Cancer from mutations

Toxicologists tend to focus their attention primarily on c.xtrapolations from cancer bioassays. However, tlicrc is also a need to evaluate the risks of lower doses to see how they affect the various organs and systems in the body. Many scientific papers focused on tlic use of a safety factor or uncertainty factor approach, since all adverse effects other than cancer and mutation-based dcvclopmcnUil effects are believed to have a tlu cshold i.e., a dose below which no adverse effect should occur. Several researchers have discussed various approaches to setting acceptable daily intakes or exposure limits for developmental and reproductive toxicants. It is Uiought Uiat an acceptable limit of exposure could be determined using cancer models, but today tliey arc considered inappropriate because of tlircsholds. ... 

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. 

I Coronary heart disease can be caused by mutations in the LDL receptor (familial hypercholesterolemia), inherited cancer syndromes can result from mutations in ... 

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... 

Pao W, Miller V, Zakowski M et al. EGF receptor gene mutations are common in lung cancers from never smokers and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl AcadSci USA 2004 101 13306-13311. 

The importance of the repair of damaged DNA in keeping the cells alive and preventing cancer is also apparent from mutations in genes involved in nucleotide excision repair. The enzymes involved in nucleotide excision repair are other tools that cells have to repair mismatched DNA. Defects in DNA nucleotide excision repair can cause skin cancer (xeroderma pigmentosa) and colon cancer. 

Takeshima, Y, K. Inai, W.P. Bennet, et al. 1994. P53 mutations in lung cancers from Japanese mustard gas workers. Carcinogenesis 15 2075-2079. 

Husgafvel-Pursiainen K, Kannio A, Oksa P, et al. 1997. Mutations, tissue accumulations, and serum levels of p53 in patients with occupational cancers from asbestos and silica exposure. Environ Mol Mutagen 30 224-230. 

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