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. The unequal distribution of DNA to daughter cells upon mitosis results in a failure to maintain euploidy (the correct number of chromosomes) leading to aneuploidy (incorrect number of chromosomes). In other words, the daughter cells do not have the same number of chromosomes as the cell they originated from.

These changes have been studied in solid tumors, which may or may not be cancerous. CIN is a common occurrence in solid and haematological cancers, especially colorectal cancer.^[1] Although many tumours show chromosomal abnormalities, CIN is characterised by an increased rate of these errors.^[2]

Criteria for CIN definition

• As chromosome instability refers to the rate that chromosomes or large portions of chromosomes are changed, there should be comparisons between cells, or cell populations rather than looking at cells individually in order to determine chromosome instability. These differences should be examined statistically as well.^[3]
• The rates in the cell population being tested should be compared to a reference cell population. This is especially true in low phenotype chromosomal instability,^[3] where the changes are subtle.
• The number of cell divisions undergone by a cell population should be related to the rate of chromosomal change.^[3]
• A chromosomal instability assay should measure not only whole chromosome change rates, but also the partial chromosomal changes such as deletions, insertions, inversion and amplifications to also take into account segmental aneuploidies.^[3] This provides a more accurate determination of the presence of chromosome instability.
• The results from polyploid and diploid cells should be identified and separately recorded from one another. This is because the fitness cost (survival to next generation) of chromosomal instability is lower in polyploid cells, as the cell has a greater number of chromosomes to make up for the chromosomal instability it experiences.^[3]
• Polyploid cells are more prone to chromosomal changes, something that should be taken into account when determining the presence and degree of chromosomal instability ^[3]

Classification

Numerical CIN is a high rate of either gain or loss of whole chromosomes; causing 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. Because aneuploidy is a common feature in tumour cells, the presence of aneuploidy in cells does not necessarily mean CIN is present; a high rate of errors is definitive of CIN.^[4] One way of differentiating aneuploidy without CIN and CIN-induced aneuploidy is that CIN causes widely variable (heterogeneous) chromosomal aberrations; whereas when CIN is not the causal factor, chromosomal alterations are often more clonal.^[5]

Structural CIN is different in that rather than whole chromosomes, fragments of chromosomes may be duplicated or deleted. The rearrangement of parts of chromosomes (translocations) and amplifications or deletions within a chromosome may also occur in structural CIN.^[4]

Effects

CIN often results in aneuploidy. There are three ways that aneuploidy can occur. It 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). All of these are hallmarks of some cancers.^[6] Segmental aneuploidy can occur due to deletions, amplifications or translocations, which arise from breaks in DNA,^[3] while loss and gain of whole chromosomes is often due to errors during mitosis.

Genome integrity

Chromosomes consist of the DNA sequence, and the proteins (such as histones) that are responsible for its packaging into chromosomes. Therefore, when referring to chromosome instability, epigenetic changes can also come into play. 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. One way that Chromosome Instability can be acquired is by exposure to ionizing radiation.^[7] Radiation 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. However, chromosomal instability syndromes such as Bloom syndrome, ataxia telangiectasia and Fanconi anaemia are inherited ^[7] and are considered to be genetic diseases. These disorders are associated with tumor genesis, but often have a phenotype on the individuals as well. The genes that control chromosome instability are known as chromosome instability genes and they control pathways such as mitosis, DNA replication, repair and modification.^[8] They also control transcription, and process nuclear transport.^[8]

Chromosome instability and cancer

The research associated with chromosomal instability is associated with solid tumors, which are tumors that refer to a solid mass of cancer cells that grow in organ systems and can occur anywhere in the body. These tumors are opposed to liquid tumors, which occur in the blood, bone marrow, and lymph nodes.^[9]

Although chromosome instability has long been proposed to promote tumor progression, recent studies suggest that chromosome instability can either promote or suppress tumor progression.^[6] The difference between the two are related to the amount of chromosomal instability taking place, as a small rate of chromosomal instability leads to tumor progression, or in other words cancer, while a large rate of chromosomal instability is often lethal to cancer.^[10] This is due to the fact that a large rate of chromosomal instability is detrimental to the survival mechanisms of the cell,^[10] and the cancer cell cannot replicate and dies (apoptosis). Therefore the relationship between chromosomal instability and cancer can also be used to assist with diagnosis of malignant vs. benign tumors.^[10]

A majority of human solid malignant tumors is characterized by chromosomal instability, and have gain or loss of whole chromosomes or fractions of chromosomes.^[3] For example, the majority of colorectal and other solid cancers have chromosomal instability (CIN).^[11] This shows that chromosomal instability can be responsible for the development of solid cancers. However, 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 ^[3]

The role of CIN in carcinogenesis has been heavily debated.^[12] 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^[13] that enables a cell to accumulate large number of mutations at the same time. Scientists active in this debate include Christoph Lengauer, Kenneth W. Kinzler, Keith R. Loeb, Lawrence A. Loeb, Bert Vogelstein and Peter Duesberg.

