How Variation Within the Human Genome Might Lead to Cancer - Essay Example

How Variation within the Human Genome Might Lead To Cancer Introduction Cancer refers to a diverse array of illnesses with a common overall phenotype that involves the uncontrollable growth and proliferation of cells. Through a multistep process, cells in cancer acquire a series of genetic variations or mutations that result in unrestrained division and growth of the cells, uninhibited differentiation of the cells, and evasion of programmed cell death (Wong et al, 2011: p428). The resultant growth of the cells into tumors stimulates acquisition of new vascular vessels, which continue to provide the tumor with nutrients and oxygen. These tumor cells are eventually able to invade neighboring tissue and spread further to other tissues via metastasis. Cancer begins after one cell undergoes one gene variation after another, until these collectively transform normal cells to uncontrollably dividing cancerous cells. Current research identifies the mutations that lead to cancer as occurring in two general genes; the proto-oncogenes and tumor suppressor genes, which normally accelerate and inhibit growth and division of cells respectively (Wong et al, 2011: p429). As a result, gene variations that over-activate proto-oncogenes and inhibit tumor suppressor genes drive the development of transformed cancer cells. These gene variants responsible for maintaining this transformed cancer phenotype are then selected for during tumorigenesis, causing cancer. Role of Mutation in Cancer Genetic instability has been identified as a fundamental hallmark of all cancerous cells. Genetic instability, in this case, is referent to increased frequency of genomic mutations. According to Almendro et al (2013: p283), this genetic instability can be seen at both the chromosomal level leading to deletions, translocations, amplifications, and aneuploidy of the entire chromosome, as well as at nucleotide level leading to point mutations. The two manifestations of genetic instability can result in an increase of mutation rates in cancerous cells through the alteration of protein function or expression. In the past five years, the most prevalent debate has been about whether changes to single nucleotides or abnormalities related to large macromolecular chromosomes tend to be more common in human cancer, as well as whether they are a causative factor in development of cancer (Almendro et al, 2013: p283). Alteration in chromosome number, also referred to as aneuploidy, is a critical characteristic of any cancers and is, in fact, one of the genetic alterations most observed in human cancers. Specific exchanges of chromosomes have been found to take place at increased frequency and are used to diagnose specific tumors. Lokody (2014: p153) has identified a positively strong correlation between the incidence of chromosomal alterations found in a cancerous tumor and the cancer’s potential to become malignant. What this could suggest is that, during carcinogenesis, there is an increasing incidence in the number of errors as diminution in the pathways used for chromosome maintenance progresses. This, in turn, promotes the development of tumors that are highly anaplastic. Chromosomal alterations normally should involve translocations, additions, and deletions of segments in the DNA, which span over millions of DNA nucleotide bases (Lokody, 2014: p153). It is conceivable that chromosomal aberrations could only be the tip of a bigger iceberg and that, underneath these large-scale rearrangements, the tumor cells’ DNA nucleotide sequences could have an even larger number of smaller alterations. Changes to the timing of phases involved in the cell cycle also provide an alternative mechanism for mutator phenotypes to develop. As the cell cycle progresses, there are a number of pathways that are tasked with the role of monitoring and checking damage repair prior to the cell cycle proceeding from one phase to another (Lokody, 2014: p154). When these checkpoints are activated, they function to arrest progress of the cell cycle transiently in order for DNA damage to be repaired, as well as for the completion of proper cell component assembly. If these cell cycle checkpoints are eliminated or stopped, a mutator phenotype could develop, for instance in the p53 gene, which would result in a decline in monitoring and checking of DNA damage stringency. This, in turn, would allow for the replication of damaged DNA in cancer cells, enabling the daughter cell to accumulate mutations that lead to genomic instability. When there is damage that is irreparable, the spread of mutations is halted by apoptosis (Lokody, 2014: p154). Again, cancer cells have mutations