Carcinogen-induced mutations in the mouse c-Ha-ras gene provide evidence of multiple pathways for tumor progression

Journal Article · Mon Jan 01 04:00:00 EST 1990 · Proceedings of the National Academy of Sciences of the United States of America; (USA)

DOI:https://doi.org/10.1073/pnas.87.2.538· OSTI ID:6936433

Brown, K; Buchmann, A; Balmain, A ^[1]

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1. Beatson Institute for Cancer Research, Bearsden (Scotland)

A number of mouse skin tumors initiated by the carcinogens N-methyl-N{prime}-nitro-N-nitrosoguanidine (MNNG), methylnitrosourea (MNU), 3-methylcholanthrene (MCA), and 7,12-dimethylbenz(a)anthracene (DMBA) have been shown to contain activated Ha-ras genes. In each case, the point mutations responsible for activation have been characterized. Results presented demonstrate the carcinogen-specific nature of these ras mutations. For each initiating agent, a distinct spectrum of mutations is observed. Most importantly, the distribution of ras gene mutations is found to differ between benign papillomas and carcinomas, suggesting that molecular events occurring at the time of initiation influence the probability with which papillomas progress to malignancy. This study provides molecular evidence in support of the existence of subsets of papillomas with differing progression frequencies. Thus, the alkylating agents MNNG and MNU induced exclusively G {yields} A transitions at codon 12, with this mutation being found predominantly in papillomas. MCA initiation produced both codon 13 G {yields} T and codon 61 A {yields} T transversions in papillomas; only the G {yields} T mutation, however, was found in carcinomas. These findings provide strong evidence that the mutational activation of Ha-ras occurs as a result of the initiation process and that the nature of the initiating event can affect the probability of progression to malignancy.

• OSTI ID: 6936433
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (USA), Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (USA) Vol. 87:2; ISSN PNASA; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

3-METHYLCHOLANTHRENE
550201 -- Biochemistry-- Tracer Techniques
560300* -- Chemicals Metabolism & Toxicology
59 BASIC BIOLOGICAL SCIENCES
63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
ALKYLATING AGENTS
ANIMALS
AROMATICS
BODY
CARBONIC ACID DERIVATIVES
CARCINOGENESIS
CELL TRANSFORMATIONS
CHEMICAL ACTIVATION
CODONS
CONDENSED AROMATICS
DIMETHYLBENZANTHRACENE
DNA BASE TRANSITIONS
GENE MUTATIONS
GENES
HYDROCARBONS
MAMMALS
METHYL NITROSOUREA
MICE
MUTAGENS
MUTATIONS
NITROSO COMPOUNDS
ONCOGENES
ONCOGENIC TRANSFORMATIONS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
ORGANS
PATHOGENESIS
POLYCYCLIC AROMATIC HYDROCARBONS
RODENTS
SKIN
VERTEBRATES