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Genomic predictors of good outcome, recurrence, or progression in high-grade T1 non-muscle-invasive bladder cancer

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dc.contributor.author Bellmunt Molins, Joaquim, 1959-
dc.contributor.author Perera Bel, Júlia
dc.contributor.author Orsola, Anna
dc.contributor.author Rodriguez-Vida, Alejo
dc.contributor.author Juanpere, Nuria
dc.contributor.author Lloreta Trull, Josep, 1958-
dc.contributor.author Hernández, Silvia
dc.contributor.author Kwiatkowski, David J.
dc.date.accessioned 2023-03-27T08:19:09Z
dc.date.available 2023-03-27T08:19:09Z
dc.date.issued 2020
dc.identifier.citation Bellmunt J, Kim J, Reardon B, Perera-Bel J, Orsola A, Rodriguez-Vida A, et al. Genomic predictors of good outcome, recurrence, or progression in high-grade T1 non-muscle-invasive bladder cancer. Cancer Res. 2020; 80(20):4476-86. DOI: 10.1158/0008-5472.CAN-20-0977
dc.identifier.issn 0008-5472
dc.identifier.uri http://hdl.handle.net/10230/56355
dc.description.abstract High-grade T1 (HGT1) bladder cancer is the highest risk subtype of non-muscle-invasive bladder cancer with unpredictable outcome and poorly understood risk factors. Here, we examined the association of somatic mutation profiles with nonrecurrent disease (GO, good outcome), recurrence (R), or progression (PD) in a cohort of HGT1 patients. Exome sequencing was performed on 62 HGT1 and 15 matched normal tissue samples. Both tumor only (TO) and paired analyses were performed, focusing on 95 genes known to be mutated in bladder cancer. Somatic mutations, copy-number alterations, mutation load, and mutation signatures were studied. Thirty-three GO, 10 R, 18 PD, and 1 unknown outcome patients were analyzed. Tumor mutational burden (TMB) was similar to muscle-invasive disease and was highest in GO, intermediate in PD, and lowest in R patients (P = 0.017). DNA damage response gene mutations were associated with higher TMB (P < 0.0001) and GO (P = 0.003). ERCC2 and BRCA2 mutations were associated with GO. TP53, ATM, ARID1A, AHR, and SMARCB1 mutations were more frequent in PD. Focal copy-number gain in CCNE1 and CDKN2A deletion was enriched in PD or R (P = 0.047; P = 0.06). APOBEC (46%) and COSMIC5 (34%) signatures were most frequent. APOBEC-A and ERCC2 mutant tumors (COSMIC5) were associated with GO (P = 0.047; P = 0.0002). pT1b microstaging was associated with a genomic cluster (P = 0.05) with focal amplifications of E2F3/SOX4, PVRL4, CCNE1, and TP53 mutations. Findings were validated using external public datasets. These findings require confirmation but suggest that management of HGT1 bladder cancer may be improved via molecular characterization to predict outcome. SIGNIFICANCE: Detailed genetic analyses of HGT1 bladder tumors identify features that correlate with outcome, e.g., high mutational burden, ERCC2 mutations, and high APOBEC-A/ERCC2 mutation signatures were associated with good outcome.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher American Association for Cancer Research (AACR)
dc.relation.ispartof Cancer Res. 2020; 80(20):4476-86
dc.rights © American Association for Cancer Research (AACR) http://dx.doi.org/10.1158/0008-5472.CAN-20-0977
dc.title Genomic predictors of good outcome, recurrence, or progression in high-grade T1 non-muscle-invasive bladder cancer
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1158/0008-5472.CAN-20-0977
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/acceptedVersion


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