Carcinogenesis Advance Access published online on May 23, 2007
Carcinogenesis, doi:10.1093/carcin/bgm116
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Promoter Hypermethylation is Associated with Current Smoking, Age, Gender, and Survival in Bladder Cancer
1 Department of Pathology and Laboratory Medicine, Brown University, Providence, RI
2 Department of Work Environment, University of Massachusetts-Lowell, Lowell, MA
3 Department of Pathology, Dartmouth Medical School, Lebanon, New Hampshire
4 Department of Community and Family Medicine, Dartmouth Medical School, Lebanon, New Hampshire
5 Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115
* To Whom Correspondence and Requests for Reprints be Addressed: Phone: 617-432-3313; Fax: 617-432-0107; E-mail: kelsey{at}hsph.harvard.edu.
Hypermethylation of tumor suppressor genes is central to the pathogenesis of human malignancy, yet this alteration's etiology remains unclear, and its clinical impact has not yet been studied using an approach that can yield directly generalizable results. Therefore, we sought to examine both of these issues in bladder cancer, seeking to understand the characteristics of epidemiologically well-defined patient tumors with differing levels of methylation silencing. We analyzed epigenetic silencing of 16 genes in a population-based incident case series of 331 bladder transitional cell carcinomas. We utilized a novel item response theory model, to examine, in an unbiased fashion, the relationship of patient characteristics, carcinogen exposure history, and tumor characteristics with the underlying propensity for gene hypermethylation. Age, male gender, and current cigarette smoking were significantly positively associated with the methylation latent trait. Promoter hypermethylation as a latent trait significantly predicted both non-invasive/high grade and invasive stage disease and was also significantly associated with survival, with each unit increase in the latent trait resulting in a 30% increase in the risk of death. This work, studying all stages and grades of incident bladder cancer, provides definitive evidence that carcinogen exposures play a critical role in selecting these alterations in tumorous clones and that epigenetic silencing is a strong and significant predictor of tumor stage and overall patient survival. Finally, our novel approach provides insight into the etiology of promoter hypermethylation, suggesting that selected, carcinogen exposed individuals have a greater propensity for hypermethylation that is associated with more aggressive, fatal disease.
Key Words: bladder cancer • hypermethylation • tobacco smoke • survival • statistical methods
Received March 13, 2007; revised April 27, 2007; accepted May 9, 2007.
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