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The Origin of Bladder Cancer from Mucosal Field Effects

ABSTRACT: The Origin of Bladder Cancer from Mucosal Field Effects

PROVIDER: PRJNA719208 | ENA |

REPOSITORIES: ENA

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The Origin of Bladder Cancer from Mucosal Field Effects [III]

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

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.

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

Project description:Genomic Whole-Organ Map of Mucosal Field Effects Initiating Human Bladder Carcinogenesis

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The Origin of Bladder Cancer from Mucosal Field Effects

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-06-03 | GSE171363 | GEO

The origin of bladder cancer from mucosal field effects.

Project description:Whole-organ mapping was used to study molecular changes in the evolution of bladder cancer from field effects. We identified more than 100 dysregulated pathways, involving immunity, differentiation, and transformation, as initiators of carcinogenesis. Dysregulation of interleukins signified the involvement of inflammation in the incipient phases of the process. An aberrant methylation/expression of multiple HOX genes signified dysregulation of the differentiation program. We identified three types of mutations based on their geographic distribution. The most common were mutations restricted to individual mucosal samples that targeted uroprogenitor cells. Two types of mutations were associated with clonal expansion and involved large areas of mucosa. The α mutations occurred at low frequencies while the β mutations increased in frequency with disease progression. Modeling revealed that bladder carcinogenesis spans 10-15 years and can be divided into dormant and progressive phases. The progressive phase lasted 1-2 years and was driven by β mutations.

| S-EPMC9209726 | biostudies-literature

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