Urine cell-free DNA multi-omics to detect MRD and predict survival in bladder cancer patients

Circulating tumor DNA (ctDNA) sensitivity remains subpar for molecular residual disease (MRD) detection in bladder cancer patients. To remedy this problem, we focused on the biofluid most proximal to the disease, urine, and analyzed urine tumor DNA in 74 localized bladder cancer patients. We integra...

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Bibliographic Details
Published in:NPJ precision oncology 2023-01, Vol.7 (1), p.6-6, Article 6
Main Authors: Chauhan, Pradeep S., Shiang, Alexander, Alahi, Irfan, Sundby, R. Taylor, Feng, Wenjia, Gungoren, Bilge, Nawaf, Cayce, Chen, Kevin, Babbra, Ramandeep K., Harris, Peter K., Qaium, Faridi, Hatscher, Casey, Antiporda, Anna, Brunt, Lindsey, Mayer, Lindsey R., Shern, Jack F., Baumann, Brian C., Kim, Eric H., Reimers, Melissa A., Smith, Zachary L., Chaudhuri, Aadel A.
Format: Article
Language:English
Subjects:
631/1647/514/2254
631/61/514/2254
631/67/1857
631/67/589/1336
631/67/69
Biomarkers
Bladder cancer
Brief Communication
Cancer Research
Gene Therapy
Genes
Human Genetics
Internal Medicine
Life expectancy
Medicine
Medicine & Public Health
Oncology
Survivor
Urinalysis
Urine
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Summary:Circulating tumor DNA (ctDNA) sensitivity remains subpar for molecular residual disease (MRD) detection in bladder cancer patients. To remedy this problem, we focused on the biofluid most proximal to the disease, urine, and analyzed urine tumor DNA in 74 localized bladder cancer patients. We integrated ultra-low-pass whole genome sequencing (ULP-WGS) with urine cancer personalized profiling by deep sequencing (uCAPP-Seq) to achieve sensitive MRD detection and predict overall survival. Variant allele frequency, inferred tumor mutational burden, and copy number-derived tumor fraction levels in urine cell-free DNA (cfDNA) significantly predicted pathologic complete response status, far better than plasma ctDNA was able to. A random forest model incorporating these urine cfDNA-derived factors with leave-one-out cross-validation was 87% sensitive for predicting residual disease in reference to gold-standard surgical pathology. Both progression-free survival (HR = 3.00, p  = 0.01) and overall survival (HR = 4.81, p  = 0.009) were dramatically worse by Kaplan–Meier analysis for patients predicted by the model to have MRD, which was corroborated by Cox regression analysis. Additional survival analyses performed on muscle-invasive, neoadjuvant chemotherapy, and held-out validation subgroups corroborated these findings. In summary, we profiled urine samples from 74 patients with localized bladder cancer and used urine cfDNA multi-omics to detect MRD sensitively and predict survival accurately.
ISSN:2397-768X
2397-768X
DOI:10.1038/s41698-022-00345-w