Somatic mutations in human cancer: applications in molecular epidemiology.
The tumour suppressor protein p53 mediates cell-cycle arrest, DNA repair and apoptosis after activation by multiple forms of cellular stresses. When activated, this "master protein" modulates its response depending on the type and intensity of the stress. The TP53 gene with its nearly 20,000 described mutations is the most mutated gene in cancer. Most mutations are missense and occur at over 200 codons within the central portion of the gene. In several cancers, the distribution of mutation types and sites follow a specific pattern reflecting the effects of environmental mutagens. An example for such a "mutagen fingerprint" is TP53 mutation at codon 249 in hepatocellular carcinoma in regions of the world characterised by high levels of the mutagen aflatoxin B1 and endemic HBV infection. Recently, TP53 mutations have been detected in surrogate sources of genetic material such as free circulating DNA isolated from plasma. Plasma TP53 mutations can be detected in the blood of pre-cancer and cancer patients, with potential application for early cancer detection. Thus, TP53 mutations have multiple applications as markers of mutagenic exposures, or as intermediate end-points in assessment of cancer occurrence and progression.
Le Roux
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Molecular Carcinogenesis Group, International Agency for Research on Cancer, 150, cours Albert-Thomas, 69372 Lyon Cedex 08.
Gormally
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Hainaut
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P
D016604:Aflatoxin B1 / Q000633:toxicity; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D003062:Codon; D004249:DNA Damage; D016172:DNA Fingerprinting; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D006509:Hepatitis B / Q000150:complications; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics; D008297:Male; D017720:Molecular Epidemiology; D009153:Mutagens / Q000633:toxicity; D009154:Mutation; D020125:Mutation, Missense; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D011230:Precancerous Conditions / Q000235:genetics; D011379:Prognosis; D012307:Risk Factors; D013997:Time Factors; D025521:Tumor Suppressor Proteins
D003062:Codon; D004273:DNA, Neoplasm; D009153:Mutagens; D025521:Tumor Suppressor Proteins; D016604:Aflatoxin B1