Genome Instability in Carcinogenesis - Report Example

Genome Instability in Carcinogenesis Cancer is a result of gradual accumulation of changes occurring at the nucleotide level. These changes may also occur at the gross chromosomal level. There are many cancer cells mainly of the colon that show genomic instability that possibly facilitates and accelerates tumour instigation and growth. In few examples “mutator mutation” (Rahman, 2008) has been evidently drawn in starting the buildup of other carcinogenic changes. For instance, “post-replicative DNA mismatch repair deficiency” (Rahman, 2008) culminates in significant increase in insertion or deletion mutations. This gives rise to microsatellite instability (MSI) phenotype. This might also incline to a range of tumours while occurring in the germline (Rahman, 2008). The cancer in humans harbors many mutations. It has been suggested that these alterations result from an “inherent genomic instability” (Sieber, Heinimann & Tomlinsoon, 2003). There are some cancer types that have established genomic instability or structures that indicate of this. The congenital cancer syndromes occur caused by poor DNA repair or due to chromosomal integrity (Sieber, Heinimann & Tomlinsoon, 2003). In comparison, the theoretical analysis along with experimental data of sporadic colorectal tumours delivers minute evidence of genomic instability in the early lesions. Such seemingly conflicting data raises questions like whether the genomic instability is essential for tumour growth. And what evidence is there to support the claim that it is in fact the usual commencing event in tumourigenesis? To answer these questions it is better to get acquainted with the details of genomic instability. The term genomic instability was introduced to specify the trend of tumour cells in acquiring novel changes per cell division (Rahman, 2008). The concept has become clearer following the study on chromosomal instability (Lengauer, Kinzler & Vogelstein, 1997) and validated by previous study on “microsatellite instability” due to inconsistent repair deficiency. The reflection of multiple mutations in a tumour is a form while genomic instability is a “rate” (Lengauer, Kinzler & Vogelstein, 1998). Nevertheless, most cases, demonstrate the two features concurrently in the same tumour. Many authors indicate phase with the term “instability”, because there are multiple mutations in cancers and it is hard to prove the “rate” of variations. Instability of genomic phenotypes is best recognized for colon cancer. Here the capricious forms of instability are observed (Rajagopalan et al. 2003). According to Rajagopalan et al. (2003) this phenomenon includes at least three forms: 1. “Chromosomal instability (CIN): occurs in the majority of colorectal cancers. It is worth noting that in many instances the cause of chromosomal instability is not clear” (Rahman, 2008). 2. “Microsatellite instability (MSI): occurs in a minority of colorectal cancers including Lynch syndrome (HNPCC). MSI is due to mutation in a mismatch repair gene (i.e. MLH1, MSH2, MSH6 and PMS2)” (Rahman & Peltomäki, 2004). 3. “The CpG island methylator phenotype (CIMP) usually overlaps with sporadic MSI and is found in most tumours with mutations in the BRAF oncogene” (Rahman, 2008). Quite recently a study suggested another form of instability; the “point mutation instability” or simply (PIN). This discovery was based on assessing the rate of acquiring random point mutations in tumour vs. normal cells. The study stated that point mutations take place at a “200-fold higher rate in cancers than in normal cells” (Bielas et al., 2006). Therefore, CIMP, CIN, MIN and the recently suggested PIN are evidences of genomic instabilities (Rahman, 2008). The aspect that makes it all too complex is why in some cases multiple forms of these instabilities exist concurrently? There are several subtypes of CIN that may exist in several tumours. Rahman (2008) studied the colon cell lines and its analysis “with 24-color FISH techniques, Spectral Karyotyping (SKY) and MFISH” reveals that most cell lines display “numerical instability” with propensity to form additional replicas of chromosomes. This strange reproduction occurs to reach a nearby “triploid karyotype with multiple trisomies” (Rahman et al., 2001). A few cell lines displayed structural instability along with the inclination of acquiring “non-balanced chromosomal translocations” (Rahman, 2008) removals and replications of chromosomal parts with elusive numerical variations. An astounding example is of the RKO cell line. The interesting thing is the inclination of “multiple reciprocal translocations” that show delicate numerical changes (Rahman et al., 2001). In addition to this another study, showed cell lines with inclination of “mitotic recombination” that results in disproportionate LOH events that have minor numerical chromosomal variations (Gaasenbeek et al., 2006). These variations probably reflect different healing flaws or exposure to different ways of DNA damage. Even though many sporadic cancers display multiple mutations that suggest unstable genome, the part of this instability in carcinogenesis, set against the influence of natural selection, is a controversial subject (Rahman, 2008). Tumours that seeming have no form of genomic instability have also been observed by