PRJNA513870
Genomic Whole-Organ Map of Mucosal Field Effects Initiating Human Bladder Carcinogenesis
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.