Above (left and center) : tobacco-related lung cancer cells and melanoma cell mitosis (on the right)

"For the first time, we have a comprehensive map of all mutations in a cancer cell," said Dr Peter Campbell, senior author on the work, from the Cancer Genome Project at the Wellcome Trust Sanger Institute, "The profile of mutations we observed is exactly that expected from tobacco, suggesting that the majority of the 23,000 we found are caused by the cocktail of chemicals found in cigarettes. On the basis of average estimates, we can say that one mutation is fixed in the genome for every 15 cigarettes smoked."

The mutations range from single-letter changes in the code to deletions or rearrangements of hundreds of thousand of letters. Most are 'passenger' mutations, previously defined by the team as mutations that do not influence the development of the cancer, but are a consequence of the highly mutagenic environment in many cancer cells.

"Cancers occur when control of cell behaviour is lost - cells grow how, when and where they shouldn't," explains Dr Andy Futreal from the Wellcome Trust Sanger Institute. "Mutations in DNA caused by, for example, cigarette smoke are passed on to every subsequent generation of daughter cells, a permanent record of the damage done. Like an archaeologist, we can begin to reconstruct the history of the cancer clone - revealing a record of past exposure and accumulated damage in the genome."

" The profile of mutations suggests that the majority of the 23,000 we found are caused by the cocktail of chemicals found in cigarettes. On the basis of average estimates, we can say that one mutation is fixed in the genome for every 15 cigarettes smoked. "

 

What causes cancer? A few mechanisms of carcinogenesis (etiology)

It is impossible to determine the initial cause for any specific cancer. However, with the help of molecular biological techniques, it is possible to characterize the mutations or chromosomal aberrations within a tumor, and rapid progress is being made in the field of predicting prognosis based on the spectrum of mutations in some cases. For example, up to half of all tumors have a defective p53 gene. This mutation is associated with poor prognosis, since those tumor cells are less likely to go into apoptosis or programmed cell death when damaged by mainstream therapy. Telomerase mutations remove additional barriers, extending the number of times a cell can divide. Other mutations enable the tumor to grow new blood vessels to provide more nutrients, or to metastasize, spreading to other parts of the body.

In order for cells to start dividing uncontrollably, genes that regulate cell growth must be damaged. Proto-oncogenes are genes that promote cell growth and mitosis, whereas tumor suppressor genes discourage cell growth, or temporarily halt cell division to carry out DNA repair. Typically, a series of several mutationsto these genes is required before a normal cell transforms into a cancer cell. This concept is sometimes termed "oncoevolution."

The transformation from a normal cell into a tumour cell is a multistage and polymorphorous process, typically a progression from a pre-cancerous lesion to malignant tumours with integrated biological changes. These changes are the result of the interaction between a person's genetic factors and external agents, some of which are:

• physical carcinogens, such as ultraviolet and ionizing radiation
• chemical carcinogens, such as asbestos, components of tobacco smoke, aflatoxin (a food contaminant) and arsenic (a drinking water contaminant)
• biological carcinogens, such as infections from certain viruses, bacteria, fungi or parasites. Some examples of infections associated with certain cancers:

• viruses: hepatitis B and liver cancer, Human Papilloma Virus (HPV) and cervical cancer, and human immunodeficiency virus (HIV) and Kaposi sarcoma.
• Bacteria: Helicobacter pylori and stomach cancer.
• Parasites: schistosomiasis and bladder cancer.

Aging and traumatic emotions are other fundamental factors for the development of cancer. The incidence of cancer rises dramatically with age, most likely due to a buildup of risks for specific cancers that increase with age. The overall risk accumulation is combined with the tendency for cellular repair mechanisms to be less effective as a person grows older.

Tobacco use, alcohol use, low fruit and vegetable intake, and chronic infections from hepatitis B (HBV), hepatitis C virus (HCV) and some types of Human Papilloma Virus (HPV) are leading risk factors for cancer in low - and middle - income countries. Cervical cancer, which is caused by HPV, is a leading cause of cancer death among women in low-income countries. In high-income countries, tobacco use, alcohol use, and being overweight or obese are major risk factors for cancer.

 

STEM CELLS AND CANCER

A new way of looking at carcinogenesis comes from integrating the ideas of developmental biology into oncology. The cancer stem cell hypothesis proposes that the different kinds of cells in a heterogeneous tumor arise from a single cell, termed Cancer Stem Cell. Cancer stem cells may arise from transformation of adult stem cells or differentiated cells within a body. These cells persist as a subcomponent of the tumor and retain key stem cell properties. They give rise to a variety of cells, are capable of self-renewal and homeostatic control. Furthermore, the relapse of cancer and the emergence of metastasis are also attributed to these cells.

 

THE TUMOR SUPPRESSOR GENES

 

 

Tumor suppressor genes code for anti-proliferation signals and proteins that suppress mitosis and cell growth. In general, tumor suppressors are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways that lead to the activation of tumor suppressor genes. The functions of such genes is to arrest the progression of cell cycle in order to carry out DNA repair, preventing mutations from passing on to daughter cells. Canonical tumor suppressors include the p53 gene, which is a transcription factor activated by many cellular stresses including hypoxia and radiation damage. Sunlight also activates this gene.

When mutagenic agents damage the tumor suppressor gene itself, or the signal pathway that activates it, this gene is switched off. The lack of sunlight can also inactivate this gene. This can hinder DNA repair, so that DNA damage accumulates, including changes that lead to cancer.

