Genetic alterations in HCA-induced tumors.
Accumulating evidence from molecular oncology indicates that carcinogens may induce tumors through characteristic mutations in characteristic genes for each agent. Identification of specific mutations induced by heterocyclic amines (HCAs), food-borne carcinogens, should facilitate risk assessment of HCAs in man. Identification of characteristic genes affected by HCAs will lead to identification of the genes involved in human carcinogenesis. We therefore examined tumors induced by various HCAs from these two viewpoints. With regard to forestomach tumors induced in CDF1 mice by 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ), mutations of Ha-ras and p53 were observed in four of eight and two of four tumors, respectively. One papilloma examined had mutations in both Ha-ras and p53, whereas two carcinomas had only one or the other. For Zymbal gland tumors induced in F344 rats by IQ, mutations of Ha- or Ki-ras were observed in both of two papillomas and in 10 of 13 squamous cell carcinomas (SCCs), while p53 mutations were limited to only four of the SCCs. The ras mutation was thus suggested to be an early event, while p53 mutation was more associated with malignancy. In liver tumors induced in F344 rats by 2-amino-3,8-dimethylimidazo[4, 5-f]quinoxaline (MeIQx), mutations of p53 were observed in one of two moderately-differentiated and two of two poorly-differentiated hepatocellular carcinomas (HCCs). No such changes were found in any of nine well-differentiated HCCs, suggesting p53 mutation to be a very late event. In colon tumors induced in F344 rats by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) (nine adenocarcinomas), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) (two adenomas and nine adenocarcinomas), or 2-amino-6-methyldipyrido[1,2-a:3', 2'-d]imidazole (Glu-P-1) (seven adenocarcinomas), a Ki-ras mutation was found in only one Glu-P-1-induced adenocarcinoma. No p53 mutations could be detected. In mammary gland carcinomas induced in F344 rats by PhIP, Ha-ras was activated in three of 17 carcinomas and p53 was mutated in one of 10 carcinomas. We therefore concluded that other genes were involved in colon and mammary carcinomas. G:C base pairs were involved in all 42 positive cases of the present study, and 36 of them were guanine base mutations. This indicates that the changes in IQ, MeIQx, PhIP and Glu-P-1 tumors were mainly caused by non-transcribed strand modifications through their major DNA adducts, N2-(guanin-8-yl)HCAs. Ha-ras mutations in the forestomach tumors induced by MeIQ were all G to T transversions at the second position of codon 13. Mutation sites of p53 did not appear to be specific in the forestomach, Zymbal gland and liver tumors.
Ushijima
T
T
Carcinogenesis Division, National Cancer Center Research Institute, Tokyo, Japan.
Makino
H
H
Kakiuchi
H
H
Inoue
R
R
Sugimura
T
T
Nagao
M
M
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D004032:Diet; D005260:Female; D005502:Food; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D007093:Imidazoles / Q000633:toxicity*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D016296:Mutagenesis; D009153:Mutagens / Q000633:toxicity; D009374:Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics* / Q000473:pathology; D017354:Point Mutation; D011804:Quinolines / Q000633:toxicity*; D011810:Quinoxalines / Q000633:toxicity*; D051381:Rats; D011916:Rats, Inbred F344; D013274:Stomach Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000473:pathology
D002273:Carcinogens; D007093:Imidazoles; D009153:Mutagens; D011804:Quinolines; D011810:Quinoxalines; C023785:2-amino-6-methyldipyrido(1,2-a-3',2'-d)imidazole; C036990:2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C036989:2-amino-3,4-dimethylimidazo(4,5-f)quinoline