Field Cancerization Is Associated with Tumor Development, T-cell Exhaustion, and Clinical Outcomes in Bladder Cancer

TY - JOUR

T1 - Field Cancerization Is Associated with Tumor Development, T-cell Exhaustion, and Clinical Outcomes in Bladder Cancer

AU - Strandgaard, Trine

AU - Nordentoft, Iver

AU - Birkenkamp-Demtröder, Karin

AU - Salminen, Liina

AU - Prip, Frederik

AU - Rasmussen, Julie

AU - Andreasen, Tine Ginnerup

AU - Lindskrog, Sia Viborg

AU - Christensen, Emil

AU - Lamy, Philippe

AU - Knudsen, Michael

AU - Steiniche, Torben

AU - Jensen, Jørgen Bjerggaard

AU - Dyrskjøt, Lars

N1 - Publisher Copyright: © 2023 The Author(s)

PY - 2024/1

Y1 - 2024/1

N2 - Background: Field cancerization is characterized by areas of normal tissue affected by mutated clones. Bladder field cancerization may explain the development and recurrence of bladder cancer and may be associated with treatment outcomes. Objective: To investigate the predictive and prognostic roles of field cancerization in patients with high-risk non–muscle-invasive bladder cancer (NMIBC) treated with bacillus Calmette-Guérin (BCG). Design, setting, and participants: We conducted comprehensive genomic and proteomic analyses for 751 bladder biopsies and 234 urine samples from 136 patients with NMIBC. The samples were collected at multiple time points during the disease course. Field cancerization in normal-appearing bladder biopsies was measured using deep-targeted sequencing and error correction models. Outcome measurements and statistical analysis: Endpoints included the rates of recurrence and progression. Cox regression and Wilcoxon rank-sum and Fisher's exact tests were used. Results and limitations: A high level of field cancerization was 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). In addition, high field cancerization was associated with worse short-term outcomes (p = 0.029). Nonsynonymous mutations in bladder cancer–associated genes such as KDM6A, ARID1A, and TP53 were identified as early disease drivers already found in normal-appearing bladder biopsies. Urinary tumor DNA (utDNA) levels reflected the bladder tumor burden and originated from tumors and field cancerization. High levels of utDNA after BCG were associated with worse clinical outcomes (p = 0.027) and with disease progression (p = 0.003). High field cancerization resulted in high urinary levels of proteins associated with angiogenesis and proliferation. Limitations include variation in the number of biopsies and time points analyzed. Conclusions: Field cancerization levels are associated with tumor development, immune responses, and clinical outcomes. utDNA measurements can be used to monitor disease status and treatment response. Patient summary: Molecular changes in the tissue lining the bladder result in tumor recurrence. Urinary measurements may be used to monitor bladder cancer status and treatment responses.

AB - Background: Field cancerization is characterized by areas of normal tissue affected by mutated clones. Bladder field cancerization may explain the development and recurrence of bladder cancer and may be associated with treatment outcomes. Objective: To investigate the predictive and prognostic roles of field cancerization in patients with high-risk non–muscle-invasive bladder cancer (NMIBC) treated with bacillus Calmette-Guérin (BCG). Design, setting, and participants: We conducted comprehensive genomic and proteomic analyses for 751 bladder biopsies and 234 urine samples from 136 patients with NMIBC. The samples were collected at multiple time points during the disease course. Field cancerization in normal-appearing bladder biopsies was measured using deep-targeted sequencing and error correction models. Outcome measurements and statistical analysis: Endpoints included the rates of recurrence and progression. Cox regression and Wilcoxon rank-sum and Fisher's exact tests were used. Results and limitations: A high level of field cancerization was 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). In addition, high field cancerization was associated with worse short-term outcomes (p = 0.029). Nonsynonymous mutations in bladder cancer–associated genes such as KDM6A, ARID1A, and TP53 were identified as early disease drivers already found in normal-appearing bladder biopsies. Urinary tumor DNA (utDNA) levels reflected the bladder tumor burden and originated from tumors and field cancerization. High levels of utDNA after BCG were associated with worse clinical outcomes (p = 0.027) and with disease progression (p = 0.003). High field cancerization resulted in high urinary levels of proteins associated with angiogenesis and proliferation. Limitations include variation in the number of biopsies and time points analyzed. Conclusions: Field cancerization levels are associated with tumor development, immune responses, and clinical outcomes. utDNA measurements can be used to monitor disease status and treatment response. Patient summary: Molecular changes in the tissue lining the bladder result in tumor recurrence. Urinary measurements may be used to monitor bladder cancer status and treatment responses.

KW - Bacillus Calmette-Guérin

KW - Biomarkers

KW - Bladder cancer

KW - Field cancerization

KW - Field effect

KW - Urinary tumor DNA

U2 - 10.1016/j.eururo.2023.07.014

DO - 10.1016/j.eururo.2023.07.014

M3 - Journal article

C2 - 37718188

AN - SCOPUS:85171281660

SN - 0302-2838

VL - 85

SP - 82

EP - 92

JO - European Urology

JF - European Urology

IS - 1

ER -