Genetic Instability in Cancer


Sheron Perera, BSc and Bharati Bapat, PhD

Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Department of Lab Medicine and Pathobiology, University of Toronto, Canada .


January 2007



Cancer is a complex disease, with multiple genes in diverse pathways involved in its initiation, progression, invasion and metastasis. In fact, it is widely accepted that the sequential accumulation of mutations that activate oncogenes and disrupt tumour suppressor genes, combined with multiple cycles of clonal selection and evolution facilitate the process of carcinogenesis. It has been estimated that disruption of about six cellular processes are required for transformation (Hanahan and Weinberg, 2000). However, a recent comprehensive sequence evaluation of colon and breast cancer genomes hints that this number may be even higher (9 for breast, 12 for colon) than previously estimated (Sjoblom et al., 2006). If this model holds true then the rate-limiting step in the process of carcinogenesis would be the rate at which new mutations occur and any factor that influences this rate should have an effect on the rate of carcinogenesis.

Genetic instability refers to a set of events capable of causing unscheduled alterations, either of a temporary or permanent nature, within the genome. This term encompasses diverse genetic changes, which can be classified in a variety of ways. For simplicity we will categorize them into two major groups, instability occurring at the chromosomal level and at the nucleotide level. Instability at the nucleotide level occurs due to faulty DNA repair pathways such as base excision repair and nucleotide excision repair and includes instability of microsatellite repeat sequences (MSI) caused by defects in the mismatch repair pathway. The second form or chromosomal instability (CIN), defines the existence of accelerated rate of chromosomal alterations, which result in gains or losses of whole chromosomes as well as inversions, deletions, duplications and translocations of large chromosomal segments. Aneuploidy, which refers to an abnormal karyotype is a hallmark of many cancer cells and is thought to develop as a result of CIN. The observation that cancer cells harbour an abnormal number of chromosomes was made almost a century ago (Boveri, 1914; von Hansemann, 1890) since then we have come a long way in understanding the causes behind this type of instability. To date several pathways and processes have been implicated in CIN including :

    a) pathways involved in telomere and centromere stability,
    b) cell cycle checkpoint pathways and kinases,
    c) pathways regulating diverse proteins via post-translational modifications,
    d) sister chromatid cohesion and chromosome segregation, and
    e) centrosome duplication (Jefford and Irminger-Finger, 2006).
Genetic instability is a very broad topic that encompasses varied fields of biology. Hence, in this article we will focus on nucleotide instability including microsatellite instability; the role of epigenetic modifications, telomeres and the environment in genetic instability; and the role of genetic instability in cancer stem cells. For further details on chromosomal instability please refer to the Deep Insight article titled Chromosomal instability by David Gisselsson.

DNA repair defects

Cells are exposed to many damaging insults capable of causing aberrations in DNA. These include environmental insults such as ultraviolet (UV) light, X-rays and genotoxic chemicals, as well the by-products of endogenous processes such as reactive oxygen species (ROS) and lipid peroxides. In addition, some chemical bonds in DNA tend to spontaneously break down under physiologic conditions, such as when spontaneous hydrolysis of nucleotides occurs resulting in abasic sites (Hoeijmakers, 2001). In order to repair these errors and restore the integrity of the genome, the cell has in place a range of overlapping DNA repair networks. Some of the best evidence for the role of genetic instability in tumourigenesis comes from examples where mutations that cause defects in dna repair mechanisms lead to syndromes of cancer susceptibility. Some of the common examples studied to date will be discussed below.

Mismatch Repair and Microsatellite Instability

Mismatch repair (MMR) has a central role in maintaining genomic stability by repairing DNA replication errors and inhibiting recombination between homologous sequences (Bellacosa, 2001). It is a post-replicative mechanism capable of eliminating base-base mismatches and insertion/deletion loops that arise during DNA synthesis. In the mammalian MMR system two heterodimeric complexes recognize mispaired bases; the hMSH2-hMSH3 (MutSs) complex, which preferentially recognizes insertion/ deletion loops; and the hMSH2-hMSH6 (MutSa) complex, which recognizes both base-base mispairs and insertion/ deletion loops. Two other proteins, hMLH1 and hPMS2, form a heterodimer (MutLa) that is then able to bind to the previously mentioned hMSH2 heterodimers. This complex is thought to interact with and recruit other proteins required for the repair process including Exo1, PCNA, RPA and Polg. In addition, a recent report demonstrated that MutLa is a latent endonuclease that is activated in the presence of a mismatch, MutSa, RFC, PCNA and ATP (Kadyrov et al., 2006). hMLH1 has been shown to form two other heterodimers, MutLs and MutLg, with the hPMS1 and hMLH3 proteins respectively. The roles of these two complexes in post-replicative error repair remains largely inconclusive, although it is believed that each could act as a "backup" for MutLa if the need arose. MMR improves the fidelity of DNA biosynthesis 100-1000 fold and reduces the error rate to one error per 1010 bases (Modrich and Lahue, 1996). Defective MMR results in mirosatellite instability (MSI), characterized by the expansion or contraction of the number of tandem repeats, due to polymerase slippage at the many microsatellite loci that occur throughout the genome.

Germline mutations in the MMR genes are associated with the inherited cancer syndrome, hereditary non-polyposis colorectal cancer (HNPCC). Instability of microsatellite repeats is seen in tumours of as many as 85% of patients with HNPCC, making it a hallmark feature of this syndrome (Aaltonen et al., 1993; Aaltonen et al., 1994). HNPCC, which accounts for about 2% of all CRC cases, is one of the most common cancer predisposition syndromes. It is an autosomal dominant disorder characterized by the development of cancer in the colon as well as in extra-colonic sites including the endometrium, stomach, urinary tract, ovaries, small bowel and brain. MMR deficiency has also been shown to give rise to sporadic colorectal, endometrial and gastric cancers. Defective mismatch repair increases the likelihood of mutations in genes containing repeat sequences that regulate growth, differentiation or apoptosis. Somatic mutations of several genes including TGFBR2, BAX, TCF4, AXIN2, and PTEN are found in MSI positive cancers.

To date there have been reports of families with individuals who have homozygous mutations in the mismatch repair genes MLH1, MSH2, MSH6 and PMS2. Such individuals develop several congenital abnormalities including haematopoietic malignancies, pediatric brain cancers, childhood leukemia, and HNPCC-related cancers and multiple cafe-au-lait spots, a common characteristic of neurofibromatosis type 1 [De Vos et al., 2004; Gallinger et al., 2004; Menko et al., 2004; Trimbath et al., 2001; Whiteside et al., 2002; De Vos et al., 2006). This phenotype manifests in an autosomal recessive fashion, because a mutant allele is inherited from each parent. In addition, there have been reports of individuals carrying compound heterozygous PMS2 mutations who develop Turcot syndrome (De Rosa et al., 2000). This syndrome is defined by the presence of brain tumors and multiple adenomas/colorectal cancers that occur at an early age and is associated with mutations in the APC and MMR genes.

