Cancer genome – a revolution in cancer therapy

As genomics get into its stride, biologists are starting to learn why cancer is such a wily foe. All cancers arise as a result of changes that have occurred in the DNA sequences of the genomes of cancer cells. Over the past quarter of the century much has been learnt about these mutations and the abnormal genes that operate in human cancers.

Throughout life, the genome within the cells of the human body is exposed to mutagens and suffers mistakes in replication. Theses corrosive influences result in progressive, subtle divergence of the DNA sequence in each cell from that originally constituted in the fertilized egg. Occasionally, one of these somatic mutations alters the function of a critical gene, providing growth advantage to the cell in which it has occurred and resulting in the emergence of an expanded clone derived from this cell. Acquisition of additional mutations and consequent waves of clonal expansion results in the evolution of the mutinous cells that invade surrounding tissues and metastasize (1).

Cancer is responsible for one in eight die worldwide (2). But recent report is that one in three people in the Western world develop cancer and one in five die of the disease (1). All cancers are thought to share a common pathogenesis. Each is the outcome of a process of Darwinian evolution occurring among cell populations within the microenvironments provided by the tissues of a multicellular organism. Analogous to Darwinian evolution occurring in the origins of species, cancer development is based on two constituent processes, the continuous acquisition of heritable genetic variation in individual cells by more-or-less random mutation and natural selection acting on the resulting phenotypic diversity (2). Within an adult human there are probably thousands of minor winners of this ongoing competition, most of which have limited abnormal growth potential and are invisible or manifest as common benign growth such as skin moles. Occasionally, however, a single cell acquires a set of sufficiently advantageous mutations that allows it to proliferate autonomously, invade tissues and metastasize (2).

Somatic mutations in a cancer cell genome may encompass several distinct classes of DNA sequence change. These include substitutions of one base by another; insertions or deletions of small or large segments of DNA; rearrangements, in which DNA has been broken and then rejoined to a DNA segment from elsewhere in the genome; copy number increases from the two copies present in the normal diploid genome, sometimes to several hundred copies (known as gene amplification); and copy number reductions that may result in complete absence of a DNA sequence from the cancer genome (2). In addition, the cancer cell may have acquired, from exogenous sources, completely new DNA sequences, notably those of virus, Epstein Barr virus, hepatitis B Virus, human T lymphotropic virus and human herpes 8, each of which is known to contribute to the genesis of one or more type of cancer (3).

Compared to the fertilized egg, the cancer cell genome will also have acquired epigenetic changes which alter chromatin structure and gene expression, and which manifest at DNA sequence level by changes in the methylation status of some cytosine residues. Epigenetic changes can be subject to the same Darwinian natural selection as genetic events, provided that there is epigenetic variation in the population of competing cells that the epigenetic changes are stably heritable from the mother to the daughter cell and that may generate phenotypic effects for selection to act on (2).

Thousands of mitochondria present each carry a circular genome of approximately 17 kilobases.  Somatic mutations in mitochondrial genomes have been reported in many human cancers, although their role in the development of the disease is not clear (4).

DNA in normal cells is continuously damaged by mutagens of both internal and external origins. Most of this damage is repaired. However, a small fraction may be converted into fixed mutation and DNA replication itself has a low intrinsic error rate. Mutation rates increase in the presence of substantial exogenous mutagenic exposure, e.g. tobacco smoke carcinogens, naturally occurring chemicals such as aflatoxins, which are produced by fungi, or various forms of radiation including UV light. These exposures are associated with increased rates of lung, liver and skin cancer, respectively and somatic mutation within such cancers often exhibit the distinctive mutational signature known to be associated with mutagen(5). The rates of the different classes of somatic mutations are also increased in several rare inherited diseases, e.g. Fanconi anemia, ataxia telangiectasia, mosaic variegated aneuploidy and xeroderma pigmentosum, each of which is associated with increased risk of cancer (6,7).

Vantana Medical Systems of Tueson, Arizona is now developing a test for the TMPRSS2-ERG  mutation in biopsied tissues of prostate, hopes to detect the RNA copies of this and other dangerous mutations in urine. Such tests could spare many men from unnecessary treatments, costs and stress. Among the most promising candidates is a test for a genetic mutation of prostate that fuses a "promoter" sequence called TMPRSS2, which boost gene activity, with a gene called ERG. Prostate cancer cells with this mutation respond to male hormone by becoming more invasive (8).

