The Role of Genome Instability in Carcinogenesis - Report Example

“THE ROLE OF GENOME INSTABILITY IN CARCINOGENESIS” INTRODUCTION: It is a well known fact by all that the ‘genome instability is the central of carcinogenesis’. These neoplastic cells generally possess numerous genomic lesions, which may include sequence alterations/ mutations (point mutations, translocation, small deletions, and inversions) or gross structural abnormalities in one or more chromosomes (large-scale deletions, rearrangements, gene amplifications). It has been concluded from various theories that the cancer cells are genetically unstable in nature and it is approximated that this genomic unstability may represent te early stage of the process of carcinogenesis and a general feature of many tumors. Nowadays a lot of research is being conducted regarding this issue. Modern scientist are using the most modern technologies to discover the ‘actual’ role of genomic instability which results in carcinogenesis. For example, studies show that all the cancers do not share the similar type of somatic mutation. Hence, it is unlikely for a cancerous cell to have a certain molecular. While looking deeper into this matter, it was discovered that the tumor cells themselves are not homogeneous genetically or phenotypically. Also tis discovery lead to the belief that most of the tumor cells were aneuploid. Since cancer cells are genetically unstable so their genomic profiling has proven very difficult despite that nearly all human solid tumor cancer samples represent a single time point. This issue was fist brought to attention by Boveri when he postulated that cancer arose from single cells as a result of ‘wrongly combined chromosomes’. But recently the scientists have dug deeper in the matter and examined genomic instability in a new light. Also they are looking deeper into the matter if the massive genetic changes that occur later lead to te cause of cancer. ANEUPLOID NATURE OF CANCEROUS CELLS: Cancerous cells some times exhibit gross chromosomal abnormalities and as discussed earlier, are aneuploid in nature. It has been discovered that the degree of aneuploidy correlates with the severity of malignancy. Not only this, but aneuploidy is also the root cause of spreading the cancer cells by alternating the normal cells into tumors. Moreover, it is believed that aneuploidy along with genetic instability may explain the rapid appearance and disappearance of multidrug resistance in tumor cells. Also, increased gene dosage in the absence of gene mutations linked with the formation of a number of cancers. Hence, the aneuploidy-driven theory of carcinogenesis suggest that disruption of gene dosage has a significant role in the initiation of cancer formation. But the good thing discovered is that these aneuploid cells are not inheritable and can not be passed onto te next generation (to an extent because some recent studies also prove that they might be inheritable in some cases) . In the aneuploidy-driven theory of carcinogenesis, aneuploidy induced by carcinogens begets more aneuploidy. This produces cells wich are heterogenous with varying unbalanced gene dosages. The more the instability of aneuploid cell genomes, the more the heterogeneity in the tumor and cancer THE FINAL STAGE OF CANCER CELLS: The cancer cells in their last stage change to such an extent that genetically they barely resemble te normal cell, and rate of the mutation caused by the internal cause i.e the endogenous mutation do not seem to be high enough to account for the number of mutations observed in cancer cells. More importantly, it was proposed that cancer cells contain thousands of mutations and that these mutations were responsible for the tumorigenic phenotype. Hence it as been demonstrated tat the cancerous cells may contain thousands of mutations. More specifically it is estimated that the colorectal cancer cells may have 104–105 mutations per cell. But the plus factor is that the genomic instability which is the root cause for accumulation of these large number of mutations appear very early during neoplastic transformation. Also, the aneuploidy in pre-neoplastic lesions frequently indicates a high risk of malignant transformation. But by now only a few mutator genes have been discovered. Thus it is a possibility aneuploidy itself may be responsible for a mutator phenotype. Regardless of its origin, a mutator phenotype that occurs early in carcinogenesis could also explain the highly pleiotropic genetic nature of malignant tumors. THE BLANKS IN THE RESEARCH: It is not yet proved that the genetic instability is merely a consequence of carcinogenesis, because otherwise all the cancer cells would then have the equivalent levels of genetic instability which they do not seem to have. However, some form of genetic instability is found in nearly every solid tumor cell. But since this instability is detected in the early stages of carcinogenesis, it may be even linked with the initiation of carcinogenesis. RESEARCH CONDUCTED BY VARIOUS SCIENTISTS: We know that epigenetic dysfunction (i.e the gene mutation caused from the external environment rather then the genetic influences) like inhibiting of different DNA repair components might play a role in human cancer development (Lahtz and Pfeifer, 2011). Dr Hsiao and Mizzen, regarding this issue, experimented the act of epigenetic changes in histones during the DNA damage signaling. 