Field cancerization impacts tumor development, T-cell exhaustion and clinical outcomes in bladder cancer

Bladder field cancerization may be associated with disease outcome in patients with bladder cancer. To investigate this, we analyzed biopsies from bladder urothelium and urine samples by genomics and proteomics analyses. Samples were procured from multiple timepoints from 134 patients with early stage bladder cancer and detailed long term follow-up. We measured the field cancerization in normal-appearing bladder biopsies and found that high levels were associated with high tumor mutational burden, high neoantigen load, and high tumor-associated CD8 T-cell exhaustion. Non-synonymous mutations in known bladder cancer driver genes such as KDM6A and TP53 were identified as early disease drivers in normal urothelium. High field cancerization was associated with worse outcome but not with response to BCG. The level of urinary tumor DNA (utDNA) reflected the bladder tumor burden and originated from both tumors and field cancerization. High utDNA levels after BCG were associated with worse clinical outcomes for the patients. Our results indicate that the level of field cancerization may affect clinical outcome, tumor development and immune responses. utDNA measurements have significant prognostic value and reflect the disease status of the bladder. ### Competing Interest Statement Lars Dyrskjot has sponsored research agreements with C2i, AstraZeneca, Natera, Photocure, and Ferring; has an advisory/consulting role at Ferring and UroGen; and is Chairman of the Board in BioXpedia A/S. Joergen Bjerggaard Jensen is proctor for Intuitive Surgery; is a member of advisory board for Olympus Europe, Cephaid, and Ferring; and has sponsored research agreements with Medac, Photocure ASA, Cephaid, and Ferring.