Nucleotide Excision Repair

Nucleotide excision repair (NER) has a broader specificity in that it is able to recognize lesions as diverse as disturbances in the double helix conformation that are caused by UV light, to chemical damage that gives rise to DNA cross links/bulky adducts. The NER pathway is a multi-step process and as many as 30 proteins assemble at the damaged site in a stepwise fashion (Hoogervorst et al., 2005). Individuals born with defects in the NER pathway develop a syndrome known as Xeroderma Pigmentosum (XP). Inherited defects in any one of the 7 nucleotide excision repair XPA-XPG genes as well as XPV (a non NER gene) have been implicated in this disease (Hoeijmakers, 1994). XP patients have a very high susceptibility to developing cancer in areas of skin exposed to the sun. The median age at which skin tumours arise in these patients is 8 years, compared with a average of 60 years observed in the normal population (Kraemer, 1997). In addition a subset of XP patients show neurological defects and emerging evidence appears to indicate that the immune system of XP patients is impaired due to UV exposure (Morison et al., 1985; Norris et al., 1990; Dupuy and Lafforet, 1974; Gaspari et al., 1993; Jimbo et al., 1992). This may indicate defective immune surveillance or increased susceptibility to UV-induced immunomodulation, which may contribute to the increased susceptibility to skin cancer (Hoogervorst et al., 2005). Two other syndromes have been associated with defective NER, the first being Cockayne syndrome characterized by neurological defects and sun sensitivity but no predisposition to skin cancer (Nance and Berry, 1992). The second syndrome trichothiodystrophy is defined by patients with brittle hair caused by a sulphur deficiency, in addition to other features such as mental retardation and small stature (Itin et al., 2001; Bergmann and Egly, 2001).

Base Excision Repair

Base excision repair (BER) is mainly responsible for repairing damage induced by endogenous metabolic processes such as methylation, deamination, reactive oxygen species (ROS) and hydrolysis (Wood et al., 2001). Multiple proteins contribute to BER pathway and enable it to correct non-bulky damaged nucleotides, abasic sites as well as single-strand breaks. The process is initiated by DNA glycosylases specific for various types of damage, which recognize and cleave the N-glycosylic bond that connects the damaged base to the DNA backbone (Barnes et al., 1993). To date, 11 such DNA glycosylases have been identified in mammals (Chan et al., 2006). Reactive oxygen species can modify the C8 position of Guanine to form 7, 8-dihydro-8-oxoguanine (8-oxoG), a major product of such damage. 8-oxoG is highly mutagenic and is able base pair with adenine and cause G:C->T:A transversions (Shibutani et al., 1991). The glycosylases most commonly involved in the removal of 8-oxoG are OGG1, MYH and MTH1. It was discovered recently that biallelic inactivation of MYH can lead to an autosomal recessive form of inherited colorectal cancer known as MYH-associate polyposis (MAP) (Al-Tassan et al., 2002). This came as a surprise to many, as unlike MMR and NER, no inherited defects in these genes had been reported prior to this (Al-Tassan et al., 2002).

Role of Epigenetic Modifications in Genetic Instability

In addition to the sequence alterations and chromosomal aberrations discussed above, epigenetic modifications that affect both DNA and the associated chromatin are capable of influencing gene expression and the stability of the genome. An important point to bear in mind is that although epigenetic modifications are mitotically heritable, they are in a state of constant flux within the lifetime of an individual. The possible contribution of the best-studied epigenetic mechanisms to genetic instability will be discussed below.

Methylation in Tumourigenesis

DNA methylation or the covalent modification of the C-5 position of cytosine residues occurs primarily at the short stretches of CG dinucleotides known as CpG islands. Recent estimates suggest that there are at least 29,000 such regions in the human genome, many of which surround the 5' ends of genes (Lander et al., 2001). In bacteria, methylation is thought to have evolved as a defense against foreign DNA. On the contrary, in eukaryotes methylation is thought to play a role in regulating gene expression and in silencing repeat elements in the genome (Jacobsen, 1999). In normal cells the pattern of expression is stably maintained following DNA replication and cell division by a maintenance enzyme, DNA methyltransferase, (DNMT1). The establishment of DNA modifications is thought to be a highly random event (Whitelaw and Whitelaw, 2006), and could be instrumental in contributing to genetic instability. This is illustrated by the example of DNMT1, which has an estimated error rate of 5%, as well as a small rate of de novo methylation (Goyal et al., 2006; Vilkaitis et al., 2005).

The first epigenetic mechanism implicated in carcinogenesis was DNA hypomethylation (Feinberg and Tycko, 2004). In addition, there have been reports of age related decreases in DNA methylation levels that occur in a tissue specific manner (Feinberg and Vogelstein, 1983; Golbus et al., 1990). It is likely that these changes contribute to the age-related increase in incidence of illnesses, such as carcinogenesis and autoimmunity (Richardson, 2003). Examples of genes hypomethylated in cancer include cyclin d2 in gastric carcinoma (Oshimo et al., 2003), Ha-RAS in lung and colon cancer (Feinberg and Vogelstein, 1983) and Maspin and S100P in pancreatic cancer (Sato et al., 2004). Several studies have implicated genomic hypomethylation in the genetic instability seen in many cancers. In a recent study of colorectal carcinomas it was shown that genome-wide hypomethylation is strongly correlated with chromosomal instability (Rodriguez et al., 2006), indicating the potential role of hypomethylation in destabilizing the genome.

CpG islands commonly occur in the promoter regions, thus hypermethylation of this region has been shown to silence gene expression (Bird, 2002). This was first identified in the retinoblastoma protein (Rb) followed by promoter hypermethylation of several other tumour suppressor and cell-cycle regulatory genes (Greger et al., 1989). It is believed that hypermethylation too is an early event that may precede the neoplastic process (Momparler, 2003; Nephew and Huang, 2003). A prime example of the role of hypermethylation in contributing to genetic instability is hMLH1 inactivation, where promoter hypermethylation is thought to be primarily responsible for approximately 15% of sporadic colorectal cancers associated with microsatellite instability (Kane et al., 1997; Herman et al., 1998). In a study by Costello et al. (Lander et al., 2001), 1184 unselected CpG islands were screened in 98 primary human tumours using restriction landmark genomic scanning (RLGS). This study found that on average about 600 CpG islands were aberrantly methylated in tumours, indicating the potentially vast number of genes likely to be aberrantly expressed due to this mechanism.

Methylation also plays an important role in inactivating one copy of the X chromosome, so that equal gene dosage is maintained in the somatic cells of males and females (Park and Kuroda, 2001). Imprinting refers to the phenomenon by which only the maternal or paternal allele of certain genes are expressed and the second allele is suppressed via methylation (Ferguson-Smith and Surani, 2001). Therefore demethylation of such imprinted genes can lead to a situation where both alleles are expressed (Feinberg, 2000; Feinberg et al., 2002). This has been shown to contribute to malignancies by activating a normally silent copy of the gene as in the case of IGF2 (Rainier et al., 1993). Aberrant imprinting can also silence a normally active copy of a gene involved in growth inhibition as shown with p57kip (Thompson et al., 1996). Loss of imprinting has also been shown to contribute to certain congenital syndromes such as the Beckwith-Wiedemann Syndrome , Prader-Willi Syndrome (PWS) and Angelman's Syndrome (AS) (Maher and Reik, 2000; Reik et al., 2001). Beckwith-Wiedmann syndrome occurs due to loss of imprinting on chromosome 11p, and is characterized by pre- and post-natal overgrowth syndrome, often accompanied by exomphalos and a predisposition for childhood tumours (Paulsen and Ferguson-Smith, 2001). Loss of imprinting on chromosome 15q of the paternal and maternal alleles, lead to PWS and AS respectively. PWS is characterized by mild mental retardation, short stature and obesity, while AS is characterized by ataxia, severe mental retardation accompanied by a lack of speech, hyperactivity and a predisposition for inappropriate bouts of laughter (Paulsen and Ferguson-Smith, 2001).

