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• W3163954519 abstract "We developed a whole organ mapping approach that combines microscopic histological assessment of the entire mucosal membrane of the bladder with comprehensive genomic profiling. We used the approach to study the locoregional molecular changes in a human bladder containing multi-focal cancer. Uniform and widespread DNA methylation changes were identified in almost the entire mucosa representing the initial field effect. The field effect was associated with sub-clonal low allele frequency mutations and a small numer of uniform DNA copy number alterations that were typically restricted to small areas. An inactivating founder mutation in the pro-apoptotic and RNA splicing gene, ACIN1, was identified in normal appearing mucosa and expanded clonally with an additional 21 mutations in the development of in situ precursor lesions, and progression to carcinoma. The patterns of mutations and copy number changes in carcinoma in situ and several foci of carcinoma were almost identical, confirming their clonal origins. Importantly, the pathways affected by the CNVs and DNA mutations, including the Kras pathway, appeared to be preceded by the field changes in DNA methylation, suggesting that the DNA-based changes reinforced mechanisms that had already been initiated by methylation. Overall, the results demonstrate that field changes in DNA methylation can serve as the initiators of carcinogenesis in the bladder." @default.
• W3163954519 created "2021-06-07" @default.
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• W3163954519 date "2018-01-01" @default.
• W3163954519 modified "2023-09-30" @default.
• W3163954519 title "Whole-organ Genomic Characterization of Mucosal Field Effects Initiating Bladder Carcinogenesis" @default.
• W3163954519 doi "https://doi.org/10.2139/ssrn.3188428" @default.
• W3163954519 hasPublicationYear "2018" @default.
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