 

How can the burden of cancer be reduced?

 

Knowledge about the causes of cancer, and interventions to prevent and manage the disease is extensive. Cancer can be reduced and controlled by implementing evidence-based strategies for cancer prevention, early detection of cancer and management of patients with cancer.

Many cancers could be prevented by modifying or avoiding key risk factors, some of which are as follows:

1. industrial tobacco use
2. being obese and overweight
3. low fruit and vegetable intake
4. physical inactivity
5. alcohol abuse
6. sexually transmitted HPV-infection
7. urban air pollution
8. indoor smoke from household use of solid fuels and other home toxins.
9. not enough sunlight.
10. too much stress and emotional trauma.

 

 

First comprehensive analysis of two cancer genomes

 

Malignant melanoma genome contains 33,000 mutations

 

Above, human melanoma cell dividing

In a landmark study, researchers have described the first comprehensive catalogue of somatic mutations in a cancer genome. The breadth and clarity of the view of the genome from a patient with malignant melanoma is matched only by a companion study on lung cancer, published in the same issue of Nature (See below for references) .

The melanoma genome contains more than 33,000 mutations, many of which bear the imprint of the most common cause of melanoma - excessive exposure to ultraviolet (UV) light. But the comprehensive catalogue of mutation reveals other more unusual mutations and many not related to exposure to UV light.

Malignant melanoma is responsible for three out of four skin cancer deaths: most forms of skin cancer are relatively treatable, especially if detected early.
"This is an unprecedented view of a cancer genome," says Professor Michael Stratton, from the Cancer Genome Project at the Wellcome Trust Sanger Institute. "Written within this code is the history of this cancer - its mutations from UV light and the mutations it acquired when it spread within the patient. We have revealed the archaeology of exposure in this cancer genome, which becomes a palimpsest of successive mutations."

"It is amazing what you can see in these genomes," comments Dr Peter Campbell from the Wellcome Trust Sanger Institute. "UV-light-induced mutations leave a typical signature, forming the vast majority of the mutations."

" We know that this cancer sample has a mutation in BRAF and other genes already implicated in melanoma. To discern all the important changes, we will need to analyse more samples. " Dr Andy Futreal

"Indeed because of the clarity of the genome data, we can distinguish some of the early, UV-induced mutations from the later mutations that do not have this signature, presumably occurring after the cancer cells spread from the skin to deeper tissues.The sequence also shows the genome's attempts to protect itself from damage, with DNA repair systems most active in gene regions, whereas the regions between genes are left less well guarded. Even with these actions, 182 changes in genes that would impair their function were charted.

"Within the lists of disrupted genes are all those that have driven the original cell to this malignant state," comments Dr Andy Futreal, from the Cancer Genome Project at the Wellcome Trust Sanger Institute. "We know that this cancer sample has a mutation in BRAF and other genes already implicated in melanoma. To discern all the important changes, we will need to analyse more samples."

The genomes - cancer cell and normal cell - were sequenced more than 70 times over to produce accurate data. The project was led by researchers from the Wellcome Trust Sanger Institute. In 2002, this group discovered that a mutation in one gene called BRAF was important in driving development of melanoma. That discovery has already driven the development of novel therapies that are in clinical trials.

 

Above: cancer cells proliferating.

 

CONCLUSION

 

THE LIMITATIONS OF GENETIC INTERVENTION IN CANCER

This news of the complete DNA sequencing of two different cancers (lungs and melanoma) has led to corporate investment in a genetic "cure" of cancer, nota bly by 2020, seen as the "new golden age of drug discovery". This approach has already led to a record number of new compounds in trials, currently estimated to be about 700. Over the next few years, there will be a marked shift in the type of agents used in the systemic treatment of cancer. They will be precisely targeted to the defined abnormalities found in individual patients.
Because we know the precise targets of these new agents, there will be a revolution in cancer therapy. Instead of defining drugs for different types of cancer empirically and relatively ineffectively, we will identify a series of molecular lesions in tumour samples. Future patients will receive drugs that target these lesions directly. The experts say that these new therapies will be more selective, less toxic and be given for prolonged periods of time, in some cases for the rest of the patient's life. This will lead to a radical overhaul of how mainstream medicine provides cancer care. Personalised medicine, based on a set of novel molecular diagnostics, will allow allopathic medicine to give the genetic-based medicine that will be monitored via blood sampling. In this perspective, tiny, implantable chips sending radio signals to a home computer will permit continuous monitoring. Individual cancer risk assessment may lead to tailored prevention messages and a specific screening programme to pick up early cancer.

In the past 20 years, a huge amount of fine detail of the basic biological processes that become disturbed in cancer has been amassed, and the pace is quickening. We now know the key elements of how signals for growth bind to cells and how messages can get corrupted, leading to uncontrolled growth or failure to die. The human genome project provides a vast repository of comparative information about normal and malignant cells. There are also cancer-promoting bio-physical properties that can be measured. These are fertile areas to look for rationally based cancer reversal approach.

However, this genome therapy comes with a hefty price tag. And may not be full proof. Like for chemo, these new drugs could be palliative, adding longer periods of remission. They do not address the "terrain" and lifestyle causes (See other link on this question).

 

REFERENCES

 

• Pleasance ED et al. (2009) A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature
  Available online at doi: 10.1038/nature08629
• Pleasance ED, Cheetham RK et al. (2009) A comprehensive catalogue of somatic mutations from a human cancer genome. Nature
  Available online at doi: 10.1038/nature08658

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