title="Molecular footprints of muscle-invasive bladder cancer in smoking and	nonsmoking patients.",
keywords="APOBEC Deaminases; Aged; Biomarkers, Tumor; Carcinogenesis; Carcinogens; Female; Gene Expression Regulation, Neoplastic; Humans; Male; Middle Aged; Mutation Rate; Non-Smokers; Receptors, G-Protein-Coupled; Receptors, Peptide; Smokers; Smoking; Survival Analysis; Tobacco; Up-Regulation; Urinary Bladder; Urinary Bladder Neoplasms; Urothelium",
abstract="Bladder cancer is the fifth most common cancer in	  the United States and smoking is the largest known risk factor. Tobacco-derived	  carcinogens may induce the accumulation of somatic mutations in urothelial cells,	  and likely promote tumorigenesis. However, it is still unknown whether	  smoking-induced bladder carcinogenesis results in tumors with distinctive molecular	  features that can be therapeutically exploited.",
title="Genomic classification and risk stratification of bladder cancer.",
keywords="Genomics; Humans; Neoplasm Invasiveness; Risk Assessment; Urinary Bladder Neoplasms",
abstract="Bladder cancer is the fourth most common cancer in men and fifth most	  common overall. The use of next-generation sequencing (NGS) approaches is crucial	  to precisely characterize the molecular defects of tumors, and this information	  could be combined with other clinical data, such as tumor histology and TNM	  staging, with the goal of precise tumor classification. In many settings, targeted	  NGS is evaluated in patients with first- and second-line metastatic cancer. Yet, in	  the decade to come we anticipate increased application of precision oncology at all	  stages of bladder cancer with the aim of customizing cancer treatment. Here, we	  review the genomic and transcriptomic features associated with risk stratification	  in bladder cancer and summarize the current efforts for precision oncology in	  localized urothelial carcinomas.",
title="The BBN model: a mouse bladder cancer model featuring basal-subtype gene expression and MLL3/MLL4 genetic disruption.",
title="Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy.",
keywords="Amino Acid Sequence; Animals; Cell Line, Tumor; Chromatin; DNA-Binding Proteins; Enhancer Elements, Genetic; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histone Demethylases; Mice, Nude; Mutation; Nuclear Proteins; PHD Zinc Fingers; Polycomb-Group Proteins; Protein Binding; Survival Analysis; Tumor Suppressor Proteins; Ubiquitin Thiolesterase",
abstract="The lysine methyltransferase KMT2C (also known as MLL3), a subunit of the COMPASS complex, implements monomethylation of Lys4 on histone H3 (H3K4) at gene enhancers. KMT2C (hereafter referred to as MLL3) frequently incurs point mutations across a range of human tumor types, but precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within the region encoding its plant homeodomain (PHD) repeats and demonstrate that this domain mediates association of MLL3 with the histone H2A deubiquitinase and tumor suppressor BAP1. Cancer-associated mutations in the sequence encoding the MLL3 PHD repeats disrupt the interaction between MLL3 and BAP1 and correlate with poor patient survival. Cancer cells that had PHD-associated MLL3 mutations or lacked BAP1 showed reduced recruitment of MLL3 and the H3K27 demethylase KDM6A (also known as UTX) to gene enhancers. As a result, inhibition of the H3K27 methyltransferase activity of the Polycomb repressive complex 2 (PRC2) in tumor cells harboring BAP1 or MLL3 mutations restored normal gene expression patterns and impaired cell proliferation in vivo. This study provides mechanistic insight into the oncogenic effects of PHD-associated mutations in MLL3 and suggests that restoration of a balanced state of Polycomb-COMPASS activity may have therapeutic efficacy in tumors that bear mutations in the genes encoding these epigenetic factors.",