Histone modification

Chromatin, which consists of repeating units called nucleosomes, is the packaged form of DNA present in the eukaryotic cell. Each nucleosome consists of DNA that is wrapped tightly around a group of conserved, highly basic proteins known as histones. Histones can be covalently modified by acetylation, methylation, phosphorylation, ubiquitination and Poly-ADP ribosylation, which ultimately influence the tightness of the protein-DNA interaction and can create a code that can be recognized by chromatin remodeling complexes (Strahl and Allis, 2000; Turner, 2002). This idea of a histone code suggests that specific patterns of modifications are read like a molecular bar code, resulting in the recruitment of cellular machinery that alter the chromatin state (Cosgrove and Wolberger, 2005). The role of histone modification and chromatin remodeling in the carcinogenic process is a rapidly evolving field. To date histone acetylation and methylation have been implicated in cancer.

It is the interplay between histone acteylases (HATs) and histone deacetylates (HDACs) that determine the precise balance of acetylation within the nucleus. Abnormal HDAC activity has been commonly observed in haemotological malignancies (Espino et al., 2005). Studies done in these cancers have shown that fusion proteins such as RAR-PML and RAR-PLZF can recruit HDACs, which in turn lead to aberrant transcriptional repression that halts differentiation (de Ruijter et al., 2003; Hong et al., 1997). It has been proposed that a dynamic relationship exists between histone modifications, chromatin structure and DNA methylation (Szyf et al., 2004; Ting et al., 2004). For example it has been shown that histone acetylation and gene activation, results in DNA demethylation (Szyf et al., 2004), while the opposite situation where low steady state level of histone acetylation and methylation, results in the recruitment of DNMT1 and DNA methylation of regulatory regions (Espino et al., 2005). Thus, it is mechanistically possible that skewed regulation of this inter-relationship could lead to genetic instability.

The role of the environment in genetic instability

Despite the many checkpoints and repair processes the cell has in place to prevent the occurrence and propagation of errors, genetic instability is a widespread phenomenon observed in many cancers. Thus, it appears likely that the environment in which these cancers arise somehow selects for and facilitates the clonal expansion of cells that show instability in their genome. This point is supported by the observation that colorectal tumours, which show an MSI or CIN phenotype exclusively, are located in anatomically distinct regions. MSI tumours are localized in the proximal section of the intestine, while CIN tumours are more frequently seen in the distal colon and rectum (Lengauer et al., 1998; Lindblom, 2001). This review will therefore briefly summarize what is currently known about the role of the macroenvironment, specifically dietary factors and the microenvironment, specifically hypoxia in the development of genetic instability.

It is possible that environmental agents are able to instigate the process of instability, as illustrated by work done in colorectal carcinogenesis. Heterocyclic amines (HAA) are carcinogens that are a common product of cooking beef, pork, poultry and fish at high temperatures. A study by Wu et al., demonstrated that patients with MSI positive cancers had significantly higher dietary exposure to heterocyclic amines, as determined by the preference for well-done meat and the frequent use of techniques that produces HAA (Wu et al., 2001). 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine or PhIP, the most abundant heterocyclic amine in the western diet, is a bulky adduct forming agent that is able to cause a variety of cancers in experimental animals (Ghoshal et al., 1994; Layton et al., 1995; Shirai et al., 1997; Tudek et al., 1989). Another powerful rodent carcinogen is MNNG (N-methyl-N'-nitro-N-nitrosoguanidine) (Sugimura and Terada, 1998). An alkylating agent, it is able to preferentially methylate the O6 position of deoxyguanosine residues in DNA. Gastrointestinal cells are continually exposed to both PhIP and MNNG at varying concentrations. In a study undertaken to determine if carcinogen exposure can influence the type of instability seen in cells, it was found that cells resistant to PhIP, developed a chromosomal instability or CIN phenotype, while cells resistant to MNNG exhibited MSI and associated mismatch repair defects (Bardelli et al., 2001). This data suggests that exposure to certain dietary carcinogens, may in fact select for cancer cells with distinct types of genetic instability and vice versa (Bardelli et al., 2001).

Role of tumour microenvironment in genetic instability

The tumour microenvironment has been proposed to contribute to the increased genetic instability seen in cancer cells. Several studies have lent support to this notion, including a study that demonstrated a higher rate of genomic instability of mouse cells when grown in vivo as subcutaneous tumour implants in syngeneic mice, as measured using an EGFP reporter gene and a genomic minisatellite locus (Li et al., 2001). More specifically, hypoxia has been singled out as a major microenvironmental factor. Hypoxia, which appears to occur transiently within the tumour microenvironment, has been shown to lead to cycles of hypoxia and reoxygenation (Bindra and Glazer, 2005). This is thought to lead to DNA damage as a result of reactive oxygen species (ROS) and the enzyme superoxide dismutase. In addition to ROS leading to the formation of 8-oxoG, and accumulating evidence suggest a role for oxygen and ROS in causing single and double strand breaks (Bindra and Glazer, 2005). In addition to its ability to cause aberrations in DNA, these cycles of hypoxia and reoxygenation have been shown to affect DNA synthesis, by both interrupting this process and by leading to over-replication after reoxygenation (Bindra and Glazer, 2005; Cuvier et al., 1997; Young. and Hill, 1990; Young et al., 1990). Other studies have found that it is hypoxia induced gene amplification of p-Glycoprotein that is responsible for the observed resistance to adriamycin and doxorubicin (Luk et al., 1990; Rice et al., 1987), indicating that gene amplification may also be caused by hypoxia. Furthermore, emerging evidence suggests that hypoxia can influence the integrity of the genome by impacting upon DNA repair pathways. As described above, MLH1 is one of the key genes involved in mismatch repair. It was shown that hypoxia downregulates the expression of the MLH1 gene at the transcriptional level and this was thought to occur via chromatin remodeling, as treatment with an histone deacteylase inhibitor prevented the aforementioned decrease (Mihaylova et al., 2003). It has also been demonstrated that hypoxia enriches for MMR deficient cells (Hardman et al., 2001). Thus, DNA damage, defective DNA synthesis, gene amplification and the deregulation of DNA repair pathways all appear to be mechanisms by which hypoxia contributes to genetic instability. Little is still known about other microenvironmental factors that may lead to instability. However, it has been suggested that the tumour microenvironment may represent in mammalian cells a conserved evolutionary mechanism that increases the rate of mutation in response to cellular stresses, which preferentially gives cancer cells a survival advantage (Bindra and Glazer, 2005).

Telomeres and Genetic Instability

One mechanism that can bring about chromosomal instability (CIN) is telomere loss. Although CIN is not addressed in detail in this paper, the role of telomeres is briefly summarized to highlight the important role it may play in carcinogenesis and the implications it may have in the field of genetic instability.

