Harvey ras (H-ras) point mutations are induced by 4-nitroquinoline-1-oxide in murine oral squamous epithelia, while squamous cell carcinomas and loss of heterozygosity occur without additional exposure.

Abstract

Tumorigenesis is a multistep genetic process requiring several somatic mutations for neoplastic transformation. These mutations appear to be sequential, random, and independent events. However, we find linked, nonrandom ras mutations occurring during 4-nitroquinoline-1-oxide-induced tumorigenesis months after exposure to the carcinogen had ceased. The carcinogen had been topically applied to the oral cavity of CBA mice for 4 to 16 weeks. Dysplasia developed after 24 weeks, and carcinoma in situ and squamous cell carcinoma developed after 28 weeks. H-ras mutations were detected in 13 of 25 tissue specimens (10 of 14 invasive carcinomas and 2 of 4 carcinoma in situ, 1 of 5 dysplastic tissue, and 0 of 2 normal tissues). Approximately one-half of the tumors had G to A point mutations at codon 12 of the cellular H-ras proto-oncogene on mouse chromosome 7. None had codon 11, 13, or 61 mutations. Loss of heterozygosity occurred in 5 of 14 invasive cancers. Larger invasive squamous cell carcinomas consistently lost the wild-type allele, whereas preneoplastic lesions and small tumors were heterozygous for ras. This suggests a causal relationship between carcinogen treatment, H-ras activation, and initiation of tumorigenesis. The wild-type allele in mouse chromosome 7 is lost with the progression of tumorigenesis long after exposure to the carcinogen. Thus, loss of heterozygosity of the ras gene appears to occur without multiple carcinogen-induced mutations, i.e., as a result of a cascade of events induced by an earlier ras mutation.

• Authors: B Yuan, B W Heniford, D M Ackermann, B L Hawkins, F J Hendler
• Journal: Cancer research (Cancer Res) Vol. 54 Issue 20 Pg. 5310-7 (Oct 15 1994) ISSN: 0008-5472 [Print] United States
• PMID: 7923158 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Codon
• 4-Nitroquinoline-1-oxide

Topics

• 4-Nitroquinoline-1-oxide
• Animals
• Base Sequence
• Carcinoma, Squamous Cell (chemically induced, genetics)
• Codon (drug effects, genetics)
• DNA Mutational Analysis
• Female
• Genes, ras (drug effects, genetics)
• Mice
• Mice, Inbred CBA
• Molecular Sequence Data
• Mouth Neoplasms (chemically induced, genetics)
• Point Mutation
• Polymorphism, Restriction Fragment Length