Wever Birgit M M, Schaafsma Mirte, Bleeker Maaike C G, van den Burgt Yara, van den Helder Rianne, Lok Christianne A R, Dijk Frederike, van der Pol Ymke, Mouliere Florent, Moldovan Norbert, van Trommel Nienke E, Steenbergen Renske D M
Amsterdam UMC, location Vrije Universiteit Amsterdam, Department of Pathology, Amsterdam, The Netherlands.
Cancer Center Amsterdam, Imaging and Biomarkers, Amsterdam, The Netherlands.
Commun Med (Lond). 2024 May 16;4(1):88. doi: 10.1038/s43856-024-00517-8.
High ovarian cancer mortality rates motivate the development of effective and patient-friendly diagnostics. Here, we explored the potential of molecular testing in patient-friendly samples for ovarian cancer detection.
Home-collected urine, cervicovaginal self-samples, and clinician-taken cervical scrapes were prospectively collected from 54 patients diagnosed with a highly suspicious ovarian mass (benign n = 25, malignant n = 29). All samples were tested for nine methylation markers, using quantitative methylation-specific PCRs that were verified on ovarian tissue samples, and compared to non-paired patient-friendly samples of 110 age-matched healthy controls. Copy number analysis was performed on a subset of urine samples of ovarian cancer patients by shallow whole-genome sequencing.
Three methylation markers are significantly elevated in full void urine of ovarian cancer patients as compared to healthy controls (C2CD4D, P = 0.008; CDO1, P = 0.022; MAL, P = 0.008), of which two are also discriminatory in cervical scrapes (C2CD4D, P = 0.001; CDO1, P = 0.004). When comparing benign and malignant ovarian masses, GHSR shows significantly elevated methylation levels in the urine sediment of ovarian cancer patients (P = 0.024). Other methylation markers demonstrate comparably high methylation levels in benign and malignant ovarian masses. Cervicovaginal self-samples show no elevated methylation levels in patients with ovarian masses as compared to healthy controls. Copy number changes are identified in 4 out of 23 urine samples of ovarian cancer patients.
Our study reveals increased methylation levels of ovarian cancer-associated genes and copy number aberrations in the urine of ovarian cancer patients. Our findings support continued research into urine biomarkers for ovarian cancer detection and highlight the importance of including benign ovarian masses in future studies to develop a clinically useful test.
卵巢癌的高死亡率促使人们研发有效且对患者友好的诊断方法。在此，我们探索了在对患者友好的样本中进行分子检测以检测卵巢癌的潜力。
前瞻性收集了54例被诊断为高度可疑卵巢肿块患者（良性25例，恶性29例）自行在家采集的尿液、宫颈阴道自我采样以及临床医生采集的宫颈刮片。使用在卵巢组织样本上验证过的定量甲基化特异性PCR对所有样本检测9种甲基化标志物，并与110例年龄匹配的健康对照的非配对对患者友好的样本进行比较。通过浅层全基因组测序对一部分卵巢癌患者的尿液样本进行拷贝数分析。
与健康对照相比，卵巢癌患者的完全排空尿液中有三种甲基化标志物显著升高（C2CD4D，P = 0.008；CDO1，P = 0.022；MAL，P = 0.008），其中两种在宫颈刮片中也具有鉴别性（C2CD4D，P = 0.001；CDO1，P = 0.004）。在比较良性和恶性卵巢肿块时，GHSR在卵巢癌患者的尿沉渣中显示出显著升高的甲基化水平（P = 0.024）。其他甲基化标志物在良性和恶性卵巢肿块中显示出相当高的甲基化水平。与健康对照相比，卵巢肿块患者的宫颈阴道自我采样未显示甲基化水平升高。在23例卵巢癌患者的尿液样本中有4例检测到拷贝数变化。
我们的研究揭示了卵巢癌患者尿液中卵巢癌相关基因的甲基化水平升高以及拷贝数畸变。我们的发现支持继续研究用于检测卵巢癌的尿液生物标志物，并强调在未来研究中纳入良性卵巢肿块以开发临床有用检测方法的重要性。
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