title="APOBEC-mediated mutagenesis in urothelial carcinoma is associated with improved survival, mutations in DNA damage response genes, and immune response.",
abstract="APOBEC enzymes are responsible for a mutation signature (TCW>T/G) implicated in a wide variety of tumors. We explore the APOBEC mutational signature in bladder cancer and the relationship with specific mutations, molecular subtype, gene expression, and survival using sequencing data from The Cancer Genome Atlas ( = 395), Beijing Genomics Institute ( = 99), and Cancer Cell Line Encyclopedia. Tumors were split into ``APOBEC-high'' and ``APOBEC-low'' based on APOBEC enrichment. Patients with APOBEC-high tumors have better overall survival compared to those with APOBEC-low tumors (38.2 vs. 18.5 months,  = 0.005). APOBEC-high tumors are more likely to have mutations in DNA damage response genes () and chromatin regulatory genes (), while APOBEC-low tumors are more likely to have mutations in  and .  and  expression correlates with mutation burden, regardless of bladder tumor molecular subtype. APOBEC mutagenesis is associated with increased expression of immune signatures, including interferon signaling, and expression of  is increased after stimulation of APOBEC-high bladder cancer cell lines with IFN{\{}{\{}{\}}{\{}{\$}{\}}{\{}{\}}{\}}{\{}{\$}{\}}{\$}$\gamma${\$}{\{}{\$}{\}}{\{}{\{}{\}}{\{}{\$}{\}}{\{}{\}}{\}}. In summary, APOBEC-high tumors are more likely to have mutations in DNA damage response and chromatin regulatory genes, potentially providing more substrate for APOBEC enzymes, leading to a hypermutational phenotype and the subsequent enhanced immune response.",
title="A Carcinogen-induced mouse model recapitulates the molecular alterations of human muscle invasive bladder cancer.",
keywords="Animals; Carcinogens; Carcinoma, Transitional Cell; Cell Transformation, Neoplastic; Cells, Cultured; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Male; Mice; Mice, Inbred C57BL; Microarray Analysis; Muscle Neoplasms; Mutation; Neoplasm Invasiveness; Transcriptome; Urinary Bladder Neoplasms",
abstract="The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model is an attractive model system of muscle-invasive bladder cancer (MIBC) as it recapitulates the histology of human tumors in a background with intact immune system. However, it was unknown whether this carcinogen-induced model also mimicked human MIBC at the molecular and mutational level. In our study, we analyzed gene expression and mutational landscape of the BBN model by next-generation sequencing followed by a bioinformatic comparison to human MIBC using data from The Cancer Genome Atlas and other repositories. BBN tumors showed overexpression of markers of basal cancer subtype, and had a high mutation burden with frequent Trp53 (80{\{}{\{}{\}}{\{}{\{}{\}}{\{}{\}}{\}}{\{}{\{}{\}}{\{}{\%}{\}}{\{}{\}}{\}}{\{}{\{}{\}}{\{}{\}}{\}}{\{}{\}}{\}}), Kmt2d (70{\{}{\{}{\}}{\{}{\{}{\}}{\{}{\}}{\}}{\{}{\{}{\}}{\{}{\%}{\}}{\{}{\}}{\}}{\{}{\{}{\}}{\{}{\}}{\}}{\{}{\}}{\}}), and Kmt2c (90{\{}{\{}{\}}{\{}{\{}{\}}{\{}{\}}{\}}{\{}{\{}{\}}{\{}{\%}{\}}{\{}{\}}{\}}{\{}{\{}{\}}{\{}{\}}{\}}{\{}{\}}{\}}) mutations by exome sequencing, similar to human MIBC. Many variants corresponded to human cancer hotspot mutations, supporting their role as driver mutations. We extracted two novel mutational signatures from the BBN mouse genomes. The integrated analysis of mutation frequencies and signatures highlighted the contribution of aberrations to chromatin regulators and genetic instability in the BBN tumors. Together, our study revealed several similarities between human MIBC and the BBN mouse model, providing a strong rationale for its use in molecular and drug discovery studies.",