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Cancer Epidemiology, Biomarkers & Prevention
Cancer Epidemiology, Biomarkers & Prevention

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Research Article

Genome-wide DNA methylation in pre-diagnostic blood and bladder cancer risk in the Women's Health Initiative

Kristina M Jordahl, Timothy W. Randolph, Xiaoling Song, Cassandra L Sather, Lesley F Tinker, Amanda I. Phipps, Karl T. Kelsey, Emily White and Parveen Bhatti
Kristina M Jordahl
School of Public Health, Department of Epidemiology, University of Washington
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Timothy W. Randolph
Biostatistics Program, Division of Public Health Sciences, Fred Hutch Cancer Research Institute
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Xiaoling Song
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center
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Cassandra L Sather
Genomics Resource, Fred Hutchinson Cancer Research Center
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Lesley F Tinker
Division of Public Health Sciences, Cancer Prevention Program, Fred Hutchinson Cancer Research Center
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Amanda I. Phipps
Epidemiology Department and Public Health Sciences Division, University of Washington and Fred Hutchinson Cancer Research Center
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Karl T. Kelsey
Epidemiology and Pathology and Laboratory Medicine, Brown University
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Emily White
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center
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Parveen Bhatti
School of Public Health, Department of Epidemiology, Fred Hutchinson Cancer Research Center
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  • For correspondence: pbhatti@fredhutch.org
DOI: 10.1158/1055-9965.EPI-17-0951
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Abstract

Background: Differential DNA methylation as measured in blood is a promising marker of bladder cancer susceptibility. However, previous studies have exclusively used post-diagnostic blood samples, meaning that observed associations may be markers of disease rather than susceptibility. Methods: Genome-wide methylation was measured in pre-diagnostic blood samples, using the Illumina Infinium HumanMethylation450 Bead Array, among 440 bladder cancer cases with the transitional cell carcinoma (TCC) subtype and 440 matched cancer-free controls from the Women's Health Initiative (WHI) cohort. After normalization and probe filtering, we used conditional logistic regression models to test for associations between methylation measurements at 361,184 CpG sites and bladder cancer risk. Results: Increased methylation at cg22748573, located in a CpG island within the 5'-UTR/first exon of the CITED4 gene, was associated with an 82% decreased risk of bladder cancer after adjusting for race/ethnicity, smoking status, pack-years of smoking, and leukocyte cell profile and accounting for multiple testing (OR=0.18, q-value = 0.05). The result was robust to sensitivity analyses accounting for time between enrollment and diagnosis, race, tumor subtype, and secondhand smoke exposure. Conclusions: While results need to be confirmed in additional prospective studies, differential methylation in CITED4, as measured in blood, is a promising marker of bladder cancer susceptibility. Impact: Identification of biomarkers of bladder cancer susceptibility in easily accessible tissues may allow targeting of screening efforts so as to improve bladder cancer prognosis. This is particularly important among women, who tend to have poorer bladder cancer outcomes than men.

  • Received October 18, 2017.
  • Revision received December 31, 2017.
  • Accepted March 9, 2018.
  • Copyright ©2018, American Association for Cancer Research.

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Published OnlineFirst March 14, 2018
doi: 10.1158/1055-9965.EPI-17-0951

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Genome-wide DNA methylation in pre-diagnostic blood and bladder cancer risk in the Women's Health Initiative
Kristina M Jordahl, Timothy W. Randolph, Xiaoling Song, Cassandra L Sather, Lesley F Tinker, Amanda I. Phipps, Karl T. Kelsey, Emily White and Parveen Bhatti
Cancer Epidemiol Biomarkers Prev March 14 2018 DOI: 10.1158/1055-9965.EPI-17-0951

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Genome-wide DNA methylation in pre-diagnostic blood and bladder cancer risk in the Women's Health Initiative
Kristina M Jordahl, Timothy W. Randolph, Xiaoling Song, Cassandra L Sather, Lesley F Tinker, Amanda I. Phipps, Karl T. Kelsey, Emily White and Parveen Bhatti
Cancer Epidemiol Biomarkers Prev March 14 2018 DOI: 10.1158/1055-9965.EPI-17-0951
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Cancer Epidemiology, Biomarkers & Prevention
eISSN: 1538-7755
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