title: DNA methylation profiles delineate etiologic heterogeneity and clinically important subgroups of bladder cancer.
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.
authors.affiliation: Department of Community Health, Center for Environmental Health and Technology, Brown University, Providence, RI 02912, USA.
authors.forename: C S
authors.initials: CS
authors.lastname: Wilhelm-Benartzi
authors.forename: D C
authors.initials: DC
authors.lastname: Koestler
authors.forename: E A
authors.initials: EA
authors.lastname: Houseman
authors.forename: B C
authors.initials: BC
authors.lastname: Christensen
authors.forename: John K
authors.initials: JK
authors.lastname: Wiencke
authors.forename: A R
authors.initials: AR
authors.lastname: Schned
authors.forename: M R
authors.initials: MR
authors.lastname: Karagas
authors.forename: K T
authors.initials: KT
authors.lastname: Kelsey
authors.forename: C J
authors.initials: CJ
authors.lastname: Marsit
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009513:New Hampshire / Q000453:epidemiology; D011379:Prognosis; D012307:Risk Factors; D012907:Smoking; D001749:Urinary Bladder Neoplasms / Q000145:classification / Q000453:epidemiology* / Q000209:etiology*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm
references.citation: J Natl Cancer Inst. 2009 Nov 18;101(22):1553-61
references.pmid: 19917915
references.citation: World J Urol. 2010 Aug;28(4):487-92
references.pmid: 19834714
references.citation: J Natl Cancer Inst. 1990 Oct 17;82(20):1636-40
references.pmid: 2213906
references.citation: Cancer Invest. 2009 Jan;27(1):70-80
references.pmid: 19160091
references.citation: Cancer. 2004 May 1;100(9):1853-8
references.pmid: 15112265
references.citation: Cancer Causes Control. 2004 Jun;15(5):465-72
references.pmid: 15286466
references.citation: Toxicol Lett. 2001 Jul 6;122(3):223-34
references.pmid: 11489357
references.citation: Regul Toxicol Pharmacol. 2008 Dec;52(3):299-310
references.pmid: 18783726
references.citation: Oncogene. 2007 Jul 12;26(32):4730-7
references.pmid: 17297452
references.citation: Mutat Res. 2003 Dec 10;533(1-2):37-65
references.pmid: 14643412
references.citation: Eur Urol. 2003 Jan;43(1):53-62
references.pmid: 12507544
references.citation: Environ Health Perspect. 2005 Jun;113(6):775-81
references.pmid: 15929903
references.citation: Cancer Res. 2005 Aug 15;65(16):7081-5
references.pmid: 16103055
references.citation: Nat Rev Genet. 2002 Jun;3(6):415-28
references.pmid: 12042769
references.citation: Cancer Prev Res (Phila). 2009 Jan;2(1):70-3
references.pmid: 19139020
references.citation: Tumori. 2004 Mar-Apr;90(2):175-80
references.pmid: 15237578
references.citation: Am J Epidemiol. 2000 Jul 1;152(1):84-90
references.pmid: 10901333
references.citation: Nat Rev Cancer. 2006 Feb;6(2):107-16
references.pmid: 16491070
references.citation: Cancer Cell. 2004 Aug;6(2):111-6
references.pmid: 15324694
references.citation: PLoS One. 2009 Sep 11;4(9):e7012
references.pmid: 19750230
references.citation: Cancer Epidemiol Biomarkers Prev. 2008 Oct;17(10):2786-94
references.pmid: 18843024
references.citation: Mutat Res. 1997 Jun;386(3):263-77
references.pmid: 9219564
references.citation: Carcinogenesis. 2009 Mar;30(3):416-22
references.pmid: 19126652
references.citation: Breast Cancer Res Treat. 2009 Apr;114(3):559-68
references.pmid: 18463976
references.citation: Carcinogenesis. 2007 Aug;28(8):1745-51
references.pmid: 17522068
references.citation: Nat Rev Drug Discov. 2010 May;9(5):363-6
references.pmid: 20431568
references.citation: Nat Clin Pract Urol. 2005 Oct;2(10):502-10
references.pmid: 16474624
references.citation: PLoS Genet. 2010 Jul 29;6(7):e1001043
references.pmid: 20686660
references.citation: Toxicol Lett. 2009 May 22;187(1):10-4
references.pmid: 19429237
references.citation: Biomarkers. 2010 Mar;15(2):167-74
references.pmid: 19958159
references.citation: Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10907-12
references.pmid: 9380733
references.citation: Lancet. 2009 Jul 18;374(9685):239-49
references.pmid: 19520422
references.citation: Scand J Urol Nephrol Suppl. 2008 Sep;(218):12-20
references.pmid: 19054893
references.citation: Genome Res. 2006 Mar;16(3):383-93
references.pmid: 16449502
references.citation: Int J Occup Med Environ Health. 2001;14(2):171-5
references.pmid: 11548067
references.citation: PLoS One. 2010 Aug 23;5(8):e12334
references.pmid: 20808801
references.citation: Int J Hyg Environ Health. 2002 Mar;205(1-2):85-94
references.pmid: 12018020
references.citation: Methods Mol Biol. 2009;507:149-63
references.pmid: 18987813
references.citation: Carcinogenesis. 2006 Jan;27(1):112-6
references.pmid: 15987713
references.citation: Environ Health Perspect. 1998 Aug;106 Suppl 4:1047-50
references.pmid: 9703491
references.citation: Clin Cancer Res. 2010 Mar 1;16(5):1682-9
references.pmid: 20179218
references.citation: Mutat Res. 2006 Sep 28;608(2):157-62
references.pmid: 16843042
references.citation: BMC Cancer. 2010 May 12;10:196
references.pmid: 20462447
references.citation: Int J Cancer. 2006 Apr 15;118(8):2040-7
references.pmid: 16284957
references.citation: Cancer Causes Control. 2010 May;21(5):745-57
references.pmid: 20084543
references.citation: N Engl J Med. 1999 May 6;340(18):1390-7
references.pmid: 10228189