Telomeres refer to the segments of DNA bound by specific proteins that cap the ends of chromosomes and in doing so acts as a buffer to prevent loss of valuable genomic sequence during replication (Hoeijmakers, 2001), as well as to prevent chromosomes fusing at the ends (Jefford and Irminger-Finger, 2006). A RNA primer is required for the process of DNA replication. Thus, when replication proceeds from the 5'->3' direction, it leaves a stretch of unreplicated DNA at the 5' end. This leads to a gradual loss of telomeric repeats and the consequent shortening of telomeres by about 50-200 base pairs, after each round of replication (Jefford and Irminger-Finger, 2006). A specific enzyme, telomerase, maintains the telomere length. Telomerase consists of two main components; the reverse trancriptase component (hTERT), which is only expressed in cells where telomerase activity is present; and the ribonucleoprotein moiety (hTERC/hTR), which is expressed ubiquitously in all cells. In adults, telomerase activity has been observed only in immature germ cells, certain stem/progenitor cells and in a subset of somatic cells such as human fibroblasts.

Telomerase is suppressed in the majority of somatic cells leading to the continuing telomere attrition, which leads to irreversible cell-cycle arrest known as replicative cell senescence. It has been demonstrated that primary human fibroblasts that have lost the ability to senesce, display telomere shortening and eventually enter a crisis stage that culminates in chromosome fusion, aneuploidy and cell death (Counter et al., 1992). It has been proposed that it is therefore important for cancer cells to regain the ability to maintain telomeres, in order to avoid senescence and extensive chromosome fusion during crisis (Counter et al., 1992; Harley, 1995). In fact it has been shown that about 85-90% of human cancers have reactivated telomerase and are able to maintain telomere length (Jefford and Irminger-Finger, 2006). Interestingly cancer cells that are deficient for telomerase activity are able to maintain telomere length via a mechanism known as alternative lengthening of telomeres or ALT. It has been suggested that the ALT mechanism makes use of DNA repair pathways and recombination to maintain telomere length (Reddel, 2003). Thus, whichever mechanism employed by the cell, it appears that maintaining telomere length is critical for tumourigenesis and cellular immortalization (Jefford and Irminger-Finger, 2006). Telomere maintenance is also required for chromosomal instability. Given that cancer cells inevitably display properties of telomere maintenance and genetic instability, it has been proposed that telomere loss could be either a cause or a consequence of genetic instability (Jefford and Irminger-Finger, 2006), or perhaps be involved in both.

However, conflicting with this view is the observation that the telomeres of invasive human cancers are often shorter than their normal counterparts (de Lange, 1995). Studies in telomerase deficient mice (mTERC-/-) provided a plausible explanation to this paradox (Ju and Rudolph, 2006). In these mice telomere shortening induced chromosome instability and in doing so increased the rate of tumour initiation (Rudolph et al., 2001). At the same time it was seen that telomere loss can inhibit tumour progression and the development of macroscopically advanced tumours (Rudolph et al., 2001; Gonzalez-Suarez et al., 2000; Greenberg et al., 1999; Rudolph et al., 1999). This indicates that the timing at which the telomeres shortening occurs plays a crucial role in cancer development (Meeker et al., 2004). In fact it was found that 88.6% of precursor lesions known as intraepithelial neoplasia lesions display shortening of telomeres (Meeker et al., 2004).

Cancer Stem Cells and Genetic instability

The stem cell model of carcinogenesis has been rapidly growing in popularity. The American Association for Cancer Research Stem Cell Workshop defined a cancer stem cell as a cell within the tumour that possesses the capacity to self-renew, and in doing so gives rise to the heterogeneous lineages that comprise the tumour. Cancer cells may arise therefore from tissue stem cells that have acquired mutations that render them cancerous, or it may be a more differentiated i.e. progenitor cell that may have "re-acquired" stem cell like properties due to mutations (Clarke et al., 2006). Either scenario is different from the widely accepted stochastic model of carcinogenesis. Cancer stem cells or cancer initiating cells have been identified to date in acute myelogenous leukemia (Bonnet and Dick, 1997), breast tumours (Al-Hajj et al., 2003), brain tumours (Singh et al., 2003; Singh et al., 2004) and most recently in a subset of colon tumours (O'Brien et al., 2006). The discovery of the existence of cancer initiating cells raises some very important questions regarding whether genetic instability exists within these cells and what role if any it plays in these cells.

There is an increased likelihood that exogenous and endogenous environmental agents cause a greater degree of genetic and epigenetic changes in stem cells; as opposed to their differentiated counterparts, who by their very definition have shorter life spans. This is a fairly novel field, and much more research needs to be undertaken to determine the relationship between genetic instability and cancer stem cells. However some preliminary evidence comes from work done in haematological malignancies and telomere instability. Haematological neoplasia can be divided in to three stages, pre-malignant, chronic and acute, with the last being the most advanced stage. Telomere loss was shown to be rapid during the progression of chronic myeloid leukemia, in fact patients in the late chronic phase had shorter telomeres than those in early chronic phase (Brummendorf et al., 2001). In addition patients with pre-malignant disease with shorter telomeres had more cytogenetic abnormalities (Ohyashiki et al., 1999) and a poorer prognosis with increased rates of leukemic transformation (Sieglova et al., 2004). These observations suggest that shortening telomeres can bring about genetic instability in cancer stem cells, which is further supported by the observation that telomere shortening occurs very early in carcinogenic cascade, indicating the likelihood that this process occurs in cancer stem cells. Additionally, progression of pre-malignant disease to acute stage was shown to correlate with telomerase activation (Ohyashiki et al., 2001). Together these observation implicate telomere attrition and telomerase reactivation as risk factors for the malignant transformation of stem cells (Ju and Rudolph, 2006). On a separate note, loss of heterozygosity of cancer related genes in mammary stem cells have been shown to contribute to genetic instability in progeny cells and result in subsequent breast cancer development (Al-Hajj et al., 2003; Deng et al., 1996; Smith and Boulanger, 2002; Nguyen and Ravid, 2006). This observation also supports the notion that the theories of genetic instability and cancer stem cells are not mutually exclusive.

Summary and Conclusion

It is well documented that the sequential accumulation of mutations in tumour suppressors and oncogenes are required for the process of tumourigenesis to proceed. Any event(s) that accelerates the spontaneous rate of alterations in the cells supports this process, illustrated by the prevalence of genetic instability in cancer cells. DNA repair processes play a critical role in repairing damaged DNA, and in ensuring faithful transmission of genetic material. Thus, it comes as no surprise that inherited defects of genes in these pathways, lead to several disorders, most of which increase susceptibility to cancer by many fold, and maybe evident by the early age at diagnosis of cancer in these in patients. In addition to genetic alterations, epigenetic modifications such as methylation and histone modification have been shown to bring about genetic instability. In addition, it is likely that the prolonged exposure to environmental agents and/ or processes may, in concert with individual genetic factors determine the establishment of tumours. Despite these observations, the existence of subsets of tumours that lack an identifiable form of instability has led to skepticism regarding the need for genetic instability in the process of cellular transformation. However, this may indicate that the importance of genetic instability in carcinogenesis differs based on several factors including an individual's genetic background, tissue of interest, baseline mutation rate, environmental exposure, age and time of onset. There also remains the question of whether genetic instability is the driving force behind the process of tumourigenesis or if it is simply a bystander effect of the process. Thus the precise role of genetic instability in the various cancers needs to be defined further. An additional challenge is posed by the prospective identification of cancer stem cells, which call for theory of genetic instability to be reviewed in a new light.


