Journal Article

Early detection of 2-amino-1-methyl-6-phenylimidazo (4,5-<i>b</i>)pyridine(PhIP)-induced mutations within the <i>Apc</i> gene of rat colon

Dominique Y. Burnouf, Roman Miturski, Minako Nagao, Hitoshi Nakagama, Marc Nothisen, Jérome Wagner and Robert P.P. Fuchs

in Carcinogenesis

Volume 22, issue 2, pages 329-335
Published in print February 2001 | ISSN: 0143-3334
Published online February 2001 | e-ISSN: 1460-2180 | DOI:
Early detection of 2-amino-1-methyl-6-phenylimidazo (4,5-b)pyridine(PhIP)-induced mutations within the Apc gene of rat colon

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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.

Keywords: Apc, adenomatous polyposis coli gene; gDNA, genomic DNA; HCA, heterocyclic amine; IS, internal standard; MAMA, mismatch amplification mutation assay; PhIP, 2-amino-1-methyl-6-phenylimidazo (4,5-b)pyridine; SML, somatic mutational load; UDG, uracil-DNA glycosylase.

Journal Article.  5489 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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