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Molecular correlates of cisplatin-based chemotherapy response in muscle invasive bladder cancer by integrated multi-omics analysis

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Overtreatment with cisplatin-based chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC), and currently none of the reported biomarkers for predicting response have been implemented in the clinic. Here we perform a comprehensive multi-omics analysis (genomics, transcriptomics, epigenomics and proteomics) of 300 MIBC patients treated with chemotherapy (neoadjuvant or first-line) to identify molecular changes associated with treatment response. DNA-based associations with response converge on genomic instability driven by a high number of chromosomal alterations, indels, signature 5 mutations and/or BRCA2 mutations. Expression data identifies the basal/squamous gene expression subtype to be associated with poor response. Immune cell infiltration and high PD-1 protein expression are associated with treatment response. Through integration of genomic and transcriptomic data, we demonstrate patient stratification to groups of low and high likelihood of cisplatin-based response. This could pave the way for future patient selection following validation in prospective clinical trials.

Original languageEnglish
Article number4858
JournalNature Communications
Number of pages15
Publication statusPublished - Sept 2020

    Research areas

  • ASSOCIATION, CARCINOMA, CLONAL EVOLUTION, CYSTECTOMY, GEMCITABINE PLUS CISPLATIN, NEOADJUVANT CHEMOTHERAPY, SENSITIVITY, SIGNATURES, SOMATIC ERCC2 MUTATIONS, SURVIVAL, Genomic Instability, Humans, Drug Therapy, Transcriptome, Gene Expression Regulation, Neoplastic/drug effects, Biomarkers, Tumor, Urinary Bladder Neoplasms/drug therapy, Programmed Cell Death 1 Receptor/genetics, BRCA2 Protein/genetics, Cisplatin/pharmacology, DNA Methylation, Neoadjuvant Therapy, Chemotherapy, Adjuvant, Mutation

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