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

Abstract

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.

An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer

“…7a for details), carcinoma cells (pan-cytokeratin, CK5/6, and GATA3) and immune recognition/escape mechanisms (PD-L1 and MHC class I). Automated image analysis algorithms 41 were applied to study the spatial organization of immune cells and immune evasion mechanisms (Fig. 4a and Supplementary Fig.…”

MMP-7 Serum and Tissue Levels Are Associated with Poor Survival in Platinum-Treated Bladder Cancer Patients

“…Gene-expression-based molecular subtypes were reported to be associated with survival in platinum-treated MIBC patients [ 8 ]. However, other authors could not confirm this observation [ 9 ]. Therefore, prediction of survival for patients who receive platinum-based chemotherapy remains an unmet clinical need.…”

“…In the last years, several potential therapy-predictive markers, such as the excision repair gene ERCC1 , HMGA2 , nucleoside transporter protein hENT1, transcription factor TFAP, apoptosis inhibitor surviving, EMMPRIN and SDC1, have been identified [ 28 , 29 , 30 , 31 , 32 ]. In addition, gene-expression-based molecular subtypes of MIBC were suggested to show different sensitivities to platinum therapy [ 8 , 9 ]. However, currently, none of these markers has become established in routine clinical practice.…”

Integrative multi-omics analysis of muscle-invasive bladder cancer identifies prognostic biomarkers for frontline chemotherapy and immunotherapy

“…Third, bulk RNA-seq and microarray GE data are confounded by signals from a mixture of cell populations, making it necessary to collaborate these RNA-based findings with multiplex immunohistochemistry to investigate tumor cell intrinsic changes and its crosstalk with the immune and stromal microenvironments that dictate therapy response. Finally, we are aware that a recent study using the consensus classification method in a different patient cohort revealed basal/squamous tumors exhibited a poor response to chemotherapy 62 . It is unclear if these findings are related to previous functional studies showing basal cancer stem cell repopulation is a contributing driver to chemoresistance 63 .…”