High-grade T1 (HGT1) bladder cancer (BC) is the highest risk subtype of non-muscle-invasive BC with unpredictable outcome and poorly understood risk factors. Here we examined the association of somatic mutation profiles with non-recurrent 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 analysis was performed, focusing on 95 genes known to be mutated in BC. 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. Mutation 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 were 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.
Cancer research. 2020 Aug 31 [Epub ahead of print]
Joaquim Bellmunt, Jaegil Kim, Brendan Reardon, Júlia Perera-Bel, Anna Orsola, Alejo Rodriguez-Vida, Stephanie A Wankowicz, Michaela Bowden, Justine A Barletta, Juan Morote, Inés de Torres, Nuria Juanpere, Josep Lloreta-Trull, Kent W Mouw, Mary-Ellen Taplin, Paloma Cejas, Henry W Long, Eliezer M Van Allen, Gad Getz, David J Kwiatkowski
Division Hematology-Oncology, Beth Israel Deaconess Medical Center ., Experimental Medicin Unit, GSK., Medical Oncology, Dana-Farber Cancer Institute., Research Programme on Biomedical Informatics (GRIB), MARGenomics, Institut Hospital del Mar d'Investigacions Mèdiques., Genitourinary Cancer, Dana-Farber Cancer Institute., Medical Oncology Department, IMIM (Hospital del Mar Research Institute)., Cancer Program, Broad Institute of Harvard and MIT., Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute., Pathology, Brigham and Women's Hospital, Harvard Medical School., Urology, Vall d'Hebron Hospital., Pathology, Hospital Universitari Vall d'Hebron., Department of Pathology, Hospital del Mar-Parc de Salut Mar., Pathology, Hospital del Mar-IMIM, Univesitat Pompeu Fabra., Radiation Oncology, Dana-Farber Cancer Institute/Brigham & Women's Hospital., GU Oncology, Dana-Farber Cancer Institute., Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute., Department of Medical Oncology, Dana-Farber Cancer Institute., Broad Institute of the Massachusetts Institute of Technology and Harvard., Division of Pulmonary Medicine, Brigham and Women's Hospital and Harvard Medical School.