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Comparative Study
. 2010 Nov;31(11):1972-6.
doi: 10.1093/carcin/bgq178. Epub 2010 Aug 28.

DNA methylation profiles delineate etiologic heterogeneity and clinically important subgroups of bladder cancer

C S Wilhelm-Benartzi  1 , D C Koestler, E A Houseman, B C Christensen, John K Wiencke, A R Schned, M R Karagas, K T Kelsey, C J Marsit
Affiliations
Comparative Study

DNA methylation profiles delineate etiologic heterogeneity and clinically important subgroups of bladder cancer

C S Wilhelm-Benartzi et al. Carcinogenesis. 2010 Nov.

Abstract

DNA methylation profiles can be used to define molecular cancer subtypes that may better inform disease etiology and clinical decision-making. This investigation aimed to create DNA methylation profiles of bladder cancer based on CpG methylation from almost 800 cancer-related genes and to then examine the relationship of those profiles with exposures related to risk and clinical characteristics. DNA, derived from formalin-fixed paraffin-embedded tumor samples obtained from incident cases involved in a population-based case-control study of bladder cancer in New Hampshire, was used for methylation profiling on the Illumina GoldenGate Methylation Bead Array. Unsupervised clustering of those loci with the greatest change in methylation between tumor and non-diseased tissue was performed to defined molecular subgroups of disease, and univariate tests of association followed by multinomial logistic regression was used to examine the association between these classes, bladder cancer risk factors and clinical phenotypes. Membership in the two most methylated classes was significantly associated with invasive disease (P < 0.001 for both class 3 and 4). Male gender (P = 0.04) and age >70 years (P = 0.05) was associated with membership in one of the most methylated classes. Finally, average water arsenic levels in the highest percentile predicted membership in an intermediately methylated class of tumors (P = 0.02 for both classes). Exposures and demographic associated with increased risk of bladder cancer specifically associate with particular subgroups of tumors defined by DNA methylation profiling and these subgroups may define more aggressive disease.

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Figures

Fig. 1.
Fig. 1.
Heatmap and mean methylation by RPMMs class. The heatmap in Panel A shows the intensity of methylation with 0 (yellow) being unmethylated and 1 (blue) being fully methylated. The columns represent the 267 CpG loci and the rows represent individual subjects. The red lines within the heatmap denote the four classes derived from the model. Panel B shows a chart of the percentages of the non-invasive and invasive cases within each RPMM class. Samples sizes are included by RPMM class. The association between having invasive bladder cancer and RPMM class was found to be significant in a permutation chi-square test, at the P < 0.05 level.
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