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Mutagens, carcinogens and oncogenes

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Mutagens and carcinogens

Mutagens are things that can cause mutations in DNA, whether at the base level or chromosome level. Many DNA mutations are the cause of cancer, therefore mutagens can be expected to also be carcinogens (things that can cause cancer).

These factors can be physical, such as UV radiation from the Sun or the radioactivity of certain chemicals such as carbon 14 (14C). They can also be chemical such as chelating agents (which bind to DNA between bases and can cause frameshifts) like ethidium bromide (mutagen), or indeed asbestos (carcinogen).




Some biological carcinogens include chemicals from the fungus Aspergillus and some bacteria.


Mutation

The Cause of Mutations

Mutations are a random occurrence during DNA replication and the rate of mutation is influenced by external factors such as UV radiation. There are different types of mutation:

1. Deletion where a nucleotide base is deleted. AGTCA becomes AGCA.

2. Substitution where a nucleotide base is replaced by another. AGTCA becomes AGTCG.

3. Insertion where a nucleotide base is added as extra. AGTCA becomes ATGTCA. 




The Effect of Mutations

Since the genetic code is degenerate, it's possible that a mutation won't have any effect whatsoever! This represents silent mutations. If 2 different triplet codes translate into the same amino acid, the polypeptide chain will remain unchanged. This of course only applies to substitutions.

Another scenario where a mutation may cause no effect is if it arises in an intron. Since these are removed before mRNA is translated, no mutations would be carried along.

What happens if a base is deleted or added? The genetic code is non-overlapping, so the error cannot simply be overlooked and the following triplets read correctly. The entire subsequent code will be shifted. This is called a frameshift

Deletion: AGT GGC TTA... --> lose the first G --> ATG GCT TA...

Insertion: AGT GGC TTA... --> insert an A after the first A --> AAG TGG CTT A...

The code is affected significantly!!! In fact, it may be totally ruined. One way this can happen is by a nonsense mutation which by a frameshift causes the code to arrive at a stop codon earlier than it's supposed to. This will result in a shorter polypeptide and therefore truncated protein which may malfunction.

missense mutation is when a substitution changes the amino acid encoded. This does not necessarily impact the overall protein, but it may result in a protein with an altered binding site and therefore affect its activity.




Mutations and Cancer

Cell division is kept in check by two kinds of genes: proto-oncogenes which trigger division, and tumour suppressor genes which inhibit division. Cancer is caused by mutated genes involved in cell division. Mutated proto-oncogenes, called oncogenes, trigger cell division at a far greater rate than normal, thus allowing cells to divide out of control.

Mutated tumour suppressor genes fail to inhibit division any longer, therefore contributing to the growth of cancerous tissue by indefinite division.


Benign and malignant tumours

Not all tumours are cancer. Tumours are tissue growths beyond the required tissue growth for healthy functioning. Benign tumours are local and cannot spread. Mostly they pose no direct health risk, and only require medical interventions such as surgery if they interfere with organ, nerve or blood vessel function by their presence (i.e. increasing local pressure).

The ability of tumour cells to spread beyond the local tumour is called metastasis and defines malignant tumours which are the basis of cancer. This is also the primary source of death related to tumours.




Benign growths keep to themselves and cannot spread through the blood system or lymphatic system. Cancer on the other hand poses a big risk to unrelated areas of the body by carrying cancer cells via the bloodstream. Therefore, a local cancer in the breast tissue can extend to the bones or liver.

The differences between benign and malignant tumours, respectively, in their appearance and behaviour include:

-slower growth versus faster growth
-capsule versus lack of capsule
-lack of necrosis versus necrosis
-lack of vessel invasion versus vessel invasion


Tumour development

Cancer is primarily an environmental/lifestyle disease, with a minority of cancer types being inheritable or caused genetically. However, the effects of the environment upon cells results in clear pathways of genetic changes such as mutation as well as epigenetic changes such as methylation.

There are multiple separate events that lead to cancer. Often they interact with and exacerbate one another. Oncogenes and tumour suppressor genes are key players that regulate the cell cycle

Oncogenes promote cell growth and division, while tumour suppressor genes suppress cell division and survival. Combinations of events involving these can lead to cancer.

Oncogenes can be duplicated, or existing oncogenes can be expressed too much. Tumour suppressor genes can be inactivated. These epigenetic events can be controlled via simple methylation.




A series of cell regulation failures ends up in malignant tumours.

Sometimes, the effects are not caused by genetic expression directly. Sex hormones have been shown to be involved in the development of some types of cancer such as breast and prostate cancer, because they promote cell division. In women whose mothers got certain breast cancers, but did not have the increased susceptibility variants BRCA1 and BRCA2, higher levels of oestrogen and progesterone were found.

Knowledge of these different gene regulation pathways leading to cancer can help in finding treatments.

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