Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma

By John N. Weinstein, Rehan Akbani, B. Broom, Wenyi Wang, R. Verhaak, D. McConkey, S. Lerner, M. Morgan, Chad Creighton, Carolyn Smith and 283 more. Nature, 2014

2,001 citations recorded by the source corpus.

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3–TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.

Subfields: Molecular Biology, Pulmonary and Respiratory Medicine, Surgery

View Paper: https://www.semanticscholar.org/paper/5c903d5383b52415b276bb45b0ef1524881097c8

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Citations in the corpus

Comprehensive Analysis of Hypermutation in Human Cancer (2017, positive): “…those by The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC), have confirmed frequent hypermutation in melanoma (Akbani et al., 2015), lung (Govindan et al., 2012), and bladder cancer (Weinstein et al., 2014) and uncovered rare cases of hypermutation in other cancers.”
The somatic mutation profiles of 2,433 breast cancers refines their genomic and transcriptomic landscapes (2016, positive): “For example, mutations in the SWI/SNF components ARID1A and PBRM1 are especially prevalent in bladder 48 and renal 49 cancers, and tumours harbouring these mutations may have dependencies on other SWI/SNF components that can be therapeutically exploited 50 .”