Carcinogen-specific mutation and amplification of Ha-ras during mouse skin carcinogenesis

Nature. 1986 Jul 3-9;322(6074):78-80. doi: 10.1038/322078a0.

Abstract

Cellular proto-oncogenes can be activated by both point mutations and chromosomal translocations, suggesting that there may be a direct link between exposure to agents which damage DNA and genetic change leading to malignancy. Several groups have therefore analysed mutations found in cellular oncogenes of tumours induced by particular physical or chemical carcinogens. Here, we have analysed the molecular changes at different stages of carcinogenesis in mouse skin tumours induced by initiating and promoting agents. Over 90% of tumours, including premalignant papillomas, initiated with dimethylbenzanthracene (DMBA) have a specific A----T transversion at the second nucleotide of codon 61 of the Harvey-ras (Ha-ras) gene. The frequency of this mutation was dependent on the initiating agent used, but not on the promoter, suggesting that the mutation occurs at the time of initiation. The mutation was heterozygous in most papillomas tested, but was homozygous or amplified in some carcinomas. The development of further chromosomal changes at the c-Ha-ras gene locus is therefore a common feature of tumour progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene
  • Animals
  • Carcinogens*
  • DNA Restriction Enzymes / metabolism
  • Deoxyribonucleases, Type II Site-Specific*
  • Gene Amplification*
  • Methylnitronitrosoguanidine
  • Mice
  • Mutation*
  • Oncogenes*
  • Papilloma / genetics
  • Polymorphism, Genetic
  • Proto-Oncogenes
  • Skin Neoplasms / genetics*

Substances

  • Carcinogens
  • Methylnitronitrosoguanidine
  • 9,10-Dimethyl-1,2-benzanthracene
  • DNA Restriction Enzymes
  • endodeoxyribonuclease XBAI
  • Deoxyribonucleases, Type II Site-Specific