Identification of methylated genes associated with aggressive bladder cancer

Carmen J. Marsit, E. Andres Houseman, Brock C. Christensen, Luc Gagne, Margaret R. Wrensch, Heather H. Nelson, Joseph Wiemels, Shichun Zheng, John K. Wiencke, Angeline S. Andrew, Alan R. Schned, Margaret R. Karagas, Karl T. Kelsey

Research output: Contribution to journalArticlepeer-review

79 Scopus citations


Approximately 500,000 individuals diagnosed with bladder cancer in the U.S. require routine cystoscopic follow-up to monitor for disease recurrences or progression, resulting in over $2 billion in annual expenditures. Identification of new diagnostic and monitoring strategies are clearly needed, and markers related to DNA methylation alterations hold great promise due to their stability, objective measurement, and known associations with the disease and with its clinical features. To identify novel epigenetic markers of aggressive bladder cancer, we utilized a high-throughput DNA methylation beadarray in two distinct population-based series of incident bladder cancer (n = 73 and n = 264, respectively). We then validated the association between methylation of these candidate loci with tumor grade in a third population (n = 245) through bisulfite pyrosequencing of candidate loci. Array based analyses identified 5 loci for further confirmation with bisulfite pyrosequencing. We identified and confirmed that increased promoter methylation of HOXB2 is significantly and independently associated with invasive bladder cancer and methylation of HOXB2, KRT13 and FRZB together significantly predict high-grade non-invasive disease. Methylation of these genes may be useful as clinical markers of the disease and may point to genes and pathways worthy of additional examination as novel targets for therapeutic treatment.

Original languageEnglish (US)
Article numbere12334
JournalPloS one
Issue number8
StatePublished - 2010


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