Genome instability
Encyclopedia
Usually, all cells in an individual in a given species (plant or animal) show a constant number of chromosome
s, which constitute what is known as the karyotype
defining this species (see also List of number of chromosomes of various organisms), although some species present a very high karyotypic variability.
Sometimes, in a species with a stable karyotype, random variations that modify the normal number of chromosomes may be observed. In other cases, there are structural alterations (chromosomal translocation
s, deletion
s ...) that modify the standard chromosomal complement. In these cases, it is indicated that the affected organism presents genome instability (sometimes, it is named genetic instability, or even chromosomic instability). The process of genome instability often leads to a situation of aneuploidy
, in which the cells present a chromosomic number that is either higher or lower than the normal complement for the species.
Cellular DNA integrity is often compromised in cancer
, and this situation can lead to instability of the cellular genome. Genome instability can refer to the accumulation of extra copies of DNA
or chromosome
s, chromosomal translocation
s, chromosomal inversion
s, chromosome deletion
s, single-strand breaks in DNA, double-strand breaks in DNA, the intercalation of foreign substances into the DNA double helix, or any abnormal changes in DNA tertiary structure that can cause either the loss of DNA, or the misexpression of genes. Situations of genome instability (as well as aneuploidy) are common in cancer cells, and they are considered a "trademark" for these cells.
It is currently accepted that sporadic tumors (non-familial ones) are originated due to the accumulation of several genetic errors. Any genetic lesion increasing the mutation
rate will have as a consequence an increase in the adquisition of new mutations, increasing then the probability to develop a tumor. During the process of tumorogenesis, it is known that diploid cells acquire mutations in genes responsible for maintaining genome integrity (caretaker gene
s), as well as in genes that are directly controlling cellular proliferation (gatekeeper genes). Genetic instability can originate due to individual mutations on a specific gene, or due to loss or gain of chromosomes, or, what seems to be more frequent, due to large scale chromosomal reorganizations. Losing genetic stability will favour tumor development, because it favours the generation of mutants that can be selected by the environment. The mutational model in the generation of tumors has two implicit implications, that are currently widely accepted:
1. aneuploidy is progressively developed starting from a diploid cell, due to the continuous loss, gain and reorganization of chromosomes, and
2. once one gatekeeper gene (a gene responsible for controlling cellular proliferation) has been lost, the chromosomal chaos is continuous, generating chromosomal instability.
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
s, which constitute what is known as the karyotype
Karyotype
A karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
defining this species (see also List of number of chromosomes of various organisms), although some species present a very high karyotypic variability.
Sometimes, in a species with a stable karyotype, random variations that modify the normal number of chromosomes may be observed. In other cases, there are structural alterations (chromosomal translocation
Chromosomal translocation
In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on...
s, deletion
Deletion
Deletion is the act of deleting or removal by striking out material, such as a word or passage, that has been removed from a body of written or printed matter.Deletion may refer to:*File deletion, a way of removing a file from a computer's file system...
s ...) that modify the standard chromosomal complement. In these cases, it is indicated that the affected organism presents genome instability (sometimes, it is named genetic instability, or even chromosomic instability). The process of genome instability often leads to a situation of aneuploidy
Aneuploidy
Aneuploidy is an abnormal number of chromosomes, and is a type of chromosome abnormality. An extra or missing chromosome is a common cause of genetic disorders . Some cancer cells also have abnormal numbers of chromosomes. Aneuploidy occurs during cell division when the chromosomes do not separate...
, in which the cells present a chromosomic number that is either higher or lower than the normal complement for the species.
Cellular DNA integrity is often compromised in cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, and this situation can lead to instability of the cellular genome. Genome instability can refer to the accumulation of extra copies of DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
or chromosome
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
s, chromosomal translocation
Chromosomal translocation
In genetics, a chromosome translocation is a chromosome abnormality caused by rearrangement of parts between nonhomologous chromosomes. A gene fusion may be created when the translocation joins two otherwise separated genes, the occurrence of which is common in cancer. It is detected on...
s, chromosomal inversion
Chromosomal inversion
An inversion is a chromosome rearrangement in which a segment of a chromosome is reversed end to end. An inversion occurs when a single chromosome undergoes breakage and rearrangement within itself. Inversions are of two types: paracentric and pericentric.Paracentric inversions do not include the...
s, chromosome deletion
Deletion
Deletion is the act of deleting or removal by striking out material, such as a word or passage, that has been removed from a body of written or printed matter.Deletion may refer to:*File deletion, a way of removing a file from a computer's file system...
s, single-strand breaks in DNA, double-strand breaks in DNA, the intercalation of foreign substances into the DNA double helix, or any abnormal changes in DNA tertiary structure that can cause either the loss of DNA, or the misexpression of genes. Situations of genome instability (as well as aneuploidy) are common in cancer cells, and they are considered a "trademark" for these cells.
It is currently accepted that sporadic tumors (non-familial ones) are originated due to the accumulation of several genetic errors. Any genetic lesion increasing the mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
rate will have as a consequence an increase in the adquisition of new mutations, increasing then the probability to develop a tumor. During the process of tumorogenesis, it is known that diploid cells acquire mutations in genes responsible for maintaining genome integrity (caretaker gene
Caretaker gene
Changes in the genome that allow uncontrolled cell proliferation or cell immortality are responsible for cancer. It is believed that the major changes in the genome that lead to cancer arise from mutations in tumor suppressor genes. In 1997, Kinzler and Bert Vogelstein grouped these cancer...
s), as well as in genes that are directly controlling cellular proliferation (gatekeeper genes). Genetic instability can originate due to individual mutations on a specific gene, or due to loss or gain of chromosomes, or, what seems to be more frequent, due to large scale chromosomal reorganizations. Losing genetic stability will favour tumor development, because it favours the generation of mutants that can be selected by the environment. The mutational model in the generation of tumors has two implicit implications, that are currently widely accepted:
1. aneuploidy is progressively developed starting from a diploid cell, due to the continuous loss, gain and reorganization of chromosomes, and
2. once one gatekeeper gene (a gene responsible for controlling cellular proliferation) has been lost, the chromosomal chaos is continuous, generating chromosomal instability.