that either delay or prevent programmed cell death responses, which enable the genetically unstable cancer cell to survive. Mutation of Proto-Oncogenes in Cancer Fundamentally, cancer is a disease that results from a failure in the regulation of tissue growth. The variation of genes that control growth and differentiation of cells, therefore, play a critical role in the transformation of normal cells into cancerous ones. Cancerous transformation can happen when normal oncogenes are over-expressed, as well as when novel oncogenes are formed. An oncogene is the mutated version of a group of cells referred to as proto-oncogenes, which often encode for proteins that inhibit cell differentiation, stimulate cell division, and halt apoptosis. However, the mutated proto-oncogene over-expresses these proteins, resulting in decreased cell differentiation, increased cell division, and inhibition of apoptosis, collectively resulting in cancer phenotypes. Lange et al (2011: p99) define oncogene products as proteins that operate through the stimulation of cell growth and division and, thus, are involved in regulation of the cell cycle. In this case, the oncogene will express proteins drive the cell cycle forward, resulting in the cell proceeding from the G phase to the chromosome segregation or chromosome replication phase. Some examples of these proteins are cell surface receptors that bind growth factors, signaling molecules involved in pathways that link these receptors to initiators of replication, and proteins that initiate replication by interacting with DNA (Lange et al, 2011: p100). Therefore, the cell cycle, rather than stop as it normally would in the G-phase, progresses to subsequent cell cycle phases, which results in uncontrolled cell division and rescue of cells from apoptosis (Podlaha et al, 2012: p155). Occasionally, genetic variations in the proto-oncogene permanently activate proteins involved in the interchange between inactive and active forms. One example is the Ras protein, which acts as a molecular switch regulated by the presence of either tri-phosphate or di-phosphate nucleotides bound to it. According to Podlaha et al (2012: p156), Ras proteins that are switched cause the proto-oncogene to relay signals that stimulate proliferation with problems arising when mutation renders Ras unable to deactivate even when an inhibitory signal is received. Another genetic variation involved in the transformation of proto-oncogenes to oncogenes is chromosomal translocation. In this case, a piece of detached chromosome reattaches non-specifically, resulting either in alterations in protein expression regulation or a resultant fusion protein that possesses the C-terminus and N-terminus of two proteins Podlaha et al (2012: p156). One oncogene that results from chromosomal translocation is the BCR/ABL, which expresses proteins with the C-terminus of ABL that relays signals for the cell to proliferate and the N-terminus of Bcr, which is a breakpoint cluster region (Kryston et al, 2011: p197). This form of chromosome is called the Philadelphia chromosome, which is prevalent in individuals with the blood cell cancer myelogenous leukemia. The Abl is rendered continuously active by the fused protein, causing unregulated cycling of cells. Oncogenes can also be generated through a process that, rather than directly alter the proto-oncogene, involves the existence of more than one copy of proto-oncogenes in the cell, which causes the over-expression of proteins like c-MYC. In this case, between eight and thirty copies of ­c-MYC exist in every HL-60 cell that is a cell line in promyelocytic leukemia. According to Shaheen et al (2011: p6080), since c-MYC is a transcription factor, an increase in its expression results, in turn, to increased expression of their targets, most of which activate the cycling of the cell. Indeed, Kasparek and Humphrey (2011: p885) note that the transformed cell phenotype is induced by only one affected chromosome because all the genetic alterations lead to increased gains in cell function. Mutation of Tumor-suppressor Genes in Cancer Unlike proto-oncogenes that promote cell growth and differentiation, tumor suppressor genes inhibit cell survival and division, which results in them sometime being referred to as anti-oncogenes. The anti-oncogene or tumor suppressor gene protects the normal cell from an important step involved in the development of cancer and, when this gene mutates to reduce or lose its function, the normal cell is transformed to a cancer cell. Stankiewicz and Lupski (2010: p439) identifies the loss of tumor suppressor genes as more critical in the formation of cancer cells than activation of proto-oncogene/oncogene. These tumor suppressor genes can