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Genetic Alterations in K-ras and p53 Cancer Genes in Lung Neoplasms from B6C3F1 Mice Exposed to Cumene

¹ Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA
² College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina, USA
³ Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, USA
⁴ Toxicology Operations Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA

Correspondence: Hue-Hua L. Hong, National Institute of Environmental Health Sciences, MD C1-04, 111 Alexander Dr., Research Triangle Park, NC 27709, USA; e-mail:hong5{at}niehs.nih.gov.

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.

Key Words: K-ras • p53 • cumene • lung • mouse

This version was published on July 1, 2008

Toxicologic Pathology, Vol. 36, No. 5, 720-726 (2008)
DOI: 10.1177/0192623308320280


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