Project description:Whole-organ histologic and genomic mapping (WOHGM) approach to analyze the molecular profile of bladder cancer evolution from mucosal field effects on a whole-organ scale.
Project description:Whole-organ histologic and genomic mapping (WOHGM) approach to analyze the molecular profile of bladder cancer evolution from mucosal field effects on a whole-organ scale.
Project description:Whole-organ histologic and genomic mapping (WOHGM) approach to analyze the molecular profile of bladder cancer evolution from mucosal field effects on a whole-organ scale
Project description:We have developed a whole organ mapping approach which combines microscopic assessment of the entire mucosal membrane of the organ affected by cancer with comprehensive genomic profiling. It was used to study the chronology of the molecular changes in the human bladder as they evolved from mucosal field effect through dysplasia and carcinoma in situ to multifocal carcinoma. The widespread methylation changes involving almost the entire mucosa were identified as a major mechanism driving the development of the initial field effect. They also involved a small number of genomic amplifications and losses confirming the clonal nature of the initiating mucosal change. The mutations of the genes which included the activating mutation of Kras and an inactivating mutation of chromatin remodeling gene ACIN1 occured with the advent of carcinoma in situ and did not change with progression to frank carcinoma. The development of carcinoma was associated with copy number gain as a dominant change. A pattern of mutations and copy number changes in carcinoma in situ and several foci of carcinoma were almost identical confirming their clonal origin. The integrated analysis disclosed a complex and accummulating pattern of alterations of multiple oncogenic pathways already evident in mucosal field change. Strikingly the alterations of Kras effector pathways associated with invasion and migration were already present in the tissue field prior to the emergence of mutant Kras. The whole organ mapping approach presented in this study provides novel clues for the understanding of occult mucosal changes that underlie bladder cancer development and have important implications for early detection, prevention and treatment.
2019-02-19 | GSE125286 | GEO
Project description:Genomic Whole-Organ Map of Mucosal Field Effects Initiating Human Bladder Carcinogenesis
Project description:We investigated a sequence of genetic hits in the region of RB1 and identified alternative target genes referred to as forerunner (FR) genes whose silencing was associated with the development of the clonal plaque-like mucosal field effects initiating bladder carcinogenesis.
Project description:Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied and relatively lacking in suitable models. Here we describe a biobank of patient-derived organoid lines that recapitulates the spectrum of human bladder cancer at the histopathological and molecular levels. Organoid lines can be established efficiently from patient biopsies, including from patients before and after disease recurrence, and are interconvertible with orthotopic xenografts. Notably, these organoid lines often retain tumor heterogeneity and exhibit changes in their mutational profiles that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Overall, our studies indicate that patient-derived bladder tumor organoids represent a model system for studying tumor evolution and treatment response in the context of precision cancer medicine.
