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Involvement of ras oncogenes in the initiation of carcinogen-induced tumors

M Barbacid1

  • 1Developmental Oncology Section, Frederick Cancer Research Facility, Maryland 21701.

Princess Takamatsu Symposia
|January 1, 1986
PubMed

Insights

Nitroso-methylurea (NMU) reliably activates H-ras-1 oncogenes through specific DNA mutations during cancer initiation. This study identifies a key cellular target for chemical carcinogen mutagenicity in tumor development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Over fifteen oncogenes are identified in human tumors.
  • The ras gene family is frequently activated in carcinogen-induced animal tumors.
  • H-ras-1 oncogenes are consistently found in NMU-induced rat mammary carcinomas.

Purpose of the Study:

  • To investigate the mutagenic mechanisms of chemical carcinogens in oncogene activation.
  • To determine if NMU specifically targets H-ras-1 during carcinogenesis.
  • To identify cellular oncogenes as direct targets of chemical carcinogen mutagenicity.

Main Methods:

  • Induction of rat mammary carcinomas using nitroso-methylurea (NMU) and dimethylbenz(a)anthracene (DMBA).
  • Analysis of oncogene activation in tumor DNA.
  • Mutation analysis to identify specific DNA transitions.

Main Results:

  • Approximately 90% of NMU-induced rat mammary carcinomas possess activated H-ras-1 oncogenes.
  • These H-ras-1 oncogenes are activated by Guanine to Adenine (G-A) transitions, a mutation type characteristic of NMU.
  • No such G-A transitions were observed in tumors induced by DMBA, suggesting carcinogen-specific mutagenic targeting.

Conclusions:

  • NMU directly activates H-ras-1 oncogenes via specific G-A mutations during the initiation of carcinogenesis.
  • This study provides the first evidence of a cellular oncogene locus being a direct target for chemical carcinogen-induced mutagenicity.
  • Findings highlight the role of specific mutagenic events in oncogene activation and tumor development.

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