In the mid 1990s, geneticists discovered BRCA1 and BRCA2, two genes that between them are responsible for just over half of all hereditary forms of breast cancer. The genes encode proteins involved in DNA repair, so when they are defectives, cells become more likely to accumulate cancer – causing mutations. The PARP inhibitor drug is effective in women with mutant BRCA2. The PARP inhibitor in a breast cancer patient, is helping to test blocks and enzyme involved in a different DNA repair pathways (8).

Initial genomic studies on a form of brain cancer known as Glioblastoma have already revealed that it is essentially two diseases with a different age of onset and pattern  of survival, depending on whether a gene called IDH1 is mutated(8).

Oncologists have discovered that 15-25 percent breast cancers are driven by mutations that cause cells to produce large amount of a cell-surface receptors called HER2. This can be targeted with an antibody called trastuzumab, better known by its brand name Herceptin. Joe. Nevins. studied (2008) studied the genomics of breast cancer at Duke University in Durham, North Carolina and he stated that in breast cancer there are multiple mechanisms and combinations of mutations arise. Hereditary nonpolyposis (HNPCC) is an inherited colorectal cancer syndrome. Other primary cancers of HNPCC - related cancers included colon cancer, endometrium, ovary, stomach, kidney – urinary tract, brain, biliary tract, central nervous system and small bowel.

International cancer genome consortium (ICGC) was setup in April 2008. The aim of this consortium is to sequence the DNA from 25,000 individual tumors to document the mutation implicated in 50 of the most common cancers. Ideally it should be organized to maximize use of resources and harmonize the product. This is the mission of the ICGC (9).

Andrew Futreal and his team released treatment response data and corresponding genomic information for hundreds of cancer samples in The Cancer Genome Project, launched in 2008.  By producing a carefully curated set of data to serve the cancer research community, they produced a database for improving patient response during cancer treatment. Researchers involved in the effort, including investigators at the Sanger Institute and the Massachusetts General Hospital Cancer Center, plan to look at how some 1,000 genetically characterized cancer cell lines respond to treatment with 400 anti-cancer treatments, alone and in combination. Findings from studies looking at the effects of 18 anti-cancer drugs on 350 genetically characterized cancer samples are being made available to other researchers through the Cancer Genome Project's Genomics of Drug Sensitivity. Along with drug sensitivity information, the team is providing genetic data on the cancer cell lines tested, including information on mutations, copy number changes, and gene expression patterns in the lines. For instance, from experiments done so far the team was able to detect some known treatment-related genetic patterns, including activating mutations in the BRAF gene in melanoma that correspond to BRAF-targeting treatment response. They clearly identified drug–gene interactions that are known to have clinical impact at an early stage in the study (10).

The Cancer Genome Atlas (TCGA) is a project to catalogue genetic mutations responsible for cancer, using genome analysis techniques started in 2005. The techniques that are being used include gene expression profiling, copy number variation profiling, SNP genotyping, genome wide methylation profiling, microRNA profiling, and exon sequencing of at least 1,200 genes. Recently the TCGA announced that they would sequence the entire genomes of some tumors and at least 6,000 candidate genes and microRNA sequences. This targeted sequencing is actively being performed by all three sequencing centers using hybrid-capture technology. A gene list is available on the TCGA website. In phase II, TCGA will perform whole exon sequencing on 80% of the cases and whole genome sequencing on 80% of the cases used in the project.

Performing genomic sequencing on cancer tumors provide clinicians with information to treat cancer more precisely, especially for patients who are resistant to conventional treatment. Therefore, the study of cancer genome provides new insights into the origin and new direction on treatment of cancer. So physicians can pinpoint the root cause of a disease. The knowledge gained from cancer genome should allowed clinicians to design treatments to address specific diseases.

References:

1. http://www.sanger.ac.uk/genetics/CGP/
2. Michael. R. et al. Nature 458:719-724 (2009)
3. Talboot. S.J and Crawford. D.H. Cancer. 40:1998-2005 (2004)
4. Chatterjee. A et al. Oncogene 25:4663-4674 (2006) 
5. Oliver. A et al. IARC. Sci.Publ. 247-270 (2004)
6. Kennedy. R.D. and D'Andrea. A.D. J.Clin.Oncol. 24:3799-3808 (2006)
7. Hanks. S. & Rahman. N. Cell Cycle 4: 225-227 (2005)
8. Geddes. L. New Scientists, 25 October 2008
9. http://www.icgc.org/home
10. http://www.genomeweb.com/dxpgx/