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

AbstractThe molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we performed a large integrative multi-omics analysis of patients diagnosed with NMIBC (n=834). Transcriptomic analysis identified four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provided independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations were significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration was associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirmed the higher infiltration of class 2b tumors and demonstrated an association between higher immune cell infiltration and lower recurrence rates. Finally, a single-sample classification tool was built and the independent prognostic value of the transcriptomic classes was documented in 1306 validation samples. The classifier provides a framework for novel biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.

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

Nature Communications ◽

10.1038/s41467-021-22465-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Sia Viborg Lindskrog ◽

Frederik Prip ◽

Philippe Lamy ◽

Ann Taber ◽

Clarice S. Groeneveld ◽

...

Keyword(s):

Bladder Cancer ◽

Chromosomal Instability ◽

Prognostic Value ◽

Immune Cell ◽

Cell Infiltration ◽

Invasive Bladder Cancer ◽

Immune Cell Infiltration ◽

Muscle Invasive Bladder Cancer ◽

Omics Analysis ◽

Muscle Invasive

AbstractThe molecular landscape in non-muscle-invasive bladder cancer (NMIBC) is characterized by large biological heterogeneity with variable clinical outcomes. Here, we perform an integrative multi-omics analysis of patients diagnosed with NMIBC (n = 834). Transcriptomic analysis identifies four classes (1, 2a, 2b and 3) reflecting tumor biology and disease aggressiveness. Both transcriptome-based subtyping and the level of chromosomal instability provide independent prognostic value beyond established prognostic clinicopathological parameters. High chromosomal instability, p53-pathway disruption and APOBEC-related mutations are significantly associated with transcriptomic class 2a and poor outcome. RNA-derived immune cell infiltration is associated with chromosomally unstable tumors and enriched in class 2b. Spatial proteomics analysis confirms the higher infiltration of class 2b tumors and demonstrates an association between higher immune cell infiltration and lower recurrence rates. Finally, the independent prognostic value of the transcriptomic classes is documented in 1228 validation samples using a single sample classification tool. The classifier provides a framework for biomarker discovery and for optimizing treatment and surveillance in next-generation clinical trials.

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

Nature Communications ◽

10.1038/s41467-020-18640-0 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 4

Author(s):

Ann Taber ◽

Emil Christensen ◽

Philippe Lamy ◽

Iver Nordentoft ◽

Frederik Prip ◽

...

Keyword(s):

Bladder Cancer ◽

Treatment Response ◽

Immune Cell ◽

Poor Response ◽

Invasive Bladder Cancer ◽

Chemotherapy Response ◽

Muscle Invasive Bladder Cancer ◽

Omics Analysis ◽

Muscle Invasive ◽

Future Patient

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.

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