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Cell Rep. 2019 Feb 19;26(8):2241-2256.e4. doi: 10.1016/j.celrep.2019.01.095.

Whole-Organ Genomic Characterization of Mucosal Field Effects Initiating Bladder Carcinogenesis.

Author information

1
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
2
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
3
Fels Institute for Cancer Research and Molecular Biology, Temple University, Philadelphia, PA, USA.
4
Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD, USA.
5
Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
6
Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
7
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
8
Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA.
9
Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
10
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: kabagger@mdanderson.org.
11
Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD, USA. Electronic address: dmcconk1@jhmi.edu.
12
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: bczernia@mdanderson.org.

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.

KEYWORDS:

DNA copy alterations; DNA methylation; Whole-organ map; bladder cancer; clonal expansion; clonal origins; field effect; founder mutation; gene signature; urothelial carcinoma

PMID:
30784602
DOI:
10.1016/j.celrep.2019.01.095
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