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Noninvasive diagnosis of urothelial cancer in urine using DNA hypermethylation signatures—Gender matters
Author(s) -
Köhler Christina U.,
Bonberg Nadine,
Ahrens Maike,
Behrens Thomas,
Hovanec Jan,
Eisenacher Martin,
Noldus Joachim,
Deix Thomas,
Braun Katharina,
Gohlke Henning,
Walter Michael,
Tannapfel Andrea,
Tam Yu,
Sommerer Florian,
Marcus Katrin,
Jöckel KarlHeinz,
Erbel Raimund,
Cantor Charles R.,
Käfferlein Heiko U.,
Brüning Thomas
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32356
Subject(s) - urine , dna methylation , methylation , urinary system , cpg site , cancer , medicine , cohort , oncology , biology , physiology , dna , genetics , gene , gene expression
Urothelial cancer (UCa) is the most predominant cancer of the urinary tract and noninvasive diagnosis using hypermethylation signatures in urinary cells is promising. Here, we assess gender differences in a newly identified set of methylation biomarkers. UCa‐associated hypermethylated sites were identified in urine of a male screening cohort ( n = 24) applying Infinium‐450K‐methylation arrays and verified in two separate mixed‐gender study groups ( n = 617 in total) using mass spectrometry as an independent technique. Additionally, tissue samples ( n = 56) of mixed‐gender UCa and urological controls (UCt) were analyzed. The hypermethylation signature of UCa in urine was specific and sensitive across all stages and grades of UCa and independent on hematuria. Individual CpG sensitivities reached up to 81.3% at 95% specificity. Albeit similar methylation differences in tissue of both genders, differences were less pronounced in urine from women, most likely due to the frequent presence of squamous epithelial cells and leukocytes. Increased repression of methylation levels was observed at leukocyte counts ≥500/μl urine which was apparent in 30% of female and 7% of male UCa cases, further confirming the significance of the relative amounts of cancerous and noncancerous cells in urine. Our study shows that gender difference is a most relevant issue when evaluating the performance of urinary biomarkers in cancer diagnostics. In case of UCa, the clinical benefits of methylation signatures to male patients may outweigh those in females due to the general composition of women's urine. Accordingly, these markers offer a diagnostic option specifically in males to decrease the number of invasive cystoscopies.