Diagnosis methods

Chromosomal instability can be diagnosed using analytical techniques at the cellular level. Often used to diagnose CIN is cytogenetics flow cytometry, Comparative genomic hybridization and Polymerase Chain Reaction.^[3] Karyotyping, and fluorescence in situ hybridization (FISH) are other techniques that can be used.^[14] In Comparative genomic hybridization, since the DNA is extracted from large cell populations it is likely that several gains and losses will be identified.^[3] Karyotyping is used for Fanconi Anemia, based on 73 hour whole-blood cultures, which are then stained with Giemsa. Following staining they are observed for microscopically visible chromatid-type aberrations ^[15]

See also

• Microsatellite instability, another form of genomic instability

References

1. Lengauer, C.; K. W. Kinzler; B. Vogelstein (1997). "Genetic instability in colorectal cancers". Nature 386: 623–627. doi:10.1038/386623a0.
2. Geigl JB, Obenauf AC, Schwarzbraun T, Speicher MR (February 2008). "Defining 'chromosomal instability'". Trends Genet. 24 (2): 64–9. doi:10.1016/j.tig.2007.11.006. PMID 18192061.
3. Geigl, Jochen B.; Obenauf, Anna C.; Schwarzbraun, Thomas; Speicher, Michael R. (Feb 2008). "Defining ‘chromosomal instability’". Trends in Genetics 24 (2): 64–69. doi:10.1016/j.tig.2007.11.006. PMID 18192061.
4. McGranahan N, Burrell RA, Endesfelder D, Novelli MR, Swanton C (June 2012). "Cancer chromosomal instability: therapeutic and diagnostic challenges". EMBO Rep. 13 (6): 528–38. doi:10.1038/embor.2012.61. PMID 22595889.
5. Bakhoum SF, Compton DA (April 2012). "Chromosomal instability and cancer: a complex relationship with therapeutic potential". J. Clin. Invest. 122 (4): 1138–43. doi:10.1172/JCI59954. PMC 3314464. PMID 22466654.
6. Yuen, Karen; Wing Yee (2010). "Chromosome Instability (CIN), Aneuploidy and Cancer". Encyclopedia of LIfe Sciences.
7. Wright, Eric G. (1 January 1999). "Inherited and inducible chromosomal instability: a fragile bridge between genome integrity mechanisms and tumourigenesis". The Journal of Pathology 187 (1): 19–27. doi:10.1002/(SICI)1096-9896(199901)187:1<19::AID-PATH233>3.0.CO;2-1.
8. Stirling, Peter C.; Bloom, Michelle S.; Solanki-Patil, Tejomayee; Smith, Stephanie; Sipahimalani, Payal; Li, Zhijian; Kofoed, Megan; Ben-Aroya, Shay; Myung, Kyungjae; Hieter, Philip; Snyder, Michael. "The Complete Spectrum of Yeast Chromosome Instability Genes Identifies Candidate CIN Cancer Genes and Functional Roles for ASTRA Complex Components". PLoS Genetics 7 (4): e1002057. doi:10.1371/journal.pgen.1002057.
9. National Cancer Institute. "Definition of Solid Tumors". Retrieved April 1, 2013.
10. Dabas, Nitika; Byrnes, Diana M.; Rosa, Ashley M.; Eller, Mark S.; Grichnik, James M. (1 January 2012). "Diagnostic Role of Chromosomal Instability in Melanoma". Journal of Skin Cancer 2012: 1–7. doi:10.1155/2012/914267.
11. Michor, Franziska; Iwasa, Yoh; Vogelstein, Bert; Lengauer, Christoph; Nowak, Martin A. "Can chromosomal instability initiate tumorigenesis?". Seminars in Cancer Biology 15 (1): 43–49. doi:10.1016/j.semcancer.2004.09.007.
12. Gibbs, W. Wayt (July 2008). "Untangling the Roots of Cancer". Scientific American 18: 30–39. doi:10.1038/scientificamerican0708-30sp.
13. Loeb, Lawrence A. (2001). "A Mutator Phenotype in Cancer". Cancer Research 61: 3230–3239. Retrieved 3 December 2014.
14. Sakamoto Hojo, E.T.; van Diemen, P.C.M.; Darroudi, F.; Natarajan, A.T. "Spontaneous chromosomal aberrations in Fanconi anaemia, ataxia telangiectasia fibroblast and Bloom's syndrome lymphoblastoid cell lines as detected by conventional cytogenetic analysis and fluorescence in situ hybridisation (FISH) technique". Mutation Research/Environmental Mutagenesis and Related Subjects 334 (1): 59–69. doi:10.1016/0165-1161(95)90031-4.
15. Oostra, Anneke B.; Nieuwint, Aggie W. M.; Joenje, Hans; de Winter, Johan P. (1 January 2012). "Diagnosis of Fanconi Anemia: Chromosomal Breakage Analysis". Anemia 2012: 1–9. doi:10.1155/2012/238731.