| Literature DB >> 30784602 |
Tadeusz Majewski1, Hui Yao2, Jolanta Bondaruk1, Woonbok Chung3, Sangkyou Lee1, June Goo Lee1, Shizhen Zhang1, David Cogdell1, Guoliang Yang1, Woonyoung Choi4, Colin Dinney5, H Barton Grossman5, Christopher Logothetis6, Steven E Scherer7, Charles C Guo1, Li Zhang8, Peng Wei9, John N Weinstein2, Jean-Pierre Issa3, Keith Baggerly10, David J McConkey11, Bogdan Czerniak12.
Abstract
We used whole-organ mapping to study the locoregional molecular changes in a human bladder containing multifocal cancer. Widespread DNA methylation changes were identified in the entire mucosa, representing the initial field effect. The field effect was associated with subclonal low-allele frequency mutations and a small number of DNA copy alterations. A founder mutation in the RNA splicing gene, ACIN1, was identified in normal mucosa and expanded clonally with an additional 21 mutations in progression to carcinoma. The patterns of mutations and copy number changes in carcinoma in situ and foci of carcinoma were almost identical, confirming their clonal origins. The pathways affected by the DNA copy alterations and mutations, including the Kras pathway, were preceded by the field changes in DNA methylation, suggesting that they reinforced mechanisms that had already been initiated by methylation. The results demonstrate that DNA methylation can serve as the initiator of bladder carcinogenesis.Entities:
Keywords: DNA copy alterations; DNA methylation; Whole-organ map; bladder cancer; clonal expansion; clonal origins; field effect; founder mutation; gene signature; urothelial carcinoma
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Year: 2019 PMID： 30784602 DOI： 10.1016/j.celrep.2019.01.095
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423