Understanding the Field Effects Which Initiate Bladder Carcinogenesis - Expert Commentary

Bladder cancer is a ‘field’ disease in which early-events occurring in morphologically-normal urothelium eventually give rise to urothelial carcinoma. A recent study published in Cell Reports by Majewski et al. examined the field defects that lead to urothelial carcinoma. The investigators performed whole-organ genomic and epigenetic mapping to identify the changes that occur in the urothelium and ultimately lead to the development of urothelial carcinoma. 

Interestingly, they identified widespread DNA methylation changes that occur at an early stage. The investigators also found a small number of DNA copy number alterations that preceded the development of urothelial carcinoma. In the patient featured in the paper, a founder mutation in the gene ACIN1, which is involved in RNA splicing, was found in the normal mucosa. This mutation continued to expand clonally and was accompanied by the development of other mutations that accumulated during the progression to urothelial carcinoma. 

These interesting findings are consistent with the previous studies that show high degrees of sub-clonal heterogeneity in advanced urothelial cancer. A deeper understanding of the field defects that precede the development of urothelial carcinoma is critical for developing strategies for early prevention. As the authors point out, several biomarker panels that include methylation markers are being developed. If these early-stage methylation defects are common in a significant number of urothelial carcinoma patients, this approach could hold promise for the early detection of field changes that pave the way to the development of urothelial carcinoma.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine

1. Majewski T, et al. Whole-Organ Genomic Characterization of Mucosal Field Effects Initiating Bladder Cell Rep. 2019 Feb 19;26(8):2241-2256.e4. doi: 10.1016/j.celrep.2019.01.095.
2. Faltas BM, Prandi D, Tagawa ST, Molina AM, Nanus DM, Sternberg C, Rosenberg J, Mosquera JM, Robinson B, Elemento O, Sboner A, Beltran H, Demichelis F, Rubin MA. Clonal evolution of chemotherapy-resistant urothelial carcinoma. Nat Genet. 2016 Dec;48(12):1490-1499. doi: 10.1038/ng.3692. Epub 2016 Oct 17.

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