The Genomics Of Cancer Biology Essay
In this new era of high end technology and ever growing field of research the word “omics” has evolved as a cynosure of many scientists across the world. It refers to “totality in terms of bio systems” either it is for genome or for proteome - in other words ‘‘omics’’ involve the measurement of large numbers of parameters, typically genes (genomics), proteins (proteomics), lipids (lipidomics) or metabolites (metabolomics) (Jackson O. Lay Jr et. al., 2006)
In modern molecular biology and genetics, the genome represents the totality of an organism's hereditary information. It is encoded either in DNA or, for many virus, in RNA. The genome comprises of both the genes and the non-coding sequences of the DNA/RNA [Ridley M., 2006]. The term “genome” was adapted in 1920 by Hans Winkler, Professor of Botany at the University Of Hamburg, Germany. In Greek, the word genome stands for "I become, I am born, to come into being". The Oxford English Dictionary suggests the name to be a blend of words gene and chromosome (Joshua Lederberg and Alexa T. McCray, 2001).The flowchart below shows modern bifurcation of Omics - -
The Human Genome Project was initialized with the intent to map and to sequence the human genome. Some other genome projects include that of mouse, rice, the plant Arabidopsis thaliana, the puffer fish, and bacteria like E. coli. In 1976, Walter Fiers at the University of Ghent (Belgium) was the pioneer toestablish the complete nucleotide sequence of a viral RNA-genome (bacteriophage MS2). Fred Sanger in 1977 sequenced the first DNA-genome project of that of phage Φ-X174 which have only about 5386 base pairs.The first bacterial genome to be completed was that of Haemophilus influenzae, completed the efforts of team at The Institute for Genomic Research in 1995. A few months later, first eukaryotic genome was completed having 16 chromosomes of budding yeast Saccharomyces cerevisiae released as a result of a European led effort initiated in the mid-80's. Recent development of novel technologies has greatly decreased the cost and the complexity of sequencing and as a result of this the number of complete genome sequences is raising rapidly. The advent of these technologies has opened new prospects of personal genome sequencing as an importent diagnostic tool. a major achievement in this regard was the decoding of full genome of DNA pioneer James D. Watson in 2007 (Wade and Nicholas, 2007)
. The first DNA sequences were obtained in the early 1970s by academic researchers using laborious methods based on two-dimensional chromatography. Subsequent to the development of dye-based sequencing methods automated sequencers were invented [Olsvik et.al. 1993]. The DNA sequencing has become comparatively easier and orders of magnitude faster (Pettersson, 2009) lately with the invent of various technologies from Roche, Illumina
GS-FLX – 454 Roche
SoLiD sequencing - ABI
Solex -Illumina sequencing
Genomics of Cancer
International cancer genome consortium is the teamed effort of various international laboratories which coordinates large-scale genome studies in 500 tumours from each of 50 different cancer types and subtypes in both adults and children, adding up to a total of 25,000 cancer genomes. This effort is expected to reveal the major repertoire of oncogenic mutations, thus allowing the definition of clinically relevant subtypes and the development of new cancer therapies (Hudson TJ, 2010). Cancer is a genomic disease associated with the accumulation of mutations (Weinberg RA, 2006).DNA sequencing can be used reveal importent information related to genes, genetic variation and gene function for biological and medical studies (David R Bentley, 2006).Genome-wide association studies (GWAS) has been performed in nearly all common malignancies and have identified more than 100 common genetic risk variants that confer a modest increased risk of cancer (Stadler et. al. 2010). The accumulation of the information from the variety of cancers can help in revolutionizing the basic and clinical cancer research (Bardelli A, Parsons DW, Silliman N, et al, 2003). Strategies for the systematic identification of cancer genes by mutational profiling of tumor genomes and is extracted from Silvia Benvenuti ,et al. FEBS Letters 579 (2005) 1884–1890.
The Table 1 extracted from Edward J. Fox, Jesse J. Salk et al . shows selected details of cancer genome sequencing studies .
TABLE 1 Selected detail of cancer genome sequencing studies
Current trends in cancer genome elucidation-
One of the most significant achievements in the scientific history is the completion of the human genome draft sequence (Lander et al. 2001; Venter et al. 2001). Analysis of this elucidated sequence represents a benchmark and is transforming our knowledge of fundamental biological processes which govern human biology and pathology. Despite of a lot of progress made in the field of genomics, the sequence based sequence based structural analysis of tumour genomes was a very laborious and complex process until recent times (Raphael et al. 2003; Volik et al. 2003). The Identification of genes whose structure and/or expression is altered due to genome rearrangements has contributed largely to our understanding of cancer progression providing important prognostic and predictive markers and targets for therapeutic intervention.(Ehrlich 2000). Shah et al have recently reported the sequencing of an entire breast cancer tumour (Shah et al, 2009). The International Cancer Genome Consortium (ICGC) announced launch of a $20 million Canadian research project on February 15, 2011. This project is intended to map the genetic structure of prostate cancer and provide information that could greatly improve the diagnosis and treatment of the disease. Projects that are currently funded are examining tumours affecting the blood, bladder, brain, bone, cervix, colon, head and neck, liver, kidney, lung, oral cavity, ovary, pancreas, skin, rectum, soft tissues, stomach and uterus etc.
