Genome instability (also "genetic instability" or "genomic instability") refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or aneuploidy. Genome instability does occur in bacteria. In multicellular organisms genome instability is central to carcinogenesis, and in humans it is also a factor in some neurodegenerative diseases such as amyotrophic lateral sclerosis or the neuromuscular disease myotonic dystrophy.
The sources of genome instability have only recently begun to be elucidated. A high frequency of externally caused DNA damage can be one source of genome instability since DNA damages can cause inaccurate translesion synthesis past the damages or errors in repair, leading to mutation. Another source of genome instability may be epigenetic or mutational reductions in expression of DNA repair genes. Because endogenous (metabolically-caused) DNA damage is very frequent, occurring on average more than 60,000 times a day in the genomes of human cells, any reduced DNA repair is likely an important source of genome instability.
The usual genome situation
Usually, all cells in an individual in a given species (plant or animal) show a constant number of chromosomes, 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. In humans, mutations that would change an amino acid within the protein coding region of the genome occur at an average of only 0.35 per generation (less than one mutated protein per generation).
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 translocations, deletions ...) that modify the standard chromosomal complement. In these cases, it is indicated that the affected organism presents genome instability (also 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.
In neuronal and neuromuscular disease
Of about 200 neurological and neuromuscular disorders, 15 have a clear link to an inherited or acquired defect in one of the DNA repair pathways or excessive genotoxic oxidative stress. Five of them (xeroderma pigmentosum, Cockayne's syndrome, trichothiodystrophy, Down's syndrome, and triple-A syndrome) have a defect in the DNA nucleotide excision repair pathway. Six (spinocerebellar ataxia with axonal neuropathy-1, Huntington's disease, Alzheimer's disease, Parkinson's disease, Down's syndrome and amyotrophic lateral sclerosis) seem to result from increased oxidative stress, and the inability of the base excision repair pathway to handle the damage to DNA that this causes. Four of them (Huntington's disease, various spinocerebellar ataxias, Friedreich’s ataxia and myotonic dystrophy types 1 and 2) often have an unusual expansion of repeat sequences in DNA, likely attributable to genome instability. Four (ataxia-telangiectasia, ataxia-telangiectasia-like disorder, Nijmegen breakage syndrome and Alzheimer's disease) are defective in genes involved in repairing DNA double-strand breaks. Overall, it seems that oxidative stress is a major cause of genomic instability in the brain. A particular neurological disease arises when a pathway that normally prevents oxidative stress is deficient, or a DNA repair pathway that normally repairs damage caused by oxidative stress is deficient.
In cancer, genome instability can occur prior to or as a consequence of transformation. Genome instability can refer to the accumulation of extra copies of DNA or chromosomes, chromosomal translocations, chromosomal inversions, chromosome deletions, 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 "hallmark" for these cells. The unpredictable nature of these events are also a main contributor to the heterogeneity observed among tumour cells.
It is currently accepted that sporadic tumors (non-familial ones) are originated due to the accumulation of several genetic errors. An average cancer of the breast or colon can have about 60 to 70 protein altering mutations, of which about 3 or 4 may be "driver" mutations, and the remaining ones may be "passenger" mutations Any genetic or epigenetic lesion increasing the mutation rate will have as a consequence an increase in the acquisition 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 genes), as well as in genes that are directly controlling cellular proliferation (gatekeeper genes). Genetic instability can originate due to deficiencies in DNA repair, or due to loss or gain of chromosomes, or 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.
Low frequency of mutations without cancer
The protein coding regions of the human genome, collectively called the exome, constitutes only 1.5% of the total genome. As pointed out above, ordinarily there are only an average of 0.35 mutations in the exome per generation (parent to child) in humans. In the entire genome (including non-protein coding regions) there are only about 70 new mutations per generation in humans.
Cause of mutations in cancer
The likely major underlying cause of mutations in cancer is DNA damage. For example, in the case of lung cancer, DNA damage is caused by agents in exogenous genotoxic tobacco smoke (e.g. acrolein, formaldehyde, acrylonitrile, 1,3-butadiene, acetaldehyde, ethylene oxide and isoprene). Endogenous (metabolically-caused) DNA damage is also very frequent, occurring on average more than 60,000 times a day in the genomes of human cells (see DNA damage (naturally occurring)). Externally and endogenously caused damages may be converted into mutations by inaccurate translesion synthesis or inaccurate DNA repair (e.g. by non-homologous end joining). In addition, DNA damages can also give rise to epigenetic alterations during DNA repair. Both mutations and epigenetic alterations (epimutations) can contribute to progression to cancer.
