Posted: October 16, 2017

View the TCGA expanded study of bladder cancer here

Expanded TCGA Study of Bladder Cancer Outlines Therapeutic Roadmap

In an expanded analysis of muscle-invasive urothelial bladder cancer (MIBC), The Cancer Genome Atlas (TCGA) Research Network molecularly characterized and subtyped 412 cases of the disease and proposed subtype-specific therapeutic strategies. A relatively common disease, bladder cancer is estimated to affect 79,000 new patients and cause 17,000 deaths this year. A previous TCGA study from 2014 with fewer samples offered a preview into the genomic aberrations and gene expression features underlying the disease. The current study, published in Cell on October 16, 2017, harnesses the power of more than triple the original number of cases to refine the previously reported subtypes and provides prognostic and therapeutic insights for each. Importantly, this study suggests particular subtypes may benefit from recently FDA approved immune checkpoint inhibitors, while other subtypes may require alternative strategies, such as the development of targeted therapies.

The researchers expanded the number of significantly mutated genes from 32 to 64 and identified hundreds of gene fusions, confirming the high mutation rate of MIBC. The researchers organized these alterations into distinct mutational signatures and canonical signaling pathways and identified potential mutagenesis processes driving each of the signatures. Signaling pathways altered included p53/cell cycle, DNA repair, PI3K-AKT, and chromatin-modifying pathways. Cancers with the highest mutation rate driven by a hallmark mutagenesis process with overexpressed APOBEC enzyme were associated with improved survival probability. In contrast, cancers with the lowest mutation rate had the poorest survival.

By integrating expression, DNA methylation and noncoding RNA data, the researchers were able to subdivide the previously defined, major luminal and basal subtypes into luminal-papillary, luminal-infiltrated, luminal, basal-squamous subtypes and a lesser known, neuronal subtype. Distinctive expression features suggest different cellular precursors and driving molecular mechanisms for each subtype. The subtypes have distinct prognoses and are critical to recognize clinically. For example, the luminal-infiltrated and basal-squamous subtypes may be appropriate for immune checkpoint therapy while the neuronal subtype may benefit instead from etoposide-cisplatin therapy.

The diverse array of mutations, altered pathways, and driving processes uncovered by the researchers demonstrates how MIBC, like many other cancers, encompasses numerous distinct diseases that each require a deep molecular understanding. Importantly, this study places the disease in context with the new immunotherapies and targeted therapies currently being developed. TCGA is a collaboration jointly supported and managed by the National Cancer Institute and the National Human Genome Research Institute, both parts of the National Institutes of Health.