Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer

Mark Kitchen, Richard Bryan, Richard D Emes, John Glossop, Christopher Luscombe, Kar Cheng, Maurice Zeegers, Nicholas James, Adam Devall, Charles A Mein, Lyndon Gommersall, Anthony Fryer, William E Farrell

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26 Citations (Scopus)
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High-grade non-muscle invasive bladder cancer (HG-NMIBC) is a clinically unpredictable disease with greater risks of recurrence and progression relative to their low-intermediate-grade counterparts. The molecular events, including those affecting the epigenome, that characterize this disease entity in the context of tumor development, recurrence, and progression, are incompletely understood. We therefore interrogated genome-wide DNA methylation using HumanMethylation450 BeadChip arrays in 21 primary HG-NMIBC tumors relative to normal bladder controls. Using strict inclusion-exclusion criteria we identified 1,057 hypermethylated CpGs within gene promoter-associated CpG islands, representing 256 genes. We validated the array data by bisulphite pyrosequencing and examined 25 array-identified candidate genes in an independent cohort of 30 HG-NMIBC and 18 low-intermediate-grade NMIBC. These analyses revealed significantly higher methylation frequencies in high-grade tumors relative to low-intermediate-grade tumors for the ATP5G2, IRX1 and VAX2 genes (P<0.05), and similarly significant increases in mean levels of methylation in high-grade tumors for the ATP5G2, VAX2, INSRR, PRDM14, VSX1, TFAP2b, PRRX1, and HIST1H4F genes (P<0.05). Although inappropriate promoter methylation was not invariantly associated with reduced transcript expression, a significant association was apparent for the ARHGEF4, PON3, STAT5a, and VAX2 gene transcripts (P<0.05). Herein, we present the first genome-wide DNA methylation analysis in a unique HG-NMIBC cohort, showing extensive and discrete methylation changes relative to normal bladder and low-intermediate-grade tumors. The genes we identified hold significant potential as targets for novel therapeutic intervention either alone, or in combination, with more conventional therapeutic options in the treatment of this clinically unpredictable disease.
Original languageEnglish
Pages (from-to)237-246
Number of pages11
JournalEpigenetics : official journal of the DNA Methylation Society
Issue number3
Early online date1 Mar 2016
Publication statusPublished - 6 Apr 2016

Bibliographical note

Publication date on PubMed is shown as 3rd March 2016.


  • Epigenetics
  • high-grade non-muscle invasive bladder cancer
  • HumanMethylation450 BeadChip Array
  • gene expression
  • methylation


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