Using comprehensive genomic- and proteomic analyses, they analyzed 751 urothelial bladder biopsies, including 662 normal-appearing biopsies, and 234 urine samples from 136 NMIBC patients. The median follow-up time was 7.7 years. Samples were procured at multiple time points during the disease courses. Field cancerization was assessed in normal-appearing biopsies using deep-targeted sequencing (mean coverage: 1,359X) with application of unique molecular identifiers and error correction models. DNA from urine was sequenced (mean coverage: 2,153X) and urine proteomics were analyzed using Olink.
They detected mutations in 458 out of 751 analyzed bladder biopsies. High levels of field cancerization were associated with high tumor mutational burden (p=0.007), high tumor neoantigen load (p=0.029), and high tumor-associated CD8 T-cell exhaustion (p=0.017). Additionally, high field cancerization was associated with worse short term outcome (p=0.029) and increased with age (p=0.0027). Non-synonymous mutations in bladder cancer driver genes such as KDM6A, ARID1A, and TP53 were identified as early
disease drivers found already in the normal-appearing bladder biopsies. utDNA levels reflected the bladder disease status and originated from field cancerization and tumors. High levels of utDNA after BCG were associated with worse clinical outcomes for the patients (p=0.027) and with disease progression (p=0.003). High field cancerization resulted in high urinary levels of proteins associated with angiogenesis, apoptosis, and tumor immunity.
In summary, field cancerization of the bladder may affect tumor development, immune responses, and clinical outcomes. utDNA measurements may have the potential to be used to monitor disease status and treatment response in patients with NMIBC.
Presented by: Trine Strandgaard, Department of Molecular Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark; Department of Clinical Medicine, Aarhus University
Written by: Stephen B. Williams, MD, MBA, MS @SWilliams_MD on Twitter during the International Bladder Cancer Network (IBCN) Annual Meeting, September 29-30, 2023, Montreal, Canada