Background cfDNA fragmentomics-based liquid biopsy is a potential option for noninvasive bladder cancer (BLCA) detection that remains an unmet clinical need. Methods 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. Results 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. Conclusions 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.

中文翻译：

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通过捕获癌症相关分子特征的尿液 cfDNA 片段化热点对基于机器学习的膀胱癌检测


背景 基于 cfDNA 片段组学的液体活检是无浸润性膀胱癌 （BLCA） 检测的一种潜在选择，但仍然是一个未满足的临床需求。方法 我们评估了 cfDNA 热点驱动的机器学习模型在 55 名 BLCA 患者、51 名良性疾病受试者和 11 名健康志愿者的队列中的诊断性能。我们进一步进行了功能生物信息学分析，以生物学理解和解释该工具的诊断能力。结果 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 87% 的灵敏度，特异性为 100%。它优于使用其他 cfDNA 衍生特征的模型。在分期分层分析中，基于尿液热点的模型对早期 （低级别 Ta 和 T1） 和晚期 （高级别 T1 和肌层浸润性） 疾病的 100% 特异性敏感性分别为 71% 和 92%。从生物学上讲，cfDNA 热点有效地检索了调节元件并与起源细胞相关。尿液 cfDNA 热点特异性捕获了 BLCA 相关的分子特征，包括关键功能通路、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，以及转录因子调控景观。结论 我们的研究结果支持尿液 cfDNA 片段化热点适用于无创 BLCA 诊断，以及未来关于其分子病理学和异质性的转化研究。