be landscaper genes, gatekeeper genes, and caretaker genes, which maintain checkpoints in the cell cycle, inhibit progression of the cell cycle, and induce apoptosis. In contrast to proto-oncogenes/oncogenes that stimulate proliferation of cells by continuously activating the cell cycle, the tumor suppressor gene expresses proteins that promote apoptosis and restricts cell growth and division (Stankiewicz & Lupski, 2010: p440). (Lange et al, 2011: p108) identifies the retinoblastoma protein or pRb, as well as its corresponding gene the RB1 as the most important factors in the tumor suppressor proteins. Because pRb activity inhibits expression of proteins that are needed for the cell cycle to progress into the S phase, alterations that inactivate it enables uncontrolled division of cells. This is a principle that can be applied to all classes of tumor suppressor genes, during which alterations in genes causing tumorigenesis inhibit regulatory proteins involved in checking proliferation of cells. The most common forms of genetic variations of mutations that inactivate pRb are deletions or frame-shifts in the RB1 gene, which leads to a stop codon being introduced prematurely and subsequent defective expression of proteins. In another instance, pRb expression could be normal, while the pathway that it is involved in is rendered defective because of other components in the pathway (Lange et al, 2011: p108). These additional components by definition, therefore, would also be tumor suppressors. The p53 gene is another tumor suppressor gene that has been implicated in the development of tumors on humans. Podlaha et al (2012: p161) states that, as a transcription factor involved in the activating of genes that, in turn, activate proteins that promote apoptosis and inhibit proliferation because of damage to the DNA, p53 has a crucial role maintaining the checkpoint between G1 and S phases of the cell cycle. Genetic variations or mutations that act to inactivate p53 inhibit the cell’s response to DNA damage, which prevents progression of the cell cycle. As a result, the cell continuously divides even when DNA damage is present. Because the inactivation of anti-oncogenes or tumor suppressor genes leads to complete absence of function, the paternal and maternal copies of the gene that code for the tumor suppressor normally needs to be mutated so that tumorigenesis proceeds Podlaha et al (2012: p161). It is possible that one functional copy of the tumor suppressor gene could sufficiently provide for the activity needed to maintain proper cell growth and division. Another example of a tumour suppressor gene whose mutation can lead to cancer is APC, which is responsible for producing a multi-functional tumour-suppressing protein known as adenomatous polyposis coli. This protein is a gate-keeper in the prevention of tumour development by regulating β-catenin that is essential in cell growth, signalling, communication, and controlled destruction, although it results in numerous cancers when unregulated (Tran et al, 2012: p657). A mutation in the APC gene results in a decline of effectiveness, in which some cells normally under its control would, instead, continue developing and transforming into cancerous cells over time. These cells manifest as polyps in familial polyposis initially as inherently benign because the first two-hit hypothesis phase has already occurred, in this case through inheriting mutations in the APC gene. The normal allele left is then deleted or mutated, which accelerates polyp generation. Increased mutations in the APC mutant cells, such as in kRAS i or p53 genes, could then lead to development of cancer (Tran et al, 2012: p657). Mutations in the TP53 gene also causes Li-Fraumeni syndrome. The TP53 tumour suppressor gene encodes for the p53 protein, which is involved in the activation of numerous genes that play a role in apoptosis, DNA repair, and cell cycle arrest, especially when there is damaged DNA (Jones, 2012: p598). Deleterious mutations that occur in this gene result in loss of defensive mechanisms by the cell, enabling the uncontrolled proliferation of cells and the progression of tumours. Individuals that have mutations in this gene have a fifty percent risk of developing LFS by the age of 30. LFS is mainly associated with germ-line TP53 mutations, while they are mainly characterized by development of adrenocortical carcinomas, sarcomas, CNS tumours, and other tumours classed as early-onset. Because of high breast cancer frequency in families with LFS, it is normal for this syndrome to overlap with HBC or hereditary cancer of the breast. Germ-line point mutations of the TP53, BRAC2, and BRAC1 genes also have association with high breast cancer risk, while