Article

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 27709, USA.
Toxicologic Pathology (Impact Factor: 1.92). 07/2008; 36(5):720-6. DOI: 10.1177/0192623308320280
Source: PubMed

ABSTRACT 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.

Download full-text

Full-text

Available from: Hue-Hua L Hong, Oct 16, 2014
0 Followers
 · 
149 Views
  • Source
    • "While alterations in TP53 protein were not observed in normal lung or spontaneous lung tumors, increased TP53 protein expression was detected by immunohistochemistry in 56% of cumene-induced neoplasms. Additionally, there was loss of heterozygosity (LOH) on chromosome 4 near the p16 gene and on chromosome 6 near the Kras gene in a subset of cumene-induced lung carcinomas, while there was no LOH observed in spontaneous carcinomas or normal lung tissue (Hong et al. 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Tumor response in the B6C3F1 mouse, F344 rat, and other animal models following exposure to various compounds provides evidence that people exposed to these or similar compounds may be at risk for developing cancer. Although tumors in rodents and humans are often morphologically similar, underlying mechanisms of tumorigenesis are often unknown and may be different between the species. Therefore, the relevance of an animal tumor response to human health would be better determined if the molecular pathogenesis were understood. The underlying molecular mechanisms leading to carcinogenesis are complex and involve multiple genetic and epigenetic events and other factors. To address the molecular pathogenesis of environmental carcinogens, the authors examine rodent tumors (e.g., lung, colon, mammary gland, skin, brain, mesothelioma) for alterations in cancer genes and epigenetic events that are associated with human cancer. National Toxicology Program (NTP) studies have identified several genetic alterations in chemically induced rodent neoplasms that are important in human cancer. Identification of such alterations in rodent models of chemical carcinogenesis caused by exposure to environmental contaminants, occupational chemicals, and other compounds lends further support that they are of potential human health risk. These studies also emphasize the importance of molecular evaluation of chemically induced rodent tumors for providing greater public health significance for NTP evaluated compounds.
    Toxicologic Pathology 10/2009; 37(7):835-48. DOI:10.1177/0192623309351726 · 1.92 Impact Factor
  • Source
    • "K-ras mutations were detected in 87% (45/52) of the cumeneinduced lung neoplasms. Mutations in p53 were detected in 52% (27/52) of the tumors and increased p53 protein expression was detected in 56% (29/52) of the tumors (Hong et al. 2008). In the current study, we further evaluated cumeneinduced lung carcinomas for additional factors that contribute to the carcinogenic properties of the chemical, including the potential roles of K-ras and p53 gene mutation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: National Toxicology Program (NTP) inhalation studies demonstrated that cumene significantly increased the incidence of alveolar/bronchiolar adenomas and carcinomas in B6C3F1 mice. Cumene or isopropylbenzene is a component of crude oil used primarily in the production of phenol and acetone. The authors performed global gene expression analysis to distinguish patterns of gene regulation between cumene-induced tumors and normal lung tissue and to look for patterns based on the presence or absence of K-ras and p53 mutations in the tumors. Principal component analysis segregated the carcinomas into groups with and without K-ras mutations, but failed to separate the tumors based on p53 mutation status. Expression of genes associated with the Erk MAP kinase signaling pathway was significantly altered in carcinomas with K-ras mutations compared to tumors without K-ras mutations or normal lung. Gene expression analysis also suggested that cumene-induced carcinomas with K-ras mutations have greater malignant potential than those without mutations. In addition, significance analysis of function and expression (SAFE) demonstrated expression changes of genes regulated by histone modification in carcinomas with K-ras mutations. The gene expression analysis suggested the formation of alveolar/bronchiolar carcinomas in cumene-exposed mice typically involves mutation of K-ras, which results in increased Erk MAP kinase signaling and modification of histones.
    Toxicologic Pathology 07/2008; 36(5):743-52. DOI:10.1177/0192623308320801 · 1.92 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Lung cancer is the number one cause of cancer-related deaths in humans worldwide. Environmental factors play an important role in the epidemiology of these cancers. Rodents are the most common experimental model to study human lung cancers and are frequently used in bioassays to identify environmental exposure hazards associated with lung cancer. Lung tumors in rodents are common, particularly in certain strains of mice. Rodent lung tumors are predominantly bronchioloalveolar carcinomas and usually follow a progressive continuum of hyperplasia to adenoma to carcinoma. Human lung cancers are phenotypically more diverse and broadly constitute 2 types: small cell lung cancers and nonsmall cell lung cancers (NSCLCs). Rodent lung tumors resulting from exposure to environmental agents are comparable with certain adenocarcinomas that are a subset of human NSCLCs. Human pulmonary carcinomas differ from rodent lung tumors by exhibiting greater morphologic heterogeneity (encompassing squamous cell, neuroendocrine, mucinous, sarcomatoid, and multiple cell combinations), higher metastatic rate, higher stromal response, aggressive clinical behavior, and lack of a clear continuum of proliferative lesions. In spite of these differences, rodent lung tumors recapitulate several fundamental aspects of human lung tumor biology at the morphologic and molecular level, especially in lung cancers resulting from exposure to environmental carcinogens.
    Toxicologic Pathology 10/2014; 43(1). DOI:10.1177/0192623314556516 · 1.92 Impact Factor
Show more