Braicu Elena Ioana, du Bois Andreas, Sehouli Jalid, Beck Julia, Prader Sonia, Kulbe Hagen, Eiben Bernd, Harter Philipp, Traut Alexander, Pietzner Klaus, Glaubitz Ralf, Ataseven Beyhan, Chekerov Radoslav, Keck Christoph, Winkler Thomas, Heikaus Sebastian, Gellendin Peggy, Schütz Ekkehard, Heitz Florian
Department for Gynecology with the Center for Oncologic Surgery Charité Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 12169 Berlin, Germany.
Department for Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte, 45136 Essen, Germany.
Cancers (Basel). 2021 Dec 30;14(1):168. doi: 10.3390/cancers14010168.
Chromosomal instability, a hallmark of cancer, results in changes in the copy number state. These deviant copy number states can be detected in the cell-free DNA (cfDNA) and provide a quantitative measure of the ctDNA levels by converting cfDNA next-generation sequencing results into a genome-wide copy number instability score (CNI-Score). Our aim was to determine the role of the CNI-Score in detecting epithelial ovarian cancer (EOC) and its role as a marker to monitor the response to treatment.
Blood samples were prospectively collected from 109 patients with high-grade EOC. cfDNA was extracted and analyzed using a clinical-grade assay designed to calculate a genome-wide CNI-Score from low-coverage sequencing data. Stored data from 241 apparently healthy controls were used as a reference set.
Comparison of the CNI-Scores of primary EOC patients versus controls yielded sensitivities of 91% at a specificity of 95% to detect OC, respectively. Significantly elevated CNI-Scores were detected in primary (median: 87, IQR: 351) and recurrent (median: 346, IQR: 1891) blood samples. Substantially reduced CNI-Scores were detected after primary debulking surgery. Using a cut-off of 24, a diagnostic sensitivity of 87% for primary and recurrent EOC was determined at a specificity of 95%. CNI-Scores above this threshold were detected in 21/23 primary tumor (91%), 36/42 of platinum-eligible recurrent (85.7%), and 19/22 of non-platinum-eligible recurrent (86.3%) samples, respectively.
ctDNA-quantification based on genomic instability determined by the CNI-Score was a biomarker with high diagnostic accuracy in high-grade EOC. The applied assay might be a promising tool for diagnostics and therapy monitoring, as it requires no a priori information about the tumor.
染色体不稳定是癌症的一个标志，会导致拷贝数状态的改变。这些异常的拷贝数状态可在游离DNA（cfDNA）中检测到，并通过将cfDNA下一代测序结果转化为全基因组拷贝数不稳定评分（CNI-Score）来提供ctDNA水平的定量测量。我们的目的是确定CNI-Score在检测上皮性卵巢癌（EOC）中的作用及其作为监测治疗反应标志物的作用。
前瞻性收集109例高级别EOC患者的血样。提取cfDNA并使用一种临床级检测方法进行分析，该方法旨在根据低覆盖度测序数据计算全基因组CNI-Score。将241名明显健康对照的存储数据用作参考集。
原发性EOC患者与对照的CNI-Score比较显示，检测OC时的敏感性分别为91%，特异性为95%。在原发性（中位数：87，四分位间距：351）和复发性（中位数：346，四分位间距：1891）血样中检测到显著升高的CNI-Score。在初次肿瘤细胞减灭术后检测到CNI-Score大幅降低。使用截断值24，确定原发性和复发性EOC的诊断敏感性为87%，特异性为95%。分别在21/23例原发性肿瘤（91%）、36/42例符合铂类治疗的复发性肿瘤（85.7%）和19/22例不符合铂类治疗的复发性肿瘤（86.3%）样本中检测到高于该阈值的CNI-Score。
基于CNI-Score确定的基因组不稳定性的ctDNA定量是高级别EOC中具有高诊断准确性的生物标志物。所应用的检测方法可能是一种用于诊断和治疗监测的有前景的工具，因为它不需要关于肿瘤的先验信息。
