Carcinogenesis Advance Access originally published online on August 11, 2007
Carcinogenesis 2007 28(9):1851-1858; doi:10.1093/carcin/bgm176
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Genetic pathways and mutation profiles of human cancers: site- and exposure-specific patterns
Integrated Laboratory Systems, Inc., Research Triangle Park, NC 27709, USA
1 National Institutes of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
* To whom correspondence should be addressed. Tel: +1 919 541 4811; Fax: +1 919 541 4255; Email: dunnickj{at}niehs.nih.gov
Correspondence may also be addressed to I.A. Lea. Tel: +1 919 544 4589; Fax: +1 919 544 0380; Email: ilea{at}ils-inc.com
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 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 mitogen-activated protein kinase 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 hot spots for lung and laryngeal cancers from smokers included codons 157, 245 and 273, whereas for oral tumors included codons 280 and 281.
Abbreviations: GAC, Genetic Alterations in Cancer; LOH, loss of heterozygosity; MAPK, mitogen-activated protein kinase
Received May 16, 2007; revised July 16, 2007; accepted July 20, 2007.
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