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

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.

Authors: Tadeusz Majewski,¹ Hui Yao, ² Jolanta Bondaruk,¹ Woonbok Chung, ³ Sangkyou Lee, ¹ June Goo Lee, ¹ Shizhen Zhang, ¹ David Cogdell, ¹ Guoliang Yang, ¹ Woonyoung Choi, ⁹ Colin Dinney, ⁴ H. Barton Grossman, ⁴ Christopher Logothetis, ⁵ Steven E. Scherer, ⁶ Charles C. Guo, ¹ Li Zhang, ⁷ Peng Wei, ⁸ John N. Weinstein, ² Jean-Pierre Issa, ³ Keith Baggerly, ², David J. McConkey,⁹, and Bogdan Czerniak ¹

Author Affiliations:
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. Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
5. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
6. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
7. Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA
8. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
9. Johns Hopkins Greenberg Bladder Cancer Institute, Johns Hopkins University, Baltimore, MD, USA

Read an Expert Commentary by Bishoy Faltas, MD

Majewski et al., 2019, Cell Reports 26, 2241–2256 February 19, 2019 ª 2019 The Author(s). https://doi.org/10.1016/j.celrep.2019.01.095

Login