Urothelial Carcinoma Detection Based on Copy Number Profiles of Urinary Cell-Free DNA by Shallow Whole-Genome Sequencing
Urothelial Carcinoma Detection Based on Copy Number Profiles of Urinary Cell-Free DNA by Shallow Whole-Genome Sequencing
复制标题
通过浅全基因组测序基于尿液游离 DNA 拷贝数图谱进行尿路上皮癌检测。
DOI：
10.1373/clinchem.2019.309633
复制
发表时间：
2020-01-01
影响因子：
9.3
通讯作者：
Ci, Weimin
中科院分区：
文献类型：
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作者：
Ge, Guangzhe;Peng, Ding;Ci, Weimin
背景
目前尿路上皮癌（UC）的非侵入性检测缺乏临床敏感性和特异性。考虑到血浆无细胞DNA（cfDNA）生物标志物的效用，尿cfDNA生物标志物的开发可以提高诊断灵敏度。
方法
我们通过对95名无癌症个体和65名UC患者、58名肾癌患者和45名前列腺癌患者的尿液cfDNA进行浅基因组测序，评估了拷贝数改变（CNA）。我们使用支持向量机开发了一个基于CNA配置文件的诊断分类器来检测UC（UCdetector）。该模型在一个独立的队列（52例患者）中得到进一步验证。使用来自90个上尿路上皮癌（UTUC）的肿瘤标本的基因组测序数据和来自癌症基因组图谱的410个膀胱尿路上皮癌（UCB）的CNA数据来验证分类器。将来自32名UC患者的尿沉渣的基因组测序数据与cfDNA进行比较。为了监测治疗效果，我们收集了7名治疗后患者的cfDNA。
结果
尿cfDNA是比尿沉渣更敏感的替代物。UC检测器可检测UC，中位临床敏感性为86.5%，特异性为94.7%。UCdetector在独立验证数据集中表现良好。值得注意的是，UCdetector选择的CNA特征是UTUC和UCB的特异性标志物。此外，cfDNA中的CNA变化与治疗效果一致。同时，同样的策略可以将70.1%的患者的泌尿生殖系统癌定位到起源组织。
结论
我们的研究结果强调了尿cfDNA CNA谱作为非侵入性UC检测和监测的基础的潜在效用。
BACKGROUND
Current noninvasive assays for urothelial carcinoma (UC) lack clinical sensitivity and specificity. Given the utility of plasma cell-free DNA (cfDNA) bio-markers, the development of urinary cfDNA biomarkers may improve the diagnostic sensitivity.
METHODS
We assessed copy number alterations (CNAs) by shallow genome-wide sequencing of urinary cfDNA in 95 cancer-free individuals and 65 patients with UC, 58 with kidney cancer, and 45 with prostate cancer. We used a support vector machine to develop a diagnostic classifier based on CNA profiles to detect UC (UCdetector). The model was further validated in an independent cohort (52 patients). Genome sequencing data of tumor specimens from 90 upper tract urothelial cancers (UTUCs) and CNA data for 410 urothelial carcinomas of bladder (UCBs) from The Cancer Genome Atlas were used to validate the classifier. Genome sequencing data for urine sediment from 32 patients with UC were compared with cfDNA. To monitor the treatment efficacy, we collected cfDNA from 7 posttreatment patients.
RESULTS
Urinary cfDNA was a more sensitive alternative to urinary sediment. The UCdetector could detect UC at a median clinical sensitivity of 86.5% and specificity of 94.7%. UCdetector performed well in an independent validation data set. Notably, the CNA features selected by UCdetector were specific markers for both UTUC and UCB. Moreover, CNA changes in cfDNA were consistent with the treatment effects. Meanwhile, the same strategy could localize genitourinary cancers to tissue of origin in 70.1% of patients.
CONCLUSIONS
Our findings underscore the potential utility of urinary cfDNA CNA profiles as a basis for non-invasive UC detection and surveillance.