Epigenetics parlances the study of heritable changes in phenotype or gene expression which are caused by mechanisms other than changes in underlying DNA sequence. These changes may remain through cell divisions for the remaining of the cell's life or may also last for multiple generations. (Bird, 2007).Non-genetic factors cause the organism's genes to express themselves differently leading to significant changes in genome which are manifested at the phenotypic level. Robin Holliday defined epigenetics as "the study of the mechanisms of temporal and spatial control of gene activity during the development of complex organisms (Holliday, 1990). However the modern usage of the word in scientific discourse is more narrow, referring to heritable traits that do not involve changes to the underlying DNA sequence (Russo, 1996).
Epigenetics in Cancer-
An ‘epigenome’ is – a representation of all epigenetic phenomena across the genome. The study of the total methylation of the cell is called as methylome (Bernstein BE, 2006). Out of the two epigenetic changes i.e. histone modification and DNA methylation, the latter one is the most common and extensively studied marker. There are compelling evidences to support the importance of DNA methylation alterations in cancer development. Both losses and gains of DNA methylation are observed, thought to contribute pathophysiologically by inactivating tumor suppressor genes, inducing chromosomal instability and ectopically activating gene expression (Marcos et. al., 2010).The DNA methylation pattern in normal and cancerous cells is shown in Fig 3 (Extracted from Esteller, M. NAT.REV.GENETICS 8(4)286-298,2007)
New technologies for genome wide DNAm (methylome) analysis, such as MeDIP-seq, have been developed; enabling the unbiased analysis of cancer methylome Using MeDIP-seq, sequencing-based comparative methylome analysis of malignant peripheral nerve sheath tumours (MPNST), benign neurofibromas, and normal Schwann cells was done. Analysis of these methylomes revealed a complex landscape of methylome alterations. Contrary to the current dogma, significant global hypomethylation was not observed in the MPNST methylome. However, a highly significant directional difference in methylome was found in satellite repeats, suggesting these repeats to be the main target for hypomethylation in MPNST. Comparative analysis of the MPNST and Schwann cell methylomes identified 101,466 cancer-associated differentially methylated regions (cDMRs). Analysis showed these cDMRs to be significantly enriched for two satellite repeat types (SATR1 and ARL) and suggests an association between aberrant DNA methylation of these sequences and transition from healthy to malignant disease. Significant enrichment of hypermethylated cDMRs in CGI (CpG islands) shores, non-CGI-associated promoters (P <104 ), and hypomethylated cDMRs in SINE repeats were also identified. Integration of DNA methylation and gene expression data showed that the expression pattern of genes associated with CGI shore cDMRs was able to discriminate between the disease phenotypes. This study establishes MeDIP-seq as an effective method to analyze cancer (Andrew Feber, 2010). Two hundred candidate genes that cluster throughout the genome of which 25 were previously reported as harbouring cancer-specific promoter methylation were studied on 20 cancer cell lines of about 5 major cancer types. The remaining 175 genes were tested for promoter methylation. this was done using bisulfite sequencing or methylation- specific PCR (MSP). Eighty-two out of 175 (47%) genes were found to be methylated in cell lines, and about 53 of these 82 genes (65%) were methylated in primary tumor tissues. out of these 53 genes, cancer-specific methylation was identified in 28 genes (28 of 53; 53%). In addition to this, 8 of the 28 newly identified cancer-specific methylated genes were tested with quantitative MSP in a panel of 300 primary tumors representing 13 diffrent types of cancer. It was found cancer-specific methylation of at least one gene with high frequency in all cancer types. Identification of a large number of genes with cancer-specific methylation leads to new targets for diagnostic and therapeutic intervention and thus opens fertile avenues for basic research in tumor biology. The summary of findings on 200 candidate methylated is given in Table 2 (Mohammad Obaidul Hoque, 2008).
The exome is the part of the genome formed by exons which are the coding portions of genes in the genome that are expressed. It provide the genetic blueprint used in the synthesis of proteins and other functional gene products. Exome is functionally most relevant part of the genome with respect to coding for proteins and thus it is most likely to govern the phenotype of an organism. the exome of human genome is estimated to comprise about 1.5 % of the total genome. [Ng, 2008].
Exome capture allows an comprihensive analysis of the complete protein-coding regions in the genome. Researchers can use exome capture to focus on any critical part of the human genome. This in facts allows larger numbers of samples than are currently practical with whole-genome sequencing (Marcos et. al., 2010).Many studies on exome have given immense outcome in regard to cancer like in myeloma cancer it was elucidated that GRIN2A gene is the most mutated (Andrew Faber, 2010) and in case of renal cancer it has been found that there is frequent mutation in SWI/SNF complex gene PBRM1(Mohammad Obaidul Hoque, 2008).
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