53BP1 is know as the protein which responses during the DNA damage that occur when the DNA double-strand breaks (DSBs) which could promote their repair by non-homologous end joining. First it was believed that the 53BP1 foci accumulated primarily on dimethylated lysine 20 in histone H4 established preceding the DNA damage by methyltransferases. Later a novel role for H4K16 acetylation in regulating 53BP1 foci dynamics was described. These discoveries uncovered that rapid induction of H4 deacetylation by DSBs affected multiple aspects of DNA damage response, suggesting that the inhibition of 53BP1 binding to H4K20me2 by H4K16 hyperacetylation may contribute to cancer therapy. Later in the next article, Dr Li told that CylinB1/Cdk1, which plays a vital role during the mammalian cell cycle (for the regulation of process of mitosis), was involved in response to radiation stress.It was further told that the phosphorylation of MnSOD produced by CyclinB1/Cdk1 resulted in increased MnSOD activity and stability, as well as the suppression of apoptosis caused by radiation. These revelations give a pro-survival mechanism involving CyclinB1/Cdk1-mediated MnSOD activation under genotoxic stress conditions. It is reported that cancer could increase the gene expression collagen type VI (Col VI), a putative extracellular matrix ligand of chondroitin sulfate proteoglycan 4 (CSPG4)/NG2, and contribute to prognostic impact of NG2. Dr Perris revealed that the NG2-mediated binding to Col VI activated the convergent cell survival- and cell adhesion/migration-promoting signal transduction pathways, by analyzing the cells with modified expression of NG2 diverged in their interaction with Col VI during te different microenvironmental conditions. According to tem the interaction between NG2 and Col VI plays a role in the regulation of the cancer cell–host microenvironment interactions for sustaining sarcoma progression. Translesion synthesis (TLS) allows the DNA replication machinery to bypass an unrepaired DNA damage site using special TLS polymerases such as polymerases κ, η, ι. Dr Choi regarding this performed structural studies on the polymerase-interacting domain of a human Rev1 protein that regulates the activities of TLS polymerases. It is told that Rev1 uses a tertiary structure and two surfaces to recruit TLS polymerases, with one site for polymerases κ, η, ι, and the other for polymerase ς. THE POTENTIAL IMPACT OF SUCH KNOWLEDGE ON FUTURE HISTOPATHOLOGY PRACTICE: The above researches give us the knowledge to not only prevent future complications caused by cancer but also may help to cure cancer itself one day. These researches show that the genomic instability is the root cause of carcinogenesis i.e formation of malignant tumors and cancerous cell. By preventing one self from the external exposure to such things which cause genetic instability through external causes, a great quantity of damage can be prevented. Furthermore, these researches will provide not only the new information for better revealing the genetic instability as a cause of cance but also contribute to the efficacy of cancer therapy. REFERENCES: Reya,T., Morrison,S.J., Clarke,M.F. and Weissman,I.L. (2001) Stem cells, cancer and cancer stem cells. Nature, 414, 105–111. Lahtz C., Pfeifer G.P. Epigenetic changes of DNA repair genes in cancer. J. Mol. Cell Biol. 2011;3:51-58. Vineis,P. (2003) Cancer as an evolutionary process at the cell level: an epidemiological perspective. Carcinogenesis, 24, 1–6. Li,R., Sonik,A., Stindl,R., Rasnick,D. and Duesberg,P. (2000) Aneuploidy vs. gene mutation hypothesis of cancer: recent study claims mutation but is found to support aneuploidy. Proc. Natl Acad. Sci. USA, 97, 3236–3241. Duesberg,P., Rasnick,D., Li,R., Winters,L., Rausch,C. and Hehlmann,R. (1999) How aneuploidy may cause cancer and genetic instability. Anticancer Res., 19, 4887–4906. Lengauer,C., Kinzler,K.W. and Vogelstein,B. (1998) Genetic instabilities in human cancers. Nature, 396, 643–649. Wu J. Genotoxic stresses and protein modifications. J. Mol. Cell Biol. 2012;4:269. Wu J. New way to tumor therapeutics. J. Mol. Cell Biol. 2013;5:1-2. Fabarius,A., Hehlmann,R. and Duesberg,P.H. (2003) Instability of chromosome structure in cancer cells increases exponentially with degrees of aneuploidy. Cancer Genet. Cytogenet, 143, 59–72. Pihan,G.A., Wallace,J., Zhou,Y. and Doxsey,S.J. (2003) Centrosome abnormalities and chromosome instability occur together in pre-invasive carcinomas. Cancer Res., 63, 1398–1404. Zimonjic,D., Brooks,M.W., Popescu,N., Weinberg,R.A. and Hahn,W.C. (2001) Derivation of human tumor cells in vitro without widespread genomic instability. Cancer Res., 61, 8838–8844. Read More