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Genetic alterations in HCA-induced tumors
T Ushijima1, H Makino, H Kakiuchi
1Carcinogenesis Division, National Cancer Center Research Institute, Tokyo, Japan.
Princess Takamatsu Symposia
|January 1, 1995
Summary
This study investigates mutations in genes like Ha-ras and p53 caused by heterocyclic amines (HCAs), which are food-borne carcinogens. Understanding these specific mutations helps assess human cancer risks from HCAs.
Area of Science:
- Molecular Oncology
- Carcinogenesis Research
- Genetic Toxicology
Background:
- Food-borne heterocyclic amines (HCAs) are carcinogens linked to specific gene mutations.
- Identifying these mutations aids in human cancer risk assessment and understanding carcinogenesis.
Purpose of the Study:
- To identify characteristic gene mutations induced by various HCAs.
- To determine the roles of specific genes (Ha-ras, p53) in tumor development caused by HCAs.
Main Methods:
- Analysis of tumors induced by HCAs (MeIQ, IQ, MeIQx, PhIP, Glu-P-1) in mice and rats.
- Mutation analysis of Ha-ras, Ki-ras, and p53 genes in various tumor types (forestomach, Zymbal gland, liver, colon, mammary gland).
Main Results:
- Ras mutations were observed in forestomach and Zymbal gland tumors, suggesting an early event.
- p53 mutations were associated with malignancy in Zymbal gland tumors and late-stage liver tumors.
- Colon and mammary carcinomas showed involvement of other genes beyond ras and p53.
- G:C base pair mutations, particularly guanine modifications, were prevalent, linked to N2-(guanin-8-yl)HCAs DNA adducts.
Conclusions:
- Specific HCAs induce characteristic mutations in genes like ras and p53.
- Ras mutations appear early, while p53 mutations are linked to later stages or malignancy.
- Carcinogenesis in colon and mammary glands by certain HCAs involves genes other than ras and p53.
- The DNA adduct N2-(guanin-8-yl)HCAs likely drives mutations in G:C base pairs.