Very frequent mutations in cancer
As noted above, about 3 or 4 driver mutations and 60 passenger mutations occur in the exome (protein coding region) of a cancer. However, a much larger number of mutations occur in the non-protein-coding regions of DNA. The average number of DNA sequence mutations in the entire genome of a breast cancer tissue sample is about 20,000. In an average melanoma tissue sample (where melanomas have a higher exome mutation frequency) the total number of DNA sequence mutations is about 80,000.
Cause of high frequency of mutations in cancer
The high frequency of mutations in the total genome within cancers suggests that, often, an early carcinogenic alteration may be a deficiency in DNA repair. Mutation rates substantially increase (sometimes by 100-fold) in cells defective in DNA mismatch repair or in homologous recombinational DNA repair. Also, chromosomal rearrangements and aneuploidy increase in humans defective in DNA repair gene BLM.
A deficiency in DNA repair, itself, can allow DNA damages to accumulate, and error-prone translesion synthesis past some of those damages may give rise to mutations. In addition, faulty repair of these accumulated DNA damages may give rise to epigenetic alterations or epimutations. While a mutation or epimutation in a DNA repair gene, itself, would not confer a selective advantage, such a repair defect may be carried along as a passenger in a cell when the cell acquires an additional mutation/epimutation that does provide a proliferative advantage. Such cells, with both proliferative advantages and one or more DNA repair defects (causing a very high mutation rate), likely give rise to the 20,000 to 80,000 total genome mutations frequently seen in cancers.
DNA repair deficiency in cancer
In somatic cells, deficiencies in DNA repair sometimes arise by mutations in DNA repair genes, but much more often are due to epigenetic reductions in expression of DNA repair genes. Thus, in a sequence of 113 colorectal cancers, only four had somatic missense mutations in the DNA repair gene MGMT, while the majority of these cancers had reduced MGMT expression due to methylation of the MGMT promoter region. Five reports, listed in the article Epigenetics (see section "DNA repair epigenetics in cancer") presented evidence that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region.
Similarly, for 119 cases of colorectal cancers classified as mismatch repair deficient and lacking DNA repair gene PMS2 expression, Pms2 was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1). The other 10 cases of loss of PMS2 expression were likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.
In cancer epigenetics (see section Frequencies of epimutations in DNA repair genes), there is a partial listing of epigenetic deficiencies found in DNA repair genes in sporadic cancers. These include frequencies of between 13–100% of epigenetic defects in genes BRCA1, WRN, FANCB, FANCF, MGMT, MLH1, MSH2, MSH4, ERCC1, XPF, NEIL1 and ATM located in cancers including breast, ovarian, colorectal and head and neck. Two or three epigenetic deficiencies in expression of ERCC1, XPF and/or PMS2 were found to occur simultaneously in the majority of the 49 colon cancers evaluated. Some of these DNA repair deficiencies can be caused by epimutations in microRNAs as summarized in the MicroRNA article section titled miRNA, DNA repair and cancer.
- Darmon, E; Leach, DRF (2014). "Bacterial Genome Instability". Microbiol. Mol. Biol. Rev. 78: 1–39. doi:10.1128/MMBR.00035-13.
- Schmitt, MW; Prindle, MJ; Loeb, LA (2012). "Implications of genetic heterogeneity in cancer". Ann N Y Acad Sci. 1267: 110–116. doi:10.1111/j.1749-6632.2012.06590.x. PMC . PMID 22954224.
- Møller, P (2005). "Genotoxicity of environmental agents assessed by the alkaline comet assay". Basic Clin Pharmacol Toxicol. 96 (Suppl 1): 1–42. PMID 15859009.
- Keightley PD (February 2012). "Rates and fitness consequences of new mutations in humans". Genetics. 190 (2): 295–304. doi:10.1534/genetics.111.134668. PMC . PMID 22345605.
- Subba Rao K. (2007). Mechanisms of disease: DNA repair defects and neurological disease. Nat Clin Pract Neurol. 3(3):162-72. Review. doi:10.1038/ncpneuro0448 PMID 17342192
- Jeppesen, DK; Bohr, VA; Stevnsner, T (2011). "DNA repair deficiency in neurodegeneration". Prog Neurobiol. 94 (2): 166–200. doi:10.1016/j.pneurobio.2011.04.013. PMID 21550379.
