The incidences of alveolar/bronchiolar
adenomas and
carcinomas in
cumene-treated B6C3F1 mice were significantly greater than those of the control animals. We evaluated these
lung neoplasms for point mutations in the K-ras and p53 genes that are often mutated in humans. K-ras and p53 mutations were detected by cycle sequencing of PCR-amplified
DNA isolated from
paraffin-embedded
neoplasms. K-ras mutations were detected in 87% of
cumene-induced
lung neoplasms, and the predominant mutations were exon 1
codon 12 G to T transversions and exon 2
codon 61 A to G transitions. P53
protein expression was detected by immunohistochemistry in 56% of
cumene-induced
neoplasms, and mutations were detected in 52% of
neoplasms. The predominant mutations were exon 5,
codon 155 G to A transitions, and
codon 133 C to T transitions. No p53 mutations and one of seven (14%) K-ras mutations were detected in spontaneous
neoplasms.
Cumene-induced lung
carcinomas showed loss of heterozygosity (LOH) on chromosome 4 near the p16 gene (13%) and on chromosome 6 near the K-ras gene (12%). No LOH was observed in spontaneous
carcinomas or normal lung tissues examined. The pattern of mutations identified in the lung
tumors suggests that DNA damage and
genomic instability may be contributing factors to the mutation profile and development of
lung cancer in mice exposed to
cumene.