The hallmarks of cancer.
Hanahan D, Weinberg RA
Cell. 2000 ; 100 (1) : 57-70.
PMID 10647931
The consensus coding sequences of human breast and colorectal cancers.
Sjöblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE
Science (New York, N.Y.). 2006 ; 314 (5797) : 268-274.
PMID 16959974
Zur Frage der Enstehung Maligner Tumoren
Boveri T
Virchows Arch. Pathol. Anat
von Hansemann D
18 ; 119 : 299-326.
Mechanisms of chromosome instability in cancers.
Jefford CE, Irminger-Finger I
Critical reviews in oncology/hematology. 2006 ; 59 (1) : 1-14.
PMID 16600619
Genome maintenance mechanisms for preventing cancer.
Hoeijmakers JH
Nature. 2001 ; 411 (6835) : 366-374.
PMID 11357144
Functional interactions and signaling properties of mammalian DNA mismatch repair proteins.
Bellacosa A
Cell death and differentiation. 2001 ; 8 (11) : 1076-1092.
PMID 11687886
Endonucleolytic function of MutLalpha in human mismatch repair.
Kadyrov FA, Dzantiev L, Constantin N, Modrich P
Cell. 2006 ; 126 (2) : 297-308.
PMID 16873062
Mismatch repair in replication fidelity, genetic recombination, and cancer biology.
Modrich P, Lahue R
Annual review of biochemistry. 1996 ; 65 : 101-133.
PMID 8811176
Clues to the pathogenesis of familial colorectal cancer.
Aaltonen LA, Peltomäki P, Leach FS, Sistonen P, Pylkkänen L, Mecklin JP, Järvinen H, Powell SM, Jen J, Hamilton SR
Science (New York, N.Y.). 1993 ; 260 (5109) : 812-816.
PMID 8484121
Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients.
Aaltonen LA, Peltomäki P, Mecklin JP, Järvinen H, Jass JR, Green JS, Lynch HT, Watson P, Tallqvist G, Juhola M
Cancer research. 1994 ; 54 (7) : 1645-1648.
PMID 8137274
Novel PMS2 pseudogenes can conceal recessive mutations causing a distinctive childhood cancer syndrome.
De Vos M, Hayward BE, Picton S, Sheridan E, Bonthron DT
American journal of human genetics. 2004 ; 74 (5) : 954-964.
PMID 15077197
Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation.
Gallinger S, Aronson M, Shayan K, Ratcliffe EM, Gerstle JT, Parkin PC, Rothenmund H, Croitoru M, Baumann E, Durie PR, Weksberg R, Pollett A, Riddell RH, Ngan BY, Cutz E, Lagarde AE, Chan HS
Gastroenterology. 2004 ; 126 (2) : 576-585.
PMID 14762794
A homozygous MSH6 mutation in a child with café-au-lait spots, oligodendroglioma and rectal cancer.
Menko FH, Kaspers GL, Meijer GA, Claes K, van Hagen JM, Gille JJ
Familial cancer. 2004 ; 3 (2) : 123-127.
PMID 15340263
Café-au-lait spots and early onset colorectal neoplasia: a variant of HNPCC?
Trimbath JD, Petersen GM, Erdman SH, Ferre M, Luce MC, Giardiello FM
Familial cancer. 2001 ; 1 (2) : 101-105.
PMID 14574005
A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple café-au-lait spots.
Whiteside D, McLeod R, Graham G, Steckley JL, Booth K, Somerville MJ, Andrew SE
Cancer research. 2002 ; 62 (2) : 359-362.
PMID 11809679
PMS2 mutations in childhood cancer.
De Vos M, Hayward BE, Charlton R, Taylor GR, Glaser AW, Picton S, Cole TR, Maher ER, McKeown CM, Mann JR, Yates JR, Baralle D, Rankin J, Bonthron DT, Sheridan E
Journal of the National Cancer Institute. 2006 ; 98 (5) : 358-361.
PMID 16507833
Evidence for a recessive inheritance of Turcot's syndrome caused by compound heterozygous mutations within the PMS2 gene.
De Rosa M, Fasano C, Panariello L, Scarano MI, Belli G, Iannelli A, Ciciliano F, Izzo P
Oncogene. 2000 ; 19 (13) : 1719-1723.
PMID 10763829
Nucleotide excision repair- and p53-deficient mouse models in cancer research.
Hoogervorst EM, van Steeg H, de Vries A
Mutation research. 2005 ; 574 (1-2) : 3-21.
PMID 15914203
Human nucleotide excision repair syndromes: molecular clues to unexpected intricacies.
Hoeijmakers JH
European journal of cancer (Oxford, England : 1990). 1994 ; 30A (13) : 1912-1921.
PMID 7734202
Sunlight and skin cancer: another link revealed.
Kraemer KH
Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (1) : 11-14.
PMID 8990152
Impaired immune function in patients with xeroderma pigmentosum.
Morison WL, Bucana C, Hashem N, Kripke ML, Cleaver JE, German JL
Cancer research. 1985 ; 45 (8) : 3929-3931.
PMID 4016759
Immune function, mutant frequency, and cancer risk in the DNA repair defective genodermatoses xeroderma pigmentosum, Cockayne's syndrome, and trichothiodystrophy.
Norris PG, Limb GA, Hamblin AS, Lehmann AR, Arlett CF, Cole J, Waugh AP, Hawk JL
The Journal of investigative dermatology. 1990 ; 94 (1) : 94-100.
PMID 2295840
A defect of cellular immunity in Xeroderma pigmentosum.
Dupuy JM, Lafforet D
Clinical immunology and immunopathology. 1974 ; 3 (1) : 52-58.
PMID 4611672
Impaired interferon production and natural killer cell activation in patients with the skin cancer-prone disorder, xeroderma pigmentosum.
Gaspari AA, Fleisher TA, Kraemer KH
The Journal of clinical investigation. 1993 ; 92 (3) : 1135-1142.
PMID 7690772
Role of excision repair in UVB-induced depletion and recovery of human epidermal Langerhans cells.
Jimbo T, Ichihashi M, Mishima Y, Fujiwara Y
Archives of dermatology. 1992 ; 128 (1) : 61-67.
PMID 1739289
Cockayne syndrome: review of 140 cases.
Nance MA, Berry SA
American journal of medical genetics. 1992 ; 42 (1) : 68-84.
PMID 1308368
Trichothiodystrophy: update on the sulfur-deficient brittle hair syndromes.
Itin PH, Sarasin A, Pittelkow MR
Journal of the American Academy of Dermatology. 2001 ; 44 (6) : 891-920.
PMID 11369901
Trichothiodystrophy, a transcription syndrome.
Bergmann E, Egly JM
Trends in genetics : TIG. 2001 ; 17 (5) : 279-286.
PMID 11335038
Human DNA repair genes
Wood RD et al
Science. 2001 ; 291 (5507) : 1284-1289.
DNA repair.
Barnes DE, Lindahl T, Sedgwick B
Current opinion in cell biology. 1993 ; 5 (3) : 424-433.
PMID 8352959
Base excision repair fidelity in normal and cancer cells.
Chan KK, Zhang QM, Dianov GL
Mutagenesis. 2006 ; 21 (3) : 173-178.
PMID 16613912
Insertion of specific bases during DNA synthesis past the oxidation-damaged base 8-oxodG.
Shibutani S, Takeshita M, Grollman AP
Nature. 1991 ; 349 (6308) : 431-434.
PMID 1992344
Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors.
Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingston AL, Williams GT, Hodges AK, Davies DR, David SS, Sampson JR, Cheadle JP
Nature genetics. 2002 ; 30 (2) : 227-232.
PMID 11818965
Initial sequencing and analysis of the human genome.
Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J, Devon K, Dewar K, Doyle M, FitzHugh W, Funke R, Gage D, Harris K, Heaford A, Howland J, Kann L, Lehoczky J, LeVine R, McEwan P, McKernan K, Meldrim J, Mesirov JP, Miranda C, Morris W, Naylor J, Raymond C, Rosetti M, Santos R, Sheridan A, Sougnez C, Stange-Thomann N, Stojanovic N, Subramanian A, Wyman D, Rogers J, Sulston J, Ainscough R, Beck S, Bentley D, Burton J, Clee C, Carter N, Coulson A, Deadman R, Deloukas P, Dunham A, Dunham I, Durbin R, French L, Grafham D, Gregory S, Hubbard T, Humphray S, Hunt A, Jones M, Lloyd C, McMurray A, Matthews L, Mercer S, Milne S, Mullikin JC, Mungall A, Plumb R, Ross M, Shownkeen R, Sims S, Waterston RH, Wilson RK, Hillier LW, McPherson JD, Marra MA, Mardis ER, Fulton LA, Chinwalla AT, Pepin KH, Gish WR, Chissoe SL, Wendl MC, Delehaunty KD, Miner TL, Delehaunty A, Kramer JB, Cook LL, Fulton RS, Johnson DL, Minx PJ, Clifton SW, Hawkins T, Branscomb E, Predki P, Richardson P, Wenning S, Slezak T, Doggett N, Cheng JF, Olsen A, Lucas S, Elkin C, Uberbacher E, Frazier M, Gibbs RA, Muzny DM, Scherer SE, Bouck JB, Sodergren EJ, Worley KC, Rives CM, Gorrell JH, Metzker ML, Naylor SL, Kucherlapati RS, Nelson DL, Weinstock GM, Sakaki Y, Fujiyama A, Hattori M, Yada T, Toyoda A, Itoh T, Kawagoe C, Watanabe H, Totoki Y, Taylor T, Weissenbach J, Heilig R, Saurin W, Artiguenave F, Brottier P, Bruls T, Pelletier E, Robert C, Wincker P, Smith DR, Doucette-Stamm L, Rubenfield M, Weinstock K, Lee HM, Dubois J, Rosenthal A, Platzer M, Nyakatura G, Taudien S, Rump A, Yang H, Yu J, Wang J, Huang G, Gu J, Hood L, Rowen L, Madan A, Qin S, Davis RW, Federspiel NA, Abola AP, Proctor MJ, Myers RM, Schmutz J, Dickson M, Grimwood J, Cox DR, Olson MV, Kaul R, Raymond C, Shimizu N, Kawasaki K, Minoshima S, Evans GA, Athanasiou M, Schultz R, Roe BA, Chen F, Pan H, Ramser J, Lehrach H, Reinhardt R, McCombie WR, de la Bastide M, Dedhia N, Blöcker H, Hornischer K, Nordsiek G, Agarwala R, Aravind L, Bailey JA, Bateman A, Batzoglou S, Birney E, Bork P, Brown DG, Burge CB, Cerutti L, Chen HC, Church D, Clamp M, Copley RR, Doerks T, Eddy SR, Eichler EE, Furey TS, Galagan J, Gilbert JG, Harmon C, Hayashizaki Y, Haussler D, Hermjakob H, Hokamp K, Jang W, Johnson LS, Jones TA, Kasif S, Kaspryzk A, Kennedy S, Kent WJ, Kitts P, Koonin EV, Korf I, Kulp D, Lancet D, Lowe TM, McLysaght A, Mikkelsen T, Moran JV, Mulder N, Pollara VJ, Ponting CP, Schuler G, Schultz J, Slater G, Smit AF, Stupka E, Szustakowski J, Thierry-Mieg D, Thierry-Mieg J, Wagner L, Wallis J, Wheeler R, Williams A, Wolf YI, Wolfe KH, Yang SP, Yeh RF, Collins F, Guyer MS, Peterson J, Felsenfeld A, Wetterstrand KA, Patrinos A, Morgan MJ, de Jong P, Catanese JJ, Osoegawa K, Shizuya H, Choi S, International Human Genome Sequencing Consortium, Chen YJ
Nature. 2001 ; 409 (6822) : 860-921.
PMID 11237011
Gene silencing: Maintaining methylation patterns.
Jacobsen SE
Current biology : CB. 1999 ; 9 (16) : R617-R619.
PMID 10469582
How lifetimes shape epigenotype within and across generations.
Whitelaw NC, Whitelaw E
Human molecular genetics. 2006 ; 15 Spec No 2 : R131-R137.
PMID 16987876
Accuracy of DNA methylation pattern preservation by the Dnmt1 methyltransferase.
Goyal R, Reinhardt R, Jeltsch A
Nucleic acids research. 2006 ; 34 (4) : 1182-1188.
PMID 16500889
Processive methylation of hemimethylated CpG sites by mouse Dnmt1 DNA methyltransferase.
Vilkaitis G, Suetake I, Klimasauskas S, Tajima S
The Journal of biological chemistry. 2005 ; 280 (1) : 64-72.
PMID 15509558
The history of cancer epigenetics.
Feinberg AP, Tycko B
Nature reviews. Cancer. 2004 ; 4 (2) : 143-153.
PMID 14732866
Hypomethylation distinguishes genes of some human cancers from their normal counterparts.
Feinberg AP, Vogelstein B
Nature. 1983 ; 301 (5895) : 89-92.
PMID 6185846
Quantitative changes in T cell DNA methylation occur during differentiation and ageing.
Golbus J, Palella TD, Richardson BC
European journal of immunology. 1990 ; 20 (8) : 1869-1872.
PMID 2209694
Impact of aging on DNA methylation.
Richardson B
Ageing research reviews. 2003 ; 2 (3) : 245-261.
PMID 12726774
Promoter methylation of cyclin D2 gene in gastric carcinoma.
Oshimo Y, Nakayama H, Ito R, Kitadai Y, Yoshida K, Chayama K, Yasui W
International journal of oncology. 2003 ; 23 (6) : 1663-1670.
PMID 14612939
Hypomethylation of ras oncogenes in primary human cancers.
Feinberg AP, Vogelstein B
Biochemical and biophysical research communications. 1983 ; 111 (1) : 47-54.
PMID 6187346
Identification of maspin and S100P as novel hypomethylation targets in pancreatic cancer using global gene expression profiling.
Sato N, Fukushima N, Matsubayashi H, Goggins M
Oncogene. 2004 ; 23 (8) : 1531-1538.
PMID 14716296
Chromosomal instability correlates with genome-wide DNA demethylation in human primary colorectal cancers.
Rodriguez J, Frigola J, Vendrell E, Risques RA, Fraga MF, Morales C, Moreno V, Esteller M, Capellà G, Ribas M, Peinado MA
Cancer research. 2006 ; 66 (17) : 8462-9468.
PMID 16951157
DNA methylation patterns and epigenetic memory.
Bird A
Genes & development. 2002 ; 16 (1) : 6-21.
PMID 11782440
Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma.
Greger V, Passarge E, Höpping W, Messmer E, Horsthemke B
Human genetics. 1989 ; 83 (2) : 155-158.
PMID 2550354
Cancer epigenetics.
Momparler RL
Oncogene. 2003 ; 22 (42) : 6479-6483.
PMID 14528271
Epigenetic gene silencing in cancer initiation and progression.
Nephew KP, Huang TH
Cancer letters. 2003 ; 190 (2) : 125-133.
PMID 12565166
Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines.
Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Jessup JM, Kolodner R
Cancer research. 1997 ; 57 (5) : 808-811.
