Urinary Molecular Pathology for Patients with Newly Diagnosed Urothelial Bladder Cancer.
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 analytic 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 CCF (cancer cell fraction), VAF (variant allele frequency) and TMB (tumor mutation burden) were invariably concordant between tDNA and utDNA, but not ctDNA. The mutational landscape 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 FGFR3 alteration and ERBB2 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.
Authors: Ruiyun Zhang, Jingyu Zang, Feng Xie, Yue Zhang, Yiqiu Wang, Ying Jing, Yi Zhang, Zhaoxiong Chen, Akezhouli Shahatiaili, Mei-Chun Cai, Zhixin Zhao, Pan Du, Shidong Jia, Guanglei Zhuang, Haige Chen