
<b>One Cell</b>
Years before the cancer becomes a lump, it starts growing from one cell -- From a cell that has lost a number of vital control systems.  The genes that control the vital control systems are on the strands of chromosomes that make up the cell's DNA, in the nucleus of the cell. 

<b>Genes and Mutation</b>
If a gene is damaged or lost, that is called a mutation.  Most mutations are "don't work" mutations.  The damaged gene creates a protein/enzyme that "doesn't work", it doesn't do what it is supposed to do. A mutation may mean that too much protein is made. Or that a protein is not made at all. 

<b>Proteins Run the Cell</b>
Proteins are the machinery, the driving forces that make the cell function. Some proteins act as 'on/off' switches that help to control how a cell behaves. For example, a hormone signal acts on a hormone receptor [a protein] in the cell or on the cell membrane. The protein then sends a signal down a chain of switches [other proteins].  This is a cascade of reactions, the final signal of which tells the cell to reproduce by dividing into two. 

<b>Mutations Prevent Proper Function</b>
A mutation may mean that too much protein is made. Or that a protein is not made at all. 
For example, a signalling protein may be permanently switched on. Other proteins, whose job is to control and limit cell division, may be permanently switched off. 

<b>Oncogenes</b>
Some genes encourage the cell to multiply or 'double'. Normally, this would not happen very often in most cells in adults. Many cells would only multiply to repair damage, for example after a wound or operation. If these genes become abnormal, they tell the cell to multiply all the time. Scientists call these genes oncogenes. This really means 'cancer genes.'   

<b>Tumour suppressor genes</b>
Some genes are in the cell specifically to stop the cell multiplying or doubling. They act as the brake to the oncogene's accelerator. If one of these 'tumour suppressor genes' becomes damaged and stops working, then the cell may carry on and on multiplying.  

<b>Genes that repair other damaged genes</b>
These genes normally repair any damage to the DNA that the cell's genes are made of. If these genes are damaged, then other mutations are not repaired and accumulation of mutations in the cell line might occur quickly. These genes have been found to be damaged in some human cancers, including colon (large bowel) cancer. 

<b>Carcinogens and Carcinogenesis</b>
Something that damages a cell and makes it more likely to be cancerous is called a 'carcinogen'.   There are carcinogens in cigarette smoke, and in barbecued or smoked food.   Many other substances are known carcinogens, including heavy metals, estrogen, some organic solvents, as well as sunlight, chemotherapy agents, radiation and some viruses.  
Carcinogenesis is the process of producing cancer.  

<b>How Cancer Starts [Carcinogenesis]</b>
Mutations occur to the genes of cells by exposure to 'ionizing' radiation [like the sun's rays, radioactivity, Xrays], or chemical mutagens [like benzene and its derivatives] or viruses [which can introduce foreign DNA into the cell's DNA] or autoantibodies to DNA [created if a person has an autoimmune disease.]  Other situations besides exposure to carcinogens can cause carcinogenesis.  One is abnormal reproduction of the cell, with the result of two abnormal daughter cells, or mismatched DNA, or chromosomes stuck onto each other abnormally.   Sometimes there are germline mutations, these are passed on in a family, and might consist of faulty guardian genes, or faulty repair genes, or specific mutations which create situations which predispose to development of specific cancers.

The usual mutation is one that causes a gene NOT to work. This means that the enzyme/protein that the gene produces [the gene product] does NOT work.  For cancer to happen, a single cell needs to accumulate five or six different mutations. The usual probability of this happening is very very small.