- Corcos, D. (2012), "Unbalanced replication as a major source of genetic instability in cancer cells", AJBR, 2 (3): 160–9, PMC , PMID 23119227
- Storchova, Z.; Pellman, D. (2004), "From polyploidy to aneuploidy, genome instability and cancer", Nat Rev Mol Cell Biol., 5 (1): 45–54, doi:10.1038/nrm1276, PMID 14708009
- Vogelstein B; Papadopoulos N; Velculescu VE; Zhou S; Diaz LA; Kinzler KW (March 2013). "Cancer genome landscapes". Science. 339 (6127): 1546–58. doi:10.1126/science.1235122. PMC . PMID 23539594.
- Nowak, M. A.; Komarova, N. L.; Sengupta, A.; Jallepalli, P.V.; Shih, I.M.; Vogelstein, B.; Lengauer, C. (2002), "The role of chromosomal instability in tumor initiation", Proc. Natl. Acad. Sci. USA, 99 (25): 16226–31, doi:10.1073/pnas.202617399, PMC , PMID 12446840
- Kinzler, K. W.; Vogelstein, B. (April 1997), "Cancer-susceptibility genes. Gatekeepers and caretakers", Nature, 386 (6627): 761–3, doi:10.1038/386761a0, PMID 9126728
- Cahill, D. P.; Kinzler, K. W.; Vogelstein, B.; Lengauer, C. (1999), "Genetic instability and darwinian selection in tumours", Trends Cell Biol., 9 (12): M57–M60, doi:10.1016/S0168-9525(99)01874-0, PMID 10611684
- Hui, T.; Zhen, G.; HuiZhong, L.; BaoFu, Z.; Gang, W.; Qing, Z.; DongSheng, P.; JunNian, Z. (2015), "DNA damage response – A double-edged sword in cancer prevention and cancer therapy", Cancer Letters, 358 (1): 8–16, doi:10.1016/j.canlet.2014.12.038, PMID 25528631
- Lander ES; Linton LM; Birren B; Nusbaum C; Zody MC; Baldwin J; Devon K; Dewar K; Doyle M; FitzHugh W; et al. (February 2001). "Initial sequencing and analysis of the human genome". Nature. 409 (6822): 860–921. doi:10.1038/35057062. PMID 11237011.
- Roach JC; Glusman G; Smit AF; et al. (April 2010). "Analysis of genetic inheritance in a family quartet by whole-genome sequencing". Science. 328 (5978): 636–9. doi:10.1126/science.1186802. PMC . PMID 20220176.
- Campbell CD; Chong JX; Malig M; et al. (November 2012). "Estimating the human mutation rate using autozygosity in a founder population". Nat. Genet. 44 (11): 1277–81. doi:10.1038/ng.2418. PMC . PMID 23001126.
- Bernstein C, Prasad AR, Nfonsam V, Bernstein H. (2013). DNA Damage, DNA Repair and Cancer, New Research Directions in DNA Repair, Prof. Clark Chen (Ed.), ISBN 978-953-51-1114-6, InTech, http://www.intechopen.com/books/new-research-directions-in-dna-repair/dna-damage-dna-repair-and-cancer
- Cunningham, FH; Fiebelkorn, S; Johnson, M; Meredith, C (2011). "A novel application of the Margin of Exposure approach: segregation of tobacco smoke toxicants". Food Chem Toxicol. 49 (11): 2921–2933. doi:10.1016/j.fct.2011.07.019. PMID 21802474.
- Cuozzo, C; Porcellini, A; Angrisano, T; Morano, A; Lee, B; Di Pardo, A; Messina, S; Iuliano, R; Fusco, A; Santillo, MR; Muller, MT; Chiariotti, L; Gottesman, ME; Avvedimento, EV (2007). "DNA damage, homology-directed repair, and DNA methylation". PLoS Genet. 3 (7): e110. doi:10.1371/journal.pgen.0030110. PMC . PMID 17616978.
- O'Hagan HM, Mohammad HP, Baylin SB. Double strand breaks can initiate gene silencing and SIRT1-dependent onset of DNA methylation in an exogenous promoter CpG island. PLoS Genet 2008;4(8) e1000155. doi:10.1371/journal.pgen.1000155 PMID 18704159
- Gottschalk AJ, Timinszky G, Kong SE, Jin J, Cai Y, Swanson SK, Washburn MP, Florens L, Ladurner AG, Conaway JW, Conaway RC (2009). Poly(ADP-ribosyl)ation directs recruitment and activation of an ATP-dependent chromatin remodeler. Proc Natl Acad Sci U S A 106(33):13770-4. doi: 10.1073/pnas.0906920106. PMID 19666485 [PubMed - indexed for MEDLINE] PMCID: PMC2722505
- Yost SE; Smith EN; Schwab RB; Bao L; Jung H; Wang X; Voest E; Pierce JP; Messer K; Parker BA; Harismendy O; Frazer KA (August 2012). "Identification of high-confidence somatic mutations in whole genome sequence of formalin-fixed breast cancer specimens". Nucleic Acids Res. 40 (14): e107. doi:10.1093/nar/gks299. PMC . PMID 22492626.
