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Carcinogenesis Advance Access published online on August 11, 2007
Carcinogenesis, doi:10.1093/carcin/bgm176
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Genetic Pathways and Mutation Profiles of Human Cancers: Site- and Exposure-Specific Patterns

IA Lea1,*, MA Jackson1, X Li1, S Bailey1, SD Peddada2 and JK Dunnick2,*

1 Integrated Laboratory Systems, Inc., Research Triangle Park, North Carolina, 27709
2 National Institutes of Environmental Health Sciences, Research Triangle Park, North Carolina, 27709

* Correspondence: National Institute of Environmental Health Sciences, MD EC-35, P.O. Box 12233, Research Triangle Park, NC 27709 or ILS, Inc., PO Box 13501, Research Triangle Park, NC 27709., E-mail: dunnickj{at}niehs.nih.gov or ilea{at}ils-inc.com, Tel: (919) 541-4811, Fax: (919) 541-4255

Cancer is a complex disease that involves the accumulation of both genetic and epigenetic alterations of numerous genes. Data in the Genetic Alterations in Cancer (GAC) database for gene mutations and allelic loss (loss of heterozygosity - LOH) in human tumors (e.g., lung, oral, esophagus, stomach and colon/rectum) were reviewed. Results for the genes and pathways implicated in tumor development at these sites are presented. Mutation incidence, spectra, and codon specificity are described for lung, larynx, and oral tumors. LOH occurred more frequently than gene mutations in tumors from all sites examined. The cell cycle gene, TP53 (all sites), and cell signaling gene, APC (colorectal and gastric cancers), were the only genes with similar incidences of LOH and mutation. Alterations of one or more cell cycle and cell signaling genes were reported for tumors from each site. Site-specific activation was apparent in the cell signaling MAPK oncogenes (KRAS in lung, HRAS in oral cancers, and BRAF in esophageal and colorectal cancers). Analysis of genetic changes in lung tumors showed that the incidence of mutations in the TP53 and KRAS genes, and the incidence of LOH in the FHIT gene were significantly greater in smokers versus non-smokers (P < 0.01). In lung and oral cancers the TP53 GC -> TA transversion frequency increased with tobacco smoke exposure (P < 0.05). Furthermore the TP53 mutational hotspots for lung and laryngeal cancers from smokers included codons 157, 245, and 273 whereas for oral tumors included codons 280 and 281.

Received May 16, 2007; revised July 16, 2007; accepted July 20, 2007.


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