Oncogenes are genes that positively enhance the cell proliferation associated with cancer development. Proto-oncogenes are the normal nonmutant forms of oncogenes. When the proto-oncogenes are activated, the normal cell will transform to cancerous cell.
There are many ways of activation of proto-oncogenes. Activation involves a gain of function. The activation can be quantitative which involve the increase of production of an unaltered product or qualitative which involve the production of a modified product as a result of a mutation. These alterations are dominant and only affect a single allele of gene. As far as the researchers know, only RET gene can be inherited to cause familial cancer when activated. The RET gene involve in multiple endocrine neoplasia and familial thyroid cancer.
Activation of Proto-oncogenes via Amplification
One of the ways of proto-oncogenes activation is via amplification. Many cancer cells contain multiple copies of structurally normal oncogenes. For examples, breast cancers amplify ERBB2 and sometimes MYC. The researchers use comparative genome hybridization (CGH) technique to reveal all regions of amplification in a single experiment.
Activation of Proto-oncogenes via Point Mutations
Another ways of proto-oncogenes activation is via point mutations. For instance, specific point mutations in ras genes are frequently found in cells from varieties of tumours like colon, lung, breast and bladder cancers. The point mutations lead t amino acid substitutions and decrease the GTPase activity of the RAS protein. Consequently, the GTP-RAS signal is inactivated more slowly, leading to excessive cellular response to the signal from the receptor.
Another example of proto-oncogenes activation by point mutations is RET. Mutations leading to amino acid substitutions at certain specific cysteine residues are found in multiple endocrine neoplasia type 2 and in medullary thyroid cancer.
Activation of Proto-oncogenes by Chromosomal Translocations
The proto-oncogenes can be activated by chromosomal translocations too. The best known example is Philadelphia chromosome, a very small acrocentric chromosome seen in 90% of patients with chronic myeloid leukemia. It is because of a balanced reciprocal 9;22 translocation. This is an example of activation by qualitative change. The breakpoint on chromosome 9 is within an intron of the ABL oncogene. The translocation joins most of the ABL genomic sequence on to a gene called breakpoint cluster region (BCR) on chromosome 22, creating a novel fusion gene. This chimeric gene is expressed to produce a tyrosine kinase related to the ABL product but with abnormal transforming properties.
There are many other rearrangements are known which produce chimeric genes. The products are transcription factors. This has been one of the most satisfying stories to emerge from cancer research, with examples of clinical phenotypes being elegantly explained by a combination of cytogenetic and molecular genetic findings.
Activation of Proto-oncogenes by Transposition to an Active Chromatin Domain
On the other hand, Burkitt’s lymphoma is one of the example of tumour that caused by activation of proto-oncogenes by transposition to an active chromatin domain. It is an example of activation by quantitative change. The oncogene was put in an environment of chromatin which is actively transcribed in antibody-producing B cells. The Burkitt’s lymphoma translocations do not create novel chimeric genes. Usually, the exon of the MYC gene is not included in the translocated material.
In conclusion, activating proto-oncogenes can cause cancer development. By knowing the ways of activation, maybe we can do something to prevent it via deeper cancer research.
(Reference: Human Molecular Genetics from Tom Strachan and Andrew P. Read)