PMID 9041175
Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma.
Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF, Kolodner RD, Vogelstein B, Kunkel TA, Baylin SB
Proceedings of the National Academy of Sciences of the United States of America. 1998 ; 95 (12) : 6870-6875.
PMID 9618505
Epigenetic aspects of X-chromosome dosage compensation.
Park Y, Kuroda MI
Science (New York, N.Y.). 2001 ; 293 (5532) : 1083-1085.
PMID 11498577
Imprinting and the epigenetic asymmetry between parental genomes.
Ferguson-Smith AC, Surani MA
Science (New York, N.Y.). 2001 ; 293 (5532) : 1086-1089.
PMID 11498578
The two-domain hypothesis in Beckwith-Wiedemann syndrome.
Feinberg AP
The Journal of clinical investigation. 2000 ; 106 (6) : 739-740.
PMID 10995782
DNA methylation and genomic imprinting: insights from cancer into epigenetic mechanisms.
Feinberg AP, Cui H, Ohlsson R
Seminars in cancer biology. 2002 ; 12 (5) : 389-398.
PMID 12191638
Relaxation of imprinted genes in human cancer.
Rainier S, Johnson LA, Dobry CJ, Ping AJ, Grundy PE, Feinberg AP
Nature. 1993 ; 362 (6422) : 747-749.
PMID 8385745
Reduced expression of the cyclin-dependent kinase inhibitor gene p57KIP2 in Wilms' tumor.
Thompson JS, Reese KJ, DeBaun MR, Perlman EJ, Feinberg AP
Cancer research. 1996 ; 56 (24) : 5723-5727.
PMID 8971182
Beckwith-Wiedemann syndrome: imprinting in clusters revisited.
Maher ER, Reik W
The Journal of clinical investigation. 2000 ; 105 (3) : 247-252.
PMID 10675349
Epigenetic reprogramming in mammalian development.
Reik W, Dean W, Walter J
Science (New York, N.Y.). 2001 ; 293 (5532) : 1089-1093.
PMID 11498579
DNA methylation in genomic imprinting, development, and disease.
Paulsen M, Ferguson-Smith AC
The Journal of pathology. 2001 ; 195 (1) : 97-110.
PMID 11568896
The language of covalent histone modifications.
Strahl BD, Allis CD
Nature. 2000 ; 403 (6765) : 41-45.
PMID 10638745
Cellular memory and the histone code.
Turner BM
Cell. 2002 ; 111 (3) : 285-291.
PMID 12419240
How does the histone code work?
Cosgrove MS, Wolberger C
Biochemistry and cell biology = Biochimie et biologie cellulaire. 2005 ; 83 (4) : 468-476.
PMID 16094450
Histone modifications as a platform for cancer therapy.
Espino PS, Drobic B, Dunn KL, Davie JR
Journal of cellular biochemistry. 2005 ; 94 (6) : 1088-1102.
PMID 15723344
Histone deacetylases (HDACs): characterization of the classical HDAC family.
de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB
The Biochemical journal. 2003 ; 370 (Pt 3) : 737-749.
PMID 12429021
SMRT corepressor interacts with PLZF and with the PML-retinoic acid receptor alpha (RARalpha) and PLZF-RARalpha oncoproteins associated with acute promyelocytic leukemia.
Hong SH, David G, Wong CW, Dejean A, Privalsky ML
Proceedings of the National Academy of Sciences of the United States of America. 1997 ; 94 (17) : 9028-9033.
PMID 9256429
DNA demethylation and cancer: therapeutic implications.
Szyf M, Pakneshan P, Rabbani SA
Cancer letters. 2004 ; 211 (2) : 133-143.
PMID 15219937
Mammalian DNA methyltransferase 1: inspiration for new directions
Ting AH et al
Cell Cycle. 2004 ; 3 (8) : 1024-1026.
Genetic instabilities in human cancers.
Lengauer C, Kinzler KW, Vogelstein B
Nature. 1998 ; 396 (6712) : 643-649.
PMID 9872311
Different mechanisms in the tumorigenesis of proximal and distal colon cancers.
Lindblom A
Current opinion in oncology. 2001 ; 13 (1) : 63-69.
PMID 11148689
Dietary heterocyclic amines and microsatellite instability in colon adenocarcinomas.
Wu AH, Shibata D, Yu MC, Lai MY, Ross RK
Carcinogenesis. 2001 ; 22 (10) : 1681-1684.
PMID 11577009
Induction of mammary tumors in female Sprague-Dawley rats by the food-derived carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and effect of dietary fat.
Ghoshal A, Preisegger KH, Takayama S, Thorgeirsson SS, Snyderwine EG
Carcinogenesis. 1994 ; 15 (11) : 2429-2433.
PMID 7955086
Cancer risk of heterocyclic amines in cooked foods: an analysis and implications for research.
Layton DW, Bogen KT, Knize MG, Hatch FT, Johnson VM, Felton JS
Carcinogenesis. 1995 ; 16 (1) : 39-52.
PMID 7834804
The prostate: a target for carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) derived from cooked foods.
Shirai T, Sano M, Tamano S, Takahashi S, Hirose M, Futakuchi M, Hasegawa R, Imaida K, Matsumoto K, Wakabayashi K, Sugimura T, Ito N
Cancer research. 1997 ; 57 (2) : 195-198.
PMID 9000552
Foci of aberrant crypts in the colons of mice and rats exposed to carcinogens associated with foods.
Tudek B, Bird RP, Bruce WR
Cancer research. 1989 ; 49 (5) : 1236-1240.
PMID 2917353
Experimental chemical carcinogenesis in the stomach and colon.
Sugimura T, Terada M
Japanese journal of clinical oncology. 1998 ; 28 (3) : 163-167.
PMID 9614437
Carcinogen-specific induction of genetic instability.
Bardelli A, Cahill DP, Lederer G, Speicher MR, Kinzler KW, Vogelstein B, Lengauer C
Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (10) : 5770-5775.
PMID 11296254
Persistent genetic instability in cancer cells induced by non-DNA-damaging stress exposures.
Li CY, Little JB, Hu K, Zhang W, Zhang L, Dewhirst MW, Huang Q
Cancer research. 2001 ; 61 (2) : 428-432.
PMID 11212225
Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis.
Bindra RS, Glazer PM
Mutation research. 2005 ; 569 (1-2) : 75-85.
PMID 15603753
Exposure to hypoxia, glucose starvation and acidosis: effect on invasive capacity of murine tumor cells and correlation with cathepsin (L + B) secretion.
Cuvier C, Jang A, Hill RP
Clinical & experimental metastasis. 1997 ; 15 (1) : 19-25.
PMID 9009102
Effects of reoxygenation on cells from hypoxic regions of solid tumors: anticancer drug sensitivity and metastatic potential.
Young SD, Hill RP
Journal of the National Cancer Institute. 1990 ; 82 (5) : 371-380.
PMID 2304086
Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells.
Young SD, Marshall RS, Hill RP
Proceedings of the National Academy of Sciences of the United States of America. 1988 ; 85 (24) : 9533-9537.
