基于 cfDNA 片段组学的液体活检是非侵入性膀胱癌 (BLCA) 检测的潜在选择，但其临床需求仍未得到满足。我们在 55 名 BLCA 患者（51 名受试者）中评估了 cfDNA 热点驱动的机器学习模型的诊断性能。健康状况良好，还有 11 名健康志愿者。我们进一步进行了功能生物信息学分析，以从生物学角度理解和解释该工具的诊断能力。基于尿液 cfDNA 热点的机器学习模型实现了有效的 BLCA 检测，实现了高性能（曲线下面积 0.96）和 100% 特异性下的 87% 灵敏度。它的性能优于使用其他 cfDNA 衍生特征的模型。在阶段分层分析中，基于尿液热点的模型对于早期（低级别 Ta 和 T1）和晚期（高级别 T1 和肌肉侵袭性）疾病的 100% 特异性灵敏度分别为 71% 和 92% 。从生物学角度来看，cfDNA 热点有效地检索调控元件并与起源细胞相关。尿液 cfDNA 热点专门捕获了 BLCA 相关分子特征，包括关键功能途径、全基因组关联研究中确定的与 BLCA 风险相关的染色体位点，或在 BLCA 肿瘤中呈现频繁的体细胞改变，以及转录因子调控格局。我们的研究结果支持尿液 cfDNA 碎片热点在无创 BLCA 诊断中的适用性，以及未来关于其分子病理学和异质性的转化研究。© Association for Diagnostics

cfDNA fragmentomics-based liquid biopsy is a potential option for noninvasive bladder cancer (BLCA) detection that remains an unmet clinical need.We assessed the diagnostic performance of cfDNA hotspot-driven machine-learning models in a cohort of 55 BLCA patients, 51 subjects with benign conditions, and 11 healthy volunteers. We further performed functional bioinformatics analysis for biological understanding and interpretation of the tool's diagnostic capability.Urinary cfDNA hotspots-based machine-learning model enabled effective BLCA detection, achieving high performance (area under curve 0.96) and an 87% sensitivity at 100% specificity. It outperformed models using other cfDNA-derived features. In stage-stratified analysis, the sensitivity at 100% specificity of the urine hotspots-based model was 71% and 92% for early (low-grade Ta and T1) and advanced (high-grade T1 and muscle-invasive) disease, respectively. Biologically, cfDNA hotspots effectively retrieved regulatory elements and were correlated with the cell of origin. Urine cfDNA hotspots specifically captured BLCA-related molecular features, including key functional pathways, chromosome loci associated with BLCA risk as identified in genome-wide association studies, or presenting frequent somatic alterations in BLCA tumors, and the transcription factor regulatory landscape.Our findings support the applicability of urine cfDNA fragmentation hotspots for noninvasive BLCA diagnosis, as well as for future translational study regarding its molecular pathology and heterogeneity.© Association for Diagnostics & Laboratory Medicine 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.