Human sporadic colorectal cancer is the result of a lengthy somatic evolutionary process facilitated by various forms of genomic instability. Such instability arises endogenously from mutations in genes whose role is to preserve genomic integrity, and exogenously from environmental agents that generate genomic damage. We have found that cigarette smoking shifts the genomic profiles and genomic instability patterns of colorectal carcinomas. The genomic profiles of 57 consecutive cancers were examined; 31 cases were current or former smokers and 26 were nonsmokers. Genome-wide allelotypes of 348 markers were examined, along with comparative genomic hybridization (CGH) on ordered BAC microarrays, microsatellite instability, and inter-(simple sequence repeat) polymerase chain reaction instability. Tumors from nonsmokers exhibited losses of heterozygosity, particularly on chromosomes 14 and 18, whereas tumors from smokers exhibited a more diffuse pattern of allelic losses. Tumors from smokers exhibited higher overall rates of loss of heterozygosity, but showed lower rates of background microsatellite instability (MSI-L). On BAC array CGH, higher levels of generalized amplifications and deletions were observed in tumors from smokers, differentially affecting male smokers. In the transforming growth factor-β signaling pathway, MADH4 mutations were more common in tumors from smokers, whereas transforming growth factor-β RII mutations were more common among nonsmokers.
|Original language||English (US)|
|Number of pages||7|
|Journal||Cancer Genetics and Cytogenetics|
|State||Published - Jul 15 2006|
Bibliographical noteFunding Information:
We thank Cindy Bates for help with the preparation of the manuscript, and Susan McCann for help with evaluating daily diet variables. This work was supported by National Institutes of Health (NIH) grant CA74127 to G. Anderson, a grant from the Charlotte Geyer Foundation to G. Anderson, and NIH Center Support Grant P30CA 16056 to the Roswell Park Cancer Institute.