Carcinogenesis, Vol. 22, No. 2, 329-335,
February 2001
© 2001 Oxford University Press
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION |
Early detection of 2-amino-1-methyl-6-phenylimidazo (4,5-b)pyridine(PhIP)-induced mutations within the Apc gene of rat colon
1 Groupe d'Epidémiologie Moléculaire du Cancer, UPR 9003, Centre National de la Recherche Scientifique, Institut de Recherche sur les Cancers de l'Appareil Digestif, 1 Place de l'Hopital, 67097 Strasbourg,France and
2 National Cancer Center Research Institute, Tsukiji 5, Chuoku, Tokyo 104-0045, Japan
A large proportion of human cancers result from exposure of individuals to environmental or occupational carcinogens. The early detection of carcinogen-induced mutations is a prerequisite for the identification of individuals at risk for developing cancer. Short G-rich repetitive sequences have been previously identified as hot-spots for frameshift mutagenesis induced by a large variety of carcinogens belonging to several families of widespread environmental pollutants. In order to test if these sequences, when mutated, might serve as biomarkers for carcinogen exposure, we designed a sensitive PCR-based strategy that allows the detection of rare mutational events within a whole genome. 2-Amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), the most abundant carcinogenic heterocyclic amine generated in cooked meat, induces mammary and colon carcinoma in F344 rats. About 25% of male rats exposed to 400 p.p.m. PhIP in the diet for >43 weeks present colon tumors with specific –1G mutations within 5'-GGGA-3' sequences of the Apc gene. Using our PCR assay we have assessed the occurrence of such specific events in rats exposed to PhIP for only 1, 2, 4 and 6 weeks. A specific amplification signal was already observed in the 1 week-treated population and increases in a treatment time-dependent manner. These data validate this approach for the early detection of mutations and demonstrate its usefulness for molecular epidemiology and early diagnosis.
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