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Genomic Predictors of Good Outcome, Recurrence, or Progression in High-Grade T1 Non-Muscle-Invasive Bladder Cancer.
Joaquim Bellmunt1,2,3,4, Jaegil Kim3, Brendan Reardon3,5
1Beth Israel Deaconess Medical Center, Boston, Massachusetts. jbellmun@bidmc.harvard.edu dk@rics.bwh.harvard.edu.
Cancer Research
|September 2, 2020
Summary
High-grade T1 bladder cancer outcomes are linked to specific genetic mutations. High tumor mutational burden and ERCC2 mutations correlate with good outcomes, suggesting molecular profiling can improve patient management.
Area of Science:
- Oncology
- Genetics
- Genomics
Background:
- High-grade T1 (HGT1) bladder cancer is an aggressive non-muscle-invasive form with unpredictable outcomes.
- Risk factors and molecular drivers of HGT1 bladder cancer progression remain poorly understood.
Purpose of the Study:
- To investigate the association between somatic mutation profiles and clinical outcomes (good outcome, recurrence, progression) in HGT1 bladder cancer patients.
- To identify specific genetic alterations and mutation signatures that predict disease behavior.
Main Methods:
- Exome sequencing of 62 HGT1 tumors and 15 matched normal tissues.
- Analysis of somatic mutations, copy-number alterations, tumor mutational burden (TMB), and mutation signatures in 95 bladder cancer-associated genes.
- Validation of findings using external public datasets.
Main Results:
- Tumor mutational burden (TMB) was highest in good outcome (GO) patients, intermediate in progression (PD), and lowest in recurrence (R) patients (P = 0.017).
- Mutations in DNA damage response genes (e.g., ERCC2, BRCA2) were associated with higher TMB and GO.
- Specific mutations (TP53, ATM, ARID1A) and copy-number alterations (CCNE1 gain, CDKN2A deletion) were enriched in PD or R patients.
- APOBEC and COSMIC5 mutation signatures were prevalent, with APOBEC-A and ERCC2 mutations linked to GO.
Conclusions:
- Molecular characterization of HGT1 bladder tumors reveals distinct genetic features correlating with patient outcomes.
- High TMB, ERCC2 mutations, and specific mutation signatures (APOBEC-A/ERCC2) are associated with a good prognosis.
- These findings suggest that integrating molecular profiling into the management of HGT1 bladder cancer could improve outcome prediction and treatment strategies.