<b>So what makes it happen?</b>
In every healthy normal cell, during reproduction there is a safety mechanism that checks that the DNA is intact and has no errors.  The p53 gene is part of this safety mechanism.  If the DNA is damaged, and cannot be repaired, then the p53 gene sets off a series of reactions that leads to apoptosis---the cell self-destructs.  The p53 gene is called "the guardian of the genome" because it does not allow faulty DNA to exist, or to be passed on in the cell line.  The "guardian of the genome" will cause a cascade of reactions that lead to apoptosis [cell suicide] in cells whose DNA is damaged and cannot be repaired.  <b>BUT What happens if the "the guardian of the genome" has a mutation? </b>

<b>If the Guardian Gene Doesn't Work</b>
So a key mutation in the development of cancer would be damage to this p53 gene, or damage somewhere in its cascade of reactions.  If the p53 cascade of reactions does not occur, then faulty DNA is passed on from the damaged cell to the cells that grow from the damaged cell [daughter cells].  Furthermore, the cell line with faulty p53 can now start collecting mutations.   If the "caretaker gene" doesn't work, it allows defective-DNA daughter cells in the next generation. The defective daughter cells then accumulate their own additional mutations, which are ALSO passed to THEIR daughters. Who also accumulate some additional mutations. Which are ALSO passed to THEIR daughters. And so on...

<b>Eventually, besides not being able to police its own DNA, there will be mutations involving reproduction and growth, invasiveness, and coherence to other cells.  One or more mutation in each of these areas, about 5 or 6 mutations, are needed to develop a cancer cell.</b>

When you have a cell that 
*cannot destroy faulty DNA, [one mutation, often involving p53]
*which has ungovernable growth, [one mutation]
*which invades neighboring tissue, and [one or more mutations]
*which can separate itself from other tissue and [one or more mutations]
*journey via lymph or bloodstream to grow in a new place, [another mutation]
you have an invasive, metastasizing cancer.  

So 'loss of function' mutations in these "caretaker genes" lead to an accumulation of mutations in the cell, and these mutations are carried through to subsequent cell generations. These cells are genetically unstable, as more and more mutations accumulate, and ARE PASSED ON to the next generation of cells. Inexorably, and inevitably, eventually, a cancerous cell will occur.  The p53 gene is damaged or missing in the majority of human cancers. 

It can take a long time before enough mutations happen for a cell to become cancerous. This is why many cancers are more common in older people. There has been more time to be exposed to carcinogens. And more time for accidents when cells reproduce. 

Some people are said to have a 'genetic predisposition' to a type of cancer.  This means they are more likely to develop that type of cancer than most people because they have been born with one of the mutations that makes a cell cancerous. They do not actually have the cancer because more than one mutation is necessary. But they are naturally further along the road towards getting cancer than people without that mutation. 
For further discussion see the Scientific American Article
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For some indication of the genetic changes in LMS tumors:
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A given mutation in a tumour may be specific to a particular carcinogen.  However, the mutation that the carcinogen causes may differ depending on the species and the cell type.  So a carcinogen will affect different types of tissues differently.
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<b>For more information on gene alterations and cancer</b>: 
The National Cancer Institute - &&url
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Genetic alteration and gene expression modulation during cancer progression -- Molecular Cancer
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<b>Dedifferentiation </b>

Cancer progresses through changes, as the cancer cells accumulate more and more mutations.  The identification of the mutations and their expression in the cell, might provide new targets for treatment or treatment design, as well as tools for early diagnosis.  ..  see below:

Cancer progresses through a series of histopathological stages [dedifferentiation]. Progression is thought to be driven by the accumulation of genetic alterations and consequently gene expression pattern changes. The identification of genes and pathways involved will not only enhance our understanding of the biology of this process, it will also provide new targets for early diagnosis and facilitate treatment design. Gene approaches have proven to be effective in detecting chromosomal alterations and identifying genes disrupted in cancer...
See the rest of this article:
Chromosomal Instability in Cancer  Causes and Consequences
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More than 100 cancer genes, each with its own blueprint for making a specific protein product, have already been identified -- about 80 oncogenes and 20 tumor suppressor genes. There are estimated at least an equal amount of cancer genes that have not been discovered yet.  
The patterns of genes that are altered in individual tumors and specific cancers are yet to be defined. The more scientists learn about the molecular signature of a particular tumor or cancer, the easier it will be to make correct diagnoses, choices of therapy, and accurate predictions of outcomes. 
National Cancer Institute: From "Gene Alterations and Cancer"                                         
   
For more information about cancer, visit NCI's website.
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NCI - &&url
NCI/CGAP - &&url
