CaltechAUTHORS
Published January 19, 2023 | Version Published
Journal Article Open

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

Creators

  • 1. ROR icon Washington University in St. Louis
  • 2. ROR icon Center for Cancer Research
  • 3. ROR icon California Institute of Technology
  • 4. ROR icon University of Rochester Medical Center

Abstract

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.

Additional Information

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. We are grateful to the patients, their families, and healthy volunteers involved in this study. We also thank A. Newman for providing critical feedback on the manuscript. Images from Biorender.com were used to create Fig. 1a. This work was supported by the National Cancer Institute (NCI) under award number K08CA238711 (A.A.C.), and the National Center for Advancing Translational Sciences (NCATS) under award number UL1TR002345 (Principal Investigator, Bradley Evanoff; A.A.C.). This work was additionally supported by the Washington University School of Medicine Dean's Medical Student Research Fellowship (A.S), the Midwest Stone Institute (Z.L.S.), the Rabushka Bladder Cancer Research Fund (Z.L.S. and A.A.C.), the Alvin J. Siteman Cancer Research Fund (A.A.C.), the Cancer Research Foundation Young Investigator Award (A.A.C.), and the V Foundation V Scholar Award (A.A.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. These authors contributed equally: Pradeep S. Chauhan, Alexander Shiang, Irfan Alahi. Data availability. All FASTQ files corresponding to sequenced patient samples are available from the sequencing read archive (SRA) under accession number PRJNA907063 and ID number 907063. Competing interests. P.S.C., I.A., R.T.S., K.C., Z.L.S., and A.A.C. have patent filings related to cancer biomarkers. F.Q. has stock options in Centene, Gilead, and Horizon Therapeutics. B.C.B. discloses honoraria from Mevion Medical Systems and consulting work for Regeneron/Sanofi, outside of the submitted work. Z.L.S. serves as a consultant/advisor for Photocure, outside the submitted work. A.A.C. has licensed technology to Droplet Biosciences, Tempus Labs, and Biocognitive Labs. A.A.C. has served as a consultant/advisor to Roche, Tempus, Illumina, Geneoscopy, NuProbe, Daiichi Sankyo, AstraZeneca, AlphaSights, DeciBio, and Guidepoint. A.A.C. has received honoraria from Roche, Foundation Medicine, and Dava Oncology. A.A.C. has stock options in Geneoscopy, research support from Roche, Illumina and Tempus Labs, and ownership interests in Droplet Biosciences and LiquidCell Dx. The remaining authors declare no competing interests.

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Additional details

Identifiers

PMCID
PMC9852243
Eprint ID
119181
Resolver ID
CaltechAUTHORS:20230209-988069100.17

Funding

NIH
K08CA238711
NIH
UL1TR002345
Washington University
Cancer Research Foundation of America
V Foundation for Cancer Research

Dates

Created
2023-03-16
Created from EPrint's datestamp field
Updated
2023-03-16
Created from EPrint's last_modified field