Development and Multicenter Case-Control Validation of Urinary Comprehensive Genomic Profiling for Urothelial Carcinoma Diagnosis, Surveillance, and Risk-Prediction.
Development and Multicenter Case-Control Validation of Urinary Comprehensive Genomic Profiling for Urothelial Carcinoma Diagnosis, Surveillance, and Risk-Prediction.
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DOI：
10.1158/1078-0432.ccr-23-0570
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发表时间：
2023-09-15
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尿综合基因组分析（uCGP）使用下一代测序来识别与尿路上皮癌相关的突变，并有可能通过非侵入性诊断疾病，预测等级和阶段以及估计复发风险来改善患者的预后。这是一项多中心病例对照研究，使用从接受初始诊断/血尿检查或尿路上皮癌监测的患者中采集的库存尿液样本。uCGP共分析了581份样本：333份用于疾病分类和分级算法开发，248份用于盲法验证。uCGP检测使用Uroplasty平台进行，该平台可识别五类突变：单核苷酸变异、拷贝数变异、小插入缺失、拷贝中性杂合性丢失和非整倍性。将预测尿路上皮癌肿瘤存在、分级和复发风险的尿路造影算法与细胞学、膀胱镜检查和病理学进行比较。uCGP算法对于血尿患者的初始癌症诊断具有95%/90%的验证灵敏度/特异性，并且证明阴性预测值（NPV）为99%。阳性诊断似然比（DLR）为9.2，阴性DLR为0.05，表明有能力对血尿患者进行风险分层。在监测患者中，尿路上皮癌二元分类显示NPV为91%。uCGP复发风险预测显著预测未来复发（风险比，6.2），而临床风险因素没有。uCGP显示阳性预测值（PPV）与细胞学相当（45% vs. 42%），但灵敏度高得多（79% vs. 25%）。最后，分子分级预测的PPV为88%，特异性为95%。uCGP能够在血尿和尿路上皮癌监测患者中进行无创、准确的尿路上皮癌诊断和风险分层。
Urinary comprehensive genomic profiling (uCGP) uses next-generation sequencing to identify mutations associated with urothelial carcinoma and has the potential to improve patient outcomes by noninvasively diagnosing disease, predicting grade and stage, and estimating recurrence risk. This is a multicenter case–control study using banked urine specimens collected from patients undergoing initial diagnosis/hematuria workup or urothelial carcinoma surveillance. A total of 581 samples were analyzed by uCGP: 333 for disease classification and grading algorithm development, and 248 for blinded validation. uCGP testing was done using the UroAmp platform, which identifies five classes of mutation: single-nucleotide variants, copy-number variants, small insertion-deletions, copy-neutral loss of heterozygosity, and aneuploidy. UroAmp algorithms predicting urothelial carcinoma tumor presence, grade, and recurrence risk were compared with cytology, cystoscopy, and pathology. uCGP algorithms had a validation sensitivity/specificity of 95%/90% for initial cancer diagnosis in patients with hematuria and demonstrated a negative predictive value (NPV) of 99%. A positive diagnostic likelihood ratio (DLR) of 9.2 and a negative DLR of 0.05 demonstrate the ability to risk-stratify patients presenting with hematuria. In surveillance patients, binary urothelial carcinoma classification demonstrated an NPV of 91%. uCGP recurrence-risk prediction significantly prognosticated future recurrence (hazard ratio, 6.2), whereas clinical risk factors did not. uCGP demonstrated positive predictive value (PPV) comparable with cytology (45% vs. 42%) with much higher sensitivity (79% vs. 25%). Finally, molecular grade predictions had a PPV of 88% and a specificity of 95%. uCGP enables noninvasive, accurate urothelial carcinoma diagnosis and risk stratification in both hematuria and urothelial carcinoma surveillance patients.