PMID 3200838
Effect of transient hypoxia on sensitivity to doxorubicin in human and murine cell lines.
Luk CK, Veinot-Drebot L, Tjan E, Tannock IF
Journal of the National Cancer Institute. 1990 ; 82 (8) : 684-692.
PMID 1969493
Frequencies of independent and simultaneous selection of Chinese hamster cells for methotrexate and doxorubicin (adriamycin) resistance.
Rice GC, Ling V, Schimke RT
Proceedings of the National Academy of Sciences of the United States of America. 1987 ; 84 (24) : 9261-9264.
PMID 2892197
Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells.
Mihaylova VT, Bindra RS, Yuan J, Campisi D, Narayanan L, Jensen R, Giordano F, Johnson RS, Rockwell S, Glazer PM
Molecular and cellular biology. 2003 ; 23 (9) : 3265-3273.
PMID 12697826
Involvement of mammalian MLH1 in the apoptotic response to peroxide-induced oxidative stress.
Hardman RA, Afshari CA, Barrett JC
Cancer research. 2001 ; 61 (4) : 1392-1397.
PMID 11245440
Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity.
Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Greider CW, Harley CB, Bacchetti S
The EMBO journal. 1992 ; 11 (5) : 1921-1929.
PMID 1582420
Telomeres and Aging, in
Harley CB
Telomeres, E.H.a.G. Blackburn, C.W., Editor. 1995, Cold Spring Harbour Press: Cold Spring Harbour. 1995.
Alternative lengthening of telomeres, telomerase, and cancer.
Reddel RR
Cancer letters. 2003 ; 194 (2) : 155-162.
PMID 12757973
Telomere dynamics and genome instability in human cancer
de Lange T
Telomeres, E.H.a.G. Blackburn, C.W., Editor. 1995, Cold Spring Harbour Press: Cold Spring Harbour. 1995 : 265-293.
Telomeres and telomerase in cancer stem cells.
Ju Z, Rudolph KL
European journal of cancer (Oxford, England : 1990). 2006 ; 42 (9) : 1197-1203.
PMID 16644207
Telomere dysfunction and evolution of intestinal carcinoma in mice and humans.
Rudolph KL, Millard M, Bosenberg MW, DePinho RA
Nature genetics. 2001 ; 28 (2) : 155-159.
PMID 11381263
Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis.
Gonz´lez-Su´ E, Samper E, Flores JM, Blasco MA
Nature genetics. 2000 ; 26 (1) : 114-117.
PMID 10973262
Short dysfunctional telomeres impair tumorigenesis in the INK4a(delta2/3) cancer-prone mouse.
Greenberg RA, Chin L, Femino A, Lee KH, Gottlieb GJ, Singer RH, Greider CW, DePinho RA
Cell. 1999 ; 97 (4) : 515-525.
PMID 10338215
Longevity, stress response, and cancer in aging telomerase-deficient mice.
Rudolph KL, Chang S, Lee HW, Blasco M, Gottlieb GJ, Greider C, DePinho RA
Cell. 1999 ; 96 (5) : 701-712.
PMID 10089885
Telomere length abnormalities occur early in the initiation of epithelial carcinogenesis.
Meeker AK, Hicks JL, Iacobuzio-Donahue CA, Montgomery EA, Westra WH, Chan TY, Ronnett BM, De Marzo AM
Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 ; 10 (10) : 3317-3326.
PMID 15161685
Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells.
Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, Visvader J, Weissman IL, Wahl GM
Cancer research. 2006 ; 66 (19) : 9339-9344.
PMID 16990346
Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.
Bonnet D, Dick JE
Nature medicine. 1997 ; 3 (7) : 730-737.
PMID 9212098
Prospective identification of tumorigenic breast cancer cells.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF
Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (7) : 3983-3988.
PMID 12629218
Identification of a cancer stem cell in human brain tumors.
Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB
Cancer research. 2003 ; 63 (18) : 5821-5828.
PMID 14522905
Identification of human brain tumour initiating cells.
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB
Nature. 2004 ; 432 (7015) : 396-401.
PMID 15549107
A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.
O'Brien CA, Pollett A, Gallinger S, Dick JE
Nature. 2007 ; 445 (7123) : 106-110.
PMID 17122772
Telomere length dynamics in normal individuals and in patients with hematopoietic stem cell-associated disorders.
Brümmendorf TH, Rufer N, Holyoake TL, Maciejewski J, Barnett MJ, Eaves CJ, Eaves AC, Young N, Lansdorp PM
Annals of the New York Academy of Sciences. 2001 ; 938 : 293-303.
PMID 11458518
Telomere stability is frequently impaired in high-risk groups of patients with myelodysplastic syndromes.
Ohyashiki JH, Iwama H, Yahata N, Ando K, Hayashi S, Shay JW, Ohyashiki K
Clinical cancer research : an official journal of the American Association for Cancer Research. 1999 ; 5 (5) : 1155-1160.
PMID 10353751
Dynamics of telomere erosion and its association with genome instability in myelodysplastic syndromes (MDS) and acute myelogenous leukemia arising from MDS: a marker of disease prognosis?
Sieglov´ Z, Zilovcov´ S, Cerm´k J, Ríhov´ H, Brezinov´ D, Dvor´kov´ R, Markov´ M, Maaloufov´ J, Sajdov´ J, Brezinov´ J, Zemanov´ Z, Michalov´ K
Leukemia research. 2004 ; 28 (10) : 1013-1021.
PMID 15289012
Telomere dynamics in myelodysplastic syndromes and acute leukemic transformation.
Ohyashiki K, Iwama H, Yahata N, Tauchi T, Kawakubo K, Shimamoto T, Ohyashiki JH
Leukemia & lymphoma. 2001 ; 42 (3) : 291-299.
PMID 11699393
Loss of heterozygosity in normal tissue adjacent to breast carcinomas.
Deng G, Lu Y, Zlotnikov G, Thor AD, Smith HS
Science (New York, N.Y.). 1996 ; 274 (5295) : 2057-2059.
PMID 8953032
Mammary stem cell repertoire: new insights in aging epithelial populations.
Smith GH, Boulanger CA
Mechanisms of ageing and development. 2002 ; 123 (11) : 1505-1519.
PMID 12425957
Tetraploidy/aneuploidy and stem cells in cancer promotion: The role of chromosome passenger proteins.
Nguyen HG, Ravid K
Journal of cellular physiology. 2006 ; 208 (1) : 12-22.
PMID 16331679
Written2007-01Sheron Perera, Bharati Bapat
Lunenfeld Research Institute, Mount Sinai Hospital, Department of Lab Medicine and Pathobiology, University of Toronto, Canada


This paper should be referenced as such :
Bapat, B ; Perera, S
Genetic instability in cancer
Atlas Genet Cytogenet Oncol Haematol. 2007;11(2):155-164.
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