Cancer proto-oncogene mutation

Blakeslee, Sandra. Genes Tell Story of Why Some Get Cancer While Others Don t. New York Times (May 17,1994) B6. Nickerson, M.L., Weirich, G., Zbar, B., L.S. Schmidt. Signature-based Analysis of MET Proto-oncogene Mutations Using DHPLC. Human Mutation 16 (2000) 68-76. 

Kambouris M, Jackson CE, Eeldman GL. Diagnosis of multiple endocrine neoplasia [MEN] 2A, 2B and familial medullary thyroid cancer [FMTG] by multiplex PCR and heteroduplex analyses of RET proto-oncogene mutations. Hum Mutat. 1996 8 64-70. 

Tumor suppressor genes contribute to the development of cancer when both copies of the gene are inactivated. This is different from the case of proto-oncogene mutations because only one allele of a proto-oncogene needs to be converted to an oncogene to initiate transformation. 

Several inherited cancer syndromes are also known to result from mutations in proto-oncogenes. An example is given by the RET proto-oncogene. Depending on the type of mutation and on which part of the gene is affected, RET mutations can lead to multiple endocrine neoplasia 2A or 2B or familial medullary thyroid carcinoma. These familial cancers are inherited in autosomal dominant fashion. A second example is the CDK4 proto-oncogene, which when mutated can cause familial melanoma. 

Unlike tumor suppressors, in which loss-of-function mutations are required in both copies of the gene in a specific cell, a single gain-of-function mutation in a proto-oncogene is usually sufficient to give rise to cancer. 

Although the study of inherited cancer syndromes has led to the identification of a number of tumor suppressor genes and oncogenes, the inherited cancer syndromes are thought to account for only about 1% of all cancers. However, somatic (as opposed to germline) mutations in many of these tumor suppressors and proto-oncogenes play a key role in the causation of noninher-... 

So far, our story has focused on mutated single proto-oncogenes—for example src or ras—as key entities in the generation of cancer. A little reflection will convince us that the story cannot be that simple. 

By now, we have put together a lot of the cancer story. We know that cancer is a disease originating in a single cell that has overcome the normal limits to its growth and proliferation and that mutations in proto-oncogenes and/or tumor suppressor genes are required for this to happen. Beyond that, we know that multiple such mutations are usually required. 

The sequence of events from mutations or damage to proto-oncogenes and leads to tumour suppressor genes, loss of development of cancer, with its metabolic disturbances and cachexia. Finally these changes can lead to... 

Ras, a historical proto-oncogene, is frequently mutated in many human cancers, including 90% of pancreatic cancers, 50% of colorectal cancers, 30% of lung cancers, and 15-30% of melanomas [10-12]. There are three Ras genes that encode four family members K-Ras (two alternatively spliced isoforms), H-Ras, and N-Ras. Mutations are most commonly found in K-Ras [13]. These mutations result in impaired GTP hydrolysis, which shifts the equilibrium toward GTP-bound active Ras, and results in constitutive intracellular signaling. 

Since point mutations of the ras proto-oncogene are often found in cancer, a vaccine was made with mutated ras peptides mixed with Detox. In a phase I study, CD4+ proliferation and CD8+ cytotoxicity specific to the mutated peptide, were observed. The side effects were minimal and one patient showed a stabilisation of the disease [213],... 

Triozzi, P.L., Stoner, G.D., and Kaumaya, P.T. (1995) Subunit peptide cancer vaccines targeting activating mutations of thep21 ras proto-oncogene. Biomed. Pept. Proteins Nucleic Acids 1, 185-192. 

Lemoine, N. R., Staddon, S., Dickson, C., Barnes, D. M., and Gullick, W. J. (1990). Absence of activating transmembrane mutations in the c-erbB-2 proto-oncogene in human breast cancer. Oncogene 5, 237-239. 

Proto-oncogenes are activated by mutation in cancer cells. 

Subsequently, Ras was found to be mutated in chemical carcinogen-induced rodent tumors and in many types of human cancer. Ras is a member of a larger group of normal cellular genes, termed proto-oncogenes, that can be altered to... 

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