significant rearrangement of the same genes have been implicated in the hereditary breast cancer phenotype (Jones, 2012: p598). Finally, mutations that occur in the PTCH1 gene, which is also a tumour suppressor gene, can cause the development of Gorlin syndrome. The PTCH1 gene has a critical role in providing instructions for the patched-1 protein to be expressed, which acts as a receptor (Wallace, 2010: p448). As with most other receptor proteins, the patched-1 receptor has specific sites for ligand binding, after which signals are triggered to influence cell function and development. In this case, patched-1 blocks the division/proliferation and growth of cells until its ligand, known as Sonic Hedgehog, is attached. As a tumour suppressor gene, the PTCH1 gene stops normal cells from proliferating uncontrollably or too rapidly. Mutations in the PTCH1 gene act to prevent patched-1 protein from being expressed, while it may also lead to abnormal forms of the patched-1 receptor being expressed (De Miranda et al, 2011: p60). When the patched-1 receptor is either missing or altered, it is unable to suppress the division and growth of cells effectively. This results in uncontrollable proliferation of cells, leading to the formation of tumours that characterize Gorlin syndrome. Conclusion Mutations or DNA variations in various distinct genes have been implicated in the development of cancer. These genes include those that stop excessive growth/activate apoptosis and those that activate growth, including tumour suppressor genes and proto-oncogenes/oncogenes. Cancer cells are simply cells gone wrong in that they are no longer responding to the body’s signals that control cell death or cellular growth. Normally, these cancer cells originate from the tissues and diverge further from normal cells due to mutations and DNA variations as they grow and divide. With time, the mutated cells tend to become more resistant to the body’s controls that are tasked with maintaining normal cells and tissue, resulting in increasingly rapid cell division than their progenitors. In addition, they become less dependent on cell growth signals from neighbouring cells. Moreover, these cells are also able to evade apoptosis, which is interesting because their numerous abnormalities would make them prime targets for programmed cell death. During the latter stages of cancer development, these cells outgrow normal boundaries of the tissue and spread to other tissues in the body, also referred to as metastasis. References Almendro, V., Marusyk, A., & Polyak, K. (January 01, 2013). Cellular heterogeneity and molecular evolution in cancer. Annual Review of Pathology, 8, 277-302. De Miranda, M., Björkman, A., & Pan-Hammarström, Q. (December 01, 2011). DNA repair: the link between primary immunodeficiency and cancer. Annals of the New York Academy of Sciences, 1246, 1, 50-63. Jones, B. (January 01, 2012). Cancer genetics: Evaluating oncogene cooperativities. Nature Reviews Genetics, 13, 9, 598 Kasparek, T. R., & Humphrey, T. C. (January 01, 2011). DNA double-strand break repair pathways, chromosomal rearrangements and cancer. Seminars in Cell & Developmental Biology, 22, 8, 886-897. Kryston, T. B., Georgiev, A. B., Pissis, P., & Georgakilas, A. G. (June 01, 2011). Role of oxidative stress and DNA damage in human carcinogenesis. Mutation Research/fundamental and Molecular Mechanisms of Mutagenesis, 711, 193-201. Lange, S. S., Takata, K., & Wood, R. D. (January 01, 2011). DNA polymerases and cancer. Nature Reviews. Cancer, 11, 2, 96-110. Lokody, I. (January 01, 2014). Cancer genetics: The origin and evolution of an ancient cancer. Nature Reviews Cancer, 14, 3, 152-159. Podlaha, O., Riester, M., De, S., & Michor, F. (January 01, 2012). Evolution of the cancer genome. Trends in Genetics: Tig, 28, 4, 155-163. Shaheen, M., Allen, C., Nickoloff, J. A., & Hromas, R. (January 01, 2011). Synthetic lethality: exploiting the addiction of cancer to DNA repair. Blood, 117, 23, 6074-6082. Stankiewicz, P., & Lupski, J. R. (February 01, 2010). Structural Variation in the Human Genome and its Role in Disease. Annual Review of Medicine, 61, 1, 437-455. Tran, B., Dancey, J. E., Kamel-Reid, S., McPherson, J. D., Bedard, P. L., Brown, A. M., Zhang, T. & Siu, L. L. (January 01, 2012). Cancer genomics: technology, discovery, and translation. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 30, 6, 647-660. Wallace, D. C. (June 01, 2010). Mitochondrial DNA mutations in disease and aging. Environmental and Molecular Mutagenesis, 51, 5, 440-450. Wong, K. M., Hudson, T. J., & McPherson, J. D. (January 01, 2011). Unraveling the genetics of cancer: genome sequencing and beyond. Annual Review of Genomics and Human Genetics, 12, 407-430. Read More