- Berger MF; Hodis E; Heffernan TP; Deribe YL; Lawrence MS; Protopopov A; Ivanova E; Watson IR; Nickerson E; Ghosh P; Zhang H; Zeid R; Ren X; Cibulskis K; Sivachenko AY; Wagle N; Sucker A; Sougnez C; Onofrio R; Ambrogio L; Auclair D; Fennell T; Carter SL; Drier Y; Stojanov P; Singer MA; Voet D; Jing R; Saksena G; Barretina J; Ramos AH; Pugh TJ; Stransky N; Parkin M; Winckler W; Mahan S; Ardlie K; Baldwin J; Wargo J; Schadendorf D; Meyerson M; Gabriel SB; Golub TR; Wagner SN; Lander ES; Getz G; Chin L; Garraway LA (May 2012). "Melanoma genome sequencing reveals frequent PREX2 mutations". Nature. 485 (7399): 502–6. doi:10.1038/nature11071. PMC . PMID 22622578.
- Narayanan L; Fritzell JA; Baker SM; Liskay RM; Glazer PM (April 1997). "Elevated levels of mutation in multiple tissues of mice deficient in the DNA mismatch repair gene Pms2". Proc. Natl. Acad. Sci. U.S.A. 94 (7): 3122–7. doi:10.1073/pnas.94.7.3122. PMC . PMID 9096356.
- Hegan DC; Narayanan L; Jirik FR; Edelmann W; Liskay RM; Glazer PM (December 2006). "Differing patterns of genetic instability in mice deficient in the mismatch repair genes Pms2, Mlh1, Msh2, Msh3 and Msh6". Carcinogenesis. 27 (12): 2402–8. doi:10.1093/carcin/bgl079. PMC . PMID 16728433.
- Tutt AN; van Oostrom CT; Ross GM; van Steeg H; Ashworth A (March 2002). "Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation". EMBO Rep. 3 (3): 255–60. doi:10.1093/embo-reports/kvf037. PMC . PMID 11850397.
- German, J (Mar 1969). "Bloom's syndrome. I. Genetical and clinical observations in the first twenty-seven patients". Am J Hum Genet. 21 (2): 196–227. PMC . PMID 5770175.
- Halford S; Rowan A; Sawyer E; Talbot I; Tomlinson I (June 2005). "O(6)-methylguanine methyltransferase in colorectal cancers: detection of mutations, loss of expression, and weak association with G:C>A:T transitions". Gut. 54 (6): 797–802. doi:10.1136/gut.2004.059535. PMC . PMID 15888787.
- Truninger, K; Menigatti, M; Luz, J; Russell, A; Haider, R; Gebbers, JO; Bannwart, F; Yurtsever, H; Neuweiler, J; Riehle, HM; Cattaruzza, MS; Heinimann, K; Schär, P; Jiricny, J; Marra, G (2005). "Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer". Gastroenterology. 128 (5): 1160–1171. doi:10.1053/j.gastro.2005.01.056. PMID 15887099.
- Valeri, N; Gasparini, P; Fabbri, M; Braconi, C; Veronese, A; Lovat, F; Adair, B; Vannini, I; Fanini, F; Bottoni, A; Costinean, S; Sandhu, SK; Nuovo, GJ; Alder, H; Gafa, R; Calore, F; Ferracin, M; Lanza, G; Volinia, S; Negrini, M; Mcllhatton, MA; Amadori, D; Fishel, R; Croce, CM (2010). "Modulation of mismatch repair and genomic stability by miR-155". Proc Natl Acad Sci USA. 107 (15): 6982–6987. doi:10.1073/pnas.1002472107. PMC . PMID 20351277.
- Facista, A; Nguyen, H; Lewis, C; Prasad, AR; Ramsey, L; Zaitlin, B; Nfonsam, V; Krouse, RS; Bernstein, H; Payne, CM; Stern, S; Oatman, N; Banerjee, B; Bernstein, C (2012). "Deficient expression of DNA repair enzymes in early progression to sporadic colon cancer". Genome Integr. 3 (1): 3. doi:10.1186/2041-9414-3-3. PMC . PMID 22494821.