps and increased risk for colon and rectal cancer) because of base pair mutations, the DNA base excision repair (BER) gene undergoes increased frequency of transversion from GC (guanine and cytosine) to TA (thymine and adenine).

• Microsatellites: These are simple repeats of one to six nucleotides. This explains why there are several hereditary cancers, including hereditary nonpolyposis colorectal cancer syndrome (HNPCC) and cancers of the stomach, ovaries, lungs, endometrium, and colon. Colorectal cancer, which shows microsatellites' genomic instability, shows a good response to chemotherapy.

What Are the Pathways Involved in the Maintenance of Genomic Stability?

The pathways that are involved are:

• DNA Damage Check Point: The p53 tumor suppressor is a major part of a complex signal transduction network called as p53 pathway. This suppressor recognizes the cells with oncogenic stress and stops the propagation of DNA damage, and in turn, repairs it. When the damage is too severe, it can cause apoptosis (destruction of cells) or senescence (loss of cell power). Ataxia telangiectasia-mutated (ATM) protein also helps in repairing DNA damage.

• DNA Repair Pathway: DNA repair is done with the help of DNA damage response (DDR) along with DNA damage sensors, transducers, effectors, and mediators proteins, which helps in the localization of specific part of genes that has to be repaired. Some DNA pathways are mismatch repair, nucleotide excision repair, DNA double-strand break repair, and base excision repair.

• Mitotic Checkpoint: There are several checkpoints to look after the completion of molecular and cellular processes before stepping into another process. Mitotic checkpoint is a type that looks after the bi-orientation attachment of spindle microtubules to chromosomes before nuclear division. Several proteins are involved in this process, such as BUB1 and 3 and MAD1, 2, and 3. Gene products are also involved, such as aurora B, shugoshin, and PP2A (Protein phosphatase 2A).

• Telomere Maintenance: Telomeres are the ends of a chromosome that prevents chromosome fusion by preventing its recognition as double-strand breaks, and they have nucleotide repeats of TTAGGG along with proteins. In the case of cancers, there is a loss of telomeres. Therefore telomere loss can lead to chromosome fusion and causes chromosome instability.

What Is the Impact of Genomic Instability on Cancer?

The changes in genes, such as mutations, chromosome rearrangements, microsatellites, and increased frequency of base pair mutations, can lead to tumor cells. The processes include:

• Loss of Gene Function, Which Leads to Mutator Phenotype: Precancerous lesions contain genomic instability caretaker genes and can lead to cancer by its increased mutation rate. In hereditary cancers, DNA repair genes are present, and any mutation can lead to genomic instability.

• Oncogene-Induced DNA Replication Stress Model: This involves a mutation in oncogenes, therefore, causing cancer. These mutations are prevented by activation of the DNA damage checkpoint and destroying cells and by inducing senescence by ARF-mediated oncogene. In this process, genomic instability occurs from the stress of DNA replication, which occurs due to increased cell proliferation. When the cell lacks the barriers, genomic instability occurs, which leads to cancer development.

• DNA Promoter Methylation: Hyper or hypomethylation of the promoter can lead to mutations. Long interspersed nuclear element (LINE) is a retrotransposon, and it is heavily methylated in all hypomethylation of LINE can lead to genomic instability and the development of cancer.

• Modifications in Histones: Alterations in histones such as methylation, phosphorylation, acetylation, and ubiquitination can lead to changes in chromatin structures. Therefore leading to genomic instability.

Conclusion:

Therefore, genomic instability can cause changes in DNA and can lead to cancer cells. There are many pathways hypothesized that maintain genomic stability, such as DNA damage checkpoint, telomere maintenance, mitotic checkpoint, and DNA repair pathway.