Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-University Bochum (IPA), Bochum, Germany.
Medical Proteome Center, Ruhr University Bochum, Bochum, Germany.
Int J Cancer. 2019 Nov 15;145(10):2861-2872. doi: 10.1002/ijc.32356. Epub 2019 May 16.
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.
尿路上皮癌（UCa）是最常见的泌尿道癌症，使用尿液细胞中的甲基化特征进行非侵入性诊断具有广阔的前景。在这里，我们评估了一组新确定的甲基化生物标志物中的性别差异。通过 Infinium-450K 甲基化芯片在男性筛查队列（n=24）的尿液中识别出与 UCa 相关的高甲基化位点，并使用质谱技术在两个独立的混合性别研究组（共 n=617）中进行验证。此外，还分析了混合性别 UCa 和尿路上皮对照组（UCt）的组织样本（n=56）。尿液中 UCa 的高甲基化特征在 UCa 的所有阶段和分级中具有特异性和敏感性，且与血尿无关。单个 CpG 的敏感性最高可达 95%特异性时的 81.3%。尽管两性的组织中存在相似的甲基化差异，但女性尿液中的差异不太明显，这很可能是由于经常存在鳞状上皮细胞和白细胞。在白细胞计数≥500/μl 尿液中观察到甲基化水平的抑制增加，这在 30%的女性和 7%的男性 UCa 病例中很明显，进一步证实了尿液中癌细胞和非癌细胞的相对数量的重要性。我们的研究表明，在评估尿液生物标志物在癌症诊断中的性能时，性别差异是一个非常重要的问题。在 UCa 的情况下，由于女性尿液的一般组成，甲基化特征对男性患者的临床益处可能大于女性患者。因此，这些标志物为男性提供了一种诊断选择，可以减少侵入性膀胱镜检查的数量。
