Cancer is a set of diseases characterised by unregulated cell growth leading to invasion of surrounding tissues and spread ''metastasis'' to other parts of the body.
Most studies revealed that cancer is caused due to mutation or damage to the gene, result in changes in cell physiology that causes a normal cell to be transformed into cancerous cell. Moreover, silencing genes are also thought to be involved in molecular pathogenesis of cancer.
There are three classes of genes that involved in tumour formation; genes that regulate cell proliferation, genes that control apoptosis (programmed cell death), and genes responsible for repairing damaged DNA. Based on that, there are two categories for cancer associated gene, depending on their effect on each process; oncogenes (over activity), and tumour suppressor gene (under activity).
In this review, I will try to cover the main aspects of molecular mechanism of tumour suppressor gene by using APC gene as an example of suppressor gene. And follow the mutation of APC gene which is known to cause colon and rectal cancer (familial adenomatous polyposis). Furthermore, I will point the correlation between viruses' benefits and carcinogenesis.
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Oncogenes, or proto-oncogenes, are stimuli for cell growth. The activates the growth of cell normally and they act on dominant manner which means one altered allele is sufficient to cause mutation in the cell. The only oncogenes example known for colon and rectal cancer is K-ras. It is located in the chromosome 12p. it works in a dominant pattern and involved in 20-30% of colon and rectal cancer.
Tumour suppressor gene
Or under activity associated gene, which creates an environment in which cancer is promoted by being less active. Anti-oncogene protects the cell from progression to cancer. When this gene is mutated, it causes a loss or reduction in its function. The cell can progress to cancer usually in combination with other genetic changes.
Tumour suppressor gene functions by inhibiting the cell growth. Mutation in the suppressor genes contribute to the development of cancer by inactivating their function.
They are known to act in recessive pattern. There are three suppressor genes involved in colon and rectal cancer. P53 gene, which induces apoptosis and found on chromosome 17p. When genetic alteration accumulate in the cells and the cells are unable to proliferate to the next generation, programmed death cell (apoptosis) take place. APC (adenomatous polyposis coli) gene, which is located in chromosome 5q. Mechanism of action is unknown for this gene. DCC gene is involved in cell adhesion and found in chromosome 18q.
APC, or adenotamous polyposis coli, is a tumour suppressor gene. APC gene is located in the chromosome 5. APC gene controls the cell divisions cycle by controlling the speed of cell division and maintain the growth in normal functional pattern. APC protein controls the movement of cells and its attachment to the tissue. It also ensures the number of chromosome in the cell after division. Other attaching and signalling proteins aid APC protein to accomplish its task.
So far, more than 700 mutation of APC gene have been identified in FAP disorders. Most of these mutation resulted in production of abnormal versions of APC protein (short, and non-functional). The abnormal APC proteins can-not fulfil its tasks and as a result, overgrowth of cells (polyps) takes place which subsequently become malignant (cancerous).
P53 refer to as'' genome guardian angel''. It is tumour suppressor gene called protein of 53 kilodaltons (hence the name came). It repairs damaged DNA and prevent cells which have sustained more damage from completing the cycle. P53 gene is located in chromosome 17p. it accomplishes its task by inducing apoptosis (programmed cell death). P53 transcription factor is encoded by the P53 gene. Tumour cells with mutated or loss P53 gene keep replicating damaged DNA and do not undergo apoptosis. MDM2 is a transcriptional target of P53. It is an oncogene which hyperproleferate cells. The negative feedback results in lowering P53 concentration. Signals from damaged DNA lead to phosphorylated P53. Which increase P53-dependent transcriptional of gene like P21.
After following the sequence of adenoma to carcinoma order, a pathway was suggested on the basis of mutation found in lesion site. Scientists believe that, mutation in APC gene occurs in first place, which leads to accelerate the cells proliferation process and forming adenoma. Activation of K-ras oncogene leads to form a doubly mutated clone and formation of an intermediate adenoma. Loss of DCC gene and mutation or loss of P53 leads to malignant transformation. It is thought carcinoma is a result of 4-12 genetics alteration and over activity of oncogenes and loss function of suppressor gene.
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This situation is thought to be caused due to the fact that the whole genome is unstable because of deficiency in its gene repair mechanism.
Colon and rectal cancer have many syndromes due to mutation of suppressor gene, and as this review is meant to be about APC gene molecular mechanism, the following will be an example of only APC gene mutation syndrome.
Familial Adenomatous Polyposis (FAP)
FAP is caused due to germline mutations in the APC gene. It is hereditary colon and rectal cancer. FAP can develop since early as teen ages. During teen ages multiple growths of benign cells in colon (polyps) occur. If left untreated or removed, these polyps will progress to be malignant cells. People with classical familial adenomatous polyposis, the number of polyps vary from hundreds to thousands of polyps which develop in the colon. These tumours could be found in the colon. . Due to it is location, one of the parent (mother or father) could inherit the gene mutation to their children. Initially, APC mutation was de novo, meaning it was inherited for the first time it occurred in a person with symptoms in the family. So this person with de novo mutation transmits them in Mendelian inheritance pattern to their children. There is 50/50 chance for parent with mutation in APC gene to have children with this disorder (disregard to the child sex).
Diagnosis of FAP can be done during the early ages. By endoscopy exam, more than 100 of colonrectal adenoma can be visualised. Also detection could be done by blood test, by running blood sample for detection of mutation of APC gene, since polyps are formed in early ages (10-12 years old). However, for the first time person, sensitivity is almost 87%. But once the mutation is identified then for the other members the accuracy could be 100% in identifying mutation in the gene.
Usually 1 individual out of 7,000-22,000 develops FAP. It occurs mostly in average between ages of 39-44 years old. In addition to this syndrome, patients with FAP may develop other tumours in other body area like duodenum, skin and bone.
Attenuated Adenomatous Polyposis
In this disorder, patients have less than a hundred polyps in the colon. And it usually occurs in people older than 40 with average of 55 years old.
However, these tumours could be found in other places of the body like skin, bone and duodenum. On the other hand, the milder type of classical familial adenomatous polyposis, or autosomal recessive familial adenomatous polyposis, fewer polyps are developed or found (less than a hundred).
FAP is caused due to mutation in either APC gene or MUTYH gene. When FAP is inherited due to APC gene mutation, it means one copy of the altered gene in each cell is sufficient to cause disorder. Mostly, to inherit disease due to mutation of APC gene requires one of the parents to have affected gene. While, when disease is acquired due to MUTYH gene mutation both parent must have the condition, as a carrier without showing symptoms. As it require both copies of the altered gene in each cell to cause disorder.
It is the process that cells undergo to become cancerous.