several groups (Jones et al., 2005). These tumours were typically linked with unusual features that include “familial clustering, young age at onset, and/or lack of other common changes” (Rahman, 2008), all observed in colorectal carcinogenesis. These observations are important for they suggest an instable form is not required in all tumours. In fact an unidentified form of instability causes the development of these tumour subsets. However, most haematological malignancies do not demonstrate clear genomic instability (Rahman, 2008). The natural consequence of instability phenotype is generating multiple tumour replicas at an accelerated rate, which is reflected in the amount of tumour heterogeneity. In Rahman’s (2008) “SKY analysis of colon cancer cell lines” some cell lines displayed improved heterogeneity, with multiple karyotypic clones as evidence. Others indicated limited inter-metaphase heterogeneity, despite multiple chromosomal changes; VACO4A and SW837 are good examples (Rahman, 2008). Similar heterogeneity in nucleotide (DNA mutation) level was observed (Rahman, 2008). The assumption is that excessive heterogeneity of tumour genomes has significant implications in treatment for cancer by generating resistant clones. The genomic instability in Lynch Syndrome is somewhat different from the rest, however. The main purpose of mismatch repair system is removing “insertion–deletion loops” and “base–base mismatches” (Rahman, 2008) that arise in DNA cloning. The later almost repairs the deficiency leading to single base replacements, however, insertion–deletion loops impact the repetitive DNA (microsatellites) involving increases or losses of nucleotide unit (Rahman, 2008). This phenomenon is called MSI. Mismatched repair genes act similar to tumour suppressors because somatic inactivation of wild type allele is needed for tumour growth. This can occur by methylation of CpG islands in the MLH1 promoter, by the loss of heterozygosity and through mutation (Rahman, 2008). This phenomenon clarifies why instability phenotype is uncertain in irregular tumours as it is a long trail in acquiring two mutations for inactivating mutator gene (Rahman, 2008), and later acquiring mutations in the carcinogenic gene (Rahman, 2008). Mutation rates in tumour cells that lack mismatch repair are 100–1000-fold compared to regular cells. Accumulation of mutations quickens tumour growth that explains why the most of ‘Lynch syndrome’ patients cultivate colon cancer, while merely 5% of the general population suffers this type (Rahman, 2008). This is a possible explanation not the absolute truth for this occurrence. The mutations through mismatch repair deficiency might impact significant growth-regulatory genes. The ones with repeat sequences showing considerable tissue specificity are specially affected. For instance, the frame-shift mutations impacting repeat areas within “TGFßRII, BAX and TCF4 genes” (Rahman, 2008) are selected in gastrointestinal malignancies. However they are not selected in endometrial cancer. This tissue-specific selection might give an explanation for ‘Lynch syndrome tumour spectrum’ (Rahman, 2008). It is noteworthy that the genetic basis of this tumour are understood only in part. Frank increase in mutation rate linked to mismatch repair deficiency is evidence supporting the hypothesis of mutator phenotype, the genomic instability. Recently studied data and statistical modelling propose that carcinogenesis is an evolutionary process instigated by selection. With the study in question the increased mutation rates because of genome instability do not seem to be an utter requirement for the duration of carcinogenesis of the sporadic cancers (Rahman, 2008). Nevertheless, in sporadic genetic cancer syndromes like Lynch syndrome, the microsatellite instability because of mismatch repair gene deficiency shows a influencing role. In Lynch syndrome, there are some areas that stay partially studied and require special attention. The FCC-X along with wider categories of ancestral and young colorectal cancer includes subsets of tumours, which are seemingly deficient in instability. They also lack major common genetic variations in colorectal cancers. The distant possibility remains that it is linked to an unidentified new forms of genomic instability, as yet, which is a most important challenge and efforts are needed to define the predilection of the syndromes in question. References 1. Bielas JH, Loeb KR, Rubin BP, True LD and Loeb LA. 2006. Human cancers express a mutator phenotype. Proc. Natl. Acad. Sci. USA. 103: 18238–18242 2. Gaasenbeek M, Howarth K, Rowan AJ, Gorman PA, Jones A, Chaplin T, Liu Y, Bicknell D, Davison EJ, Fiegler H, Carter NP, Roylance RR, Tomlinson IP. 2006. Combined array-comparative genomic hybridization and single-nucleotide polymorphism-loss of heterozygosity analysis reveals complex changes and multiple forms of chromosomal instability in colorectal cancers. Cancer Res.66: 3471–3479 3. Jones AM, Douglas EJ, Halford SER, Fiegler H, Gorman PA, Roylance RR, Carter NP, Tomlinson IPM. 2005. 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The significance of unstable chromosomes in colorectal cancer. Nat. Rev. Cancer. 3:695–701. 10. Sieber, O. M., Heinimann, K. & Tomlinsoon, I.P. 2003. Genomic instability—the engine of tumourigenisis? Nat Rev Cancer. 3(9) 701-708 Read More