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.
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.
Yuan
B
B
Department of Biochemistry, Henry Vogt Research Institute of the James Graham Brown Cancer Center, University of Louisville, Kentucky.
Heniford
B W
BW
Ackermann
D M
DM
Hawkins
B L
BL
Hendler
F J
FJ
D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D001483:Base Sequence; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics*; D003062:Codon / Q000187:drug effects / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D011905:Genes, ras / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008808:Mice, Inbred CBA; D008969:Molecular Sequence Data; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000235:genetics*; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length
D003062:Codon; D015112:4-Nitroquinoline-1-oxide