Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
J Urol. 2021 Oct;206(4):873-884. doi: 10.1097/JU.0000000000001878. Epub 2021 Jun 1.
Next-generation sequencing (NGS)-based profiling of both urinary tumor DNA (utDNA) and circulating tumor DNA (ctDNA) shows promise for noninvasive detection and surveillance of urothelial bladder cancer (UBC). However, the analytical performance of these assays remains undefined in the real-world setting. Here, we sought to evaluate the concordance between tumor DNA (tDNA) profiling and utDNA or ctDNA assays using a UBC patient cohort from the intended-use population.
Fifty-nine cases with pathologically confirmed disease and matching tissue/urine pairs were prospectively enrolled. Baseline peripheral blood mononuclear cell and plasma specimens were collected during clinic visits. The PredicineCARE NGS assay was applied for ultra-deep targeted sequencing and somatic alteration identification in tDNA, utDNA and ctDNA.
Diverse quantitative metrics including cancer cell fraction, variant allele frequency and tumor mutation burden were invariably concordant between tDNA and utDNA, but not ctDNA. The mutational landscapes captured by tDNA or utDNA were highly similar, whereas a considerable proportion of ctDNA aberrations stemmed from clonal hematopoiesis. Using tDNA-informed somatic events as reference, utDNA assays achieved a specificity of 99.3%, a sensitivity of 86.7%, a positive predictive value of 67.2%, a negative predictive value of 99.8% and a diagnostic accuracy of 99.1%. Higher preoperative utDNA or tDNA abundance correlated with worse relapse-free survival. Actionable variants including alteration and amplification were identified in utDNA.
Urine-based molecular pathology provides a valid and complete genetic profile of bladder cancer, and represents a faithful surrogate for genotyping and monitoring newly diagnosed UBC.
基于下一代测序（NGS）的尿肿瘤 DNA（utDNA）和循环肿瘤 DNA（ctDNA）分析在无创检测和监测尿路上皮膀胱癌（UBC）方面显示出前景。然而，这些检测方法在实际环境中的分析性能仍然没有定义。在这里，我们试图使用来自预期用途人群的 UBC 患者队列评估肿瘤 DNA（tDNA）分析与 utDNA 或 ctDNA 检测之间的一致性。
前瞻性纳入了 59 例经病理证实的疾病和匹配的组织/尿液对的病例。在就诊期间采集基线外周血单核细胞和血浆标本。应用 PredicineCARE NGS 检测方法对 tDNA、utDNA 和 ctDNA 进行超深度靶向测序和体细胞改变识别。
包括肿瘤细胞分数、变异等位基因频率和肿瘤突变负担在内的各种定量指标在 tDNA 和 utDNA 之间始终一致，但在 ctDNA 中不一致。tDNA 或 utDNA 捕获的突变景观非常相似，而 ctDNA 中的相当一部分异常源自克隆性造血。使用 tDNA 指导的体细胞事件作为参考，utDNA 检测的特异性为 99.3%，灵敏度为 86.7%，阳性预测值为 67.2%，阴性预测值为 99.8%，诊断准确性为 99.1%。术前 utDNA 或 tDNA 丰度较高与无复发生存率较差相关。在 utDNA 中鉴定出了包括 改变和 扩增在内的可操作变异。
基于尿液的分子病理学提供了膀胱癌的有效和完整的遗传谱，是对新诊断的 UBC 进行基因分型和监测的可靠替代方法。
