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p53 mutation and cancer

p53 MUTATIONS IN LIVER CANCER

Staib, F., Hussain, S.P., Hofseth, L.J., Wang, X.W. and Harris, C.C. (2003) TP53 and liver carcinogenesis. Hum Mutat, 21, 201-216.-> Download.

Liver Cancer

A number of epidemiological studies have established a strong association between infection with hepatitis B virus and hepatocellular carcinoma. Aflatoxin B1 has been considered to be a significant etiological factor for liver cancer in southern Africa and Asia. Aflatoxins are compounds produced by fungal strains (such as Aspergilus flavus for aflatoxins B1) that are known food contaminants in these countries. Aflatoxins are highly carcinogenic in experimental animals, producing liver tumours in newborn mice, rats, fish, ducks and monkeys, although clear evidence for a causal association with human cancer has been difficult to obtain.

In 1991, two reports showed that of all the mutations in the p53 gene in hepatocellular carcinoma, there was a predominance of the G:C to T:A transversions at the third base of codon 249 (Arg to Ser) in patients from Mozambique and China. Worldwide epidemiological studies showed that the mutation in codon 249 was strictly specific to countries in which food was contaminated by aflatoxin B1. In Mozambique, for example, more than 50% of the mutations were found in codon 249 and aflatoxin B1 is a common contaminant. In Transkei, which borders on Mozambique and has a similar rate of chronic HBV infection, but less aflatoxin B1 contaminantion, the mutation rate at codon 249 was less than 10%. A similar situation has been observed in various parts of China which differ in their levels of aflatoxin exposure. In countries which do not consume contaminated food (including Europe and the USA), the rate of p53 mutations in hepatocellular carcinoma is low and the mutations are scattered along the central part of p53, as for the other types of cancer.

Left: Aflatoxins, metabolites of the fungus aspergilus flavus, are potent liver toxins and carcinogens in animals. Aspergilus flavus is common in corn and cotton seed mill. Growing season conditions associated with drought and high temperature during grain fill are associated with aflatoxin contamination. In order to detect aflatoxin, proper sampling and testing is essential. Postharvest aflatoxin contamination can develop when grain is improperly managed or stored. Right: Aflatoxin almost exclusively directs its attack to G residues in the CpG sequence context. Aflatoxin also illustrates the important point that most mutagens and carcinogens do not start out as reactive chemicals in themselves, but rather require activation by a metabolic process. Hence the importance of metabolic polymorphism in cytochromes (e.g. CYP2D6), glutathione S-transferases (e.g. GSTM1) and acetyl transferases (e.g. NAT2) etc. in determining susceptibility to such agents.

It has been demonstrated in vitro and in vivo , in human cells, that this phenomenon is due to the very high sensitivity of the p53 codon 249 to the action of aflatoxin B1. This observation, along with the fact that this 249 mutation is deleterious for p53 function, explains the existence of this mutational hot-spot.

more information about aspergilus contamination at :
http://www.agweb.okstate.edu/pearl/agecon/farm/wf233.htm

more information about aflatoxin at :
http://193.51.164.11/htdocs/Monographs/Vol56/09-afl.htm

Spectrum of p53 mutations in liver cancer

DISTRIBUTION OF p53 MUTATIONS IN LIVER CANCER

MUTATIONAL EVENTS IN LIVER CANCER

p53 mutations at codon 249 in liver cancer are found in region with the highest exposition to aflatoxin B1.

p53 mutations at codon 249 in liver cancer are found in region with the highest exposition to aflatoxin B1.

Key References

Hsu, I.C., et al. (1991) Mutational hotspot in the p53 gene in human hepatocellular carcinomas, Nature 350, 427-428.

Bressac, B., Kew, M., Wands, J. and Ozturk, M. (1991) Selective G-mutation to T-mutation of p53 gene in hepatocellular carcinoma from southern africa, Nature 350, 429-431.

Ozturk, M. and Other (1991) p53 mutation in hepatocellular carcinoma after aflatoxin exposure, Lancet 338, 1356-1359.

Aguilar, F., Harris, C.C., Sun, T., Hollstein, M. and Cerutti, P. (1994) Geographic variation of p53 mutational profile in nonmalignant human liver, Science 264, 1317-1319.

Puisieux, A., Lim, S., Groopman, J. and Ozturk, M. (1991) Selective targeting of p53 gene mutational hotspots in human cancers by etiologically defined carcinogens, Cancer Res. 51, 6185-6189.