Recurring urothelial carcinomas show genomic rearrangements incompatible with a direct relationship, implications for tumor development.

We made use of the fact that patients with non-muscle invasive tumors show frequent local recurrences and multiple tumors to study re-initiation of tumor growth from the same urothelium. By extensive genomic analyses we show that tumors from the same patient are clonal. We show that gross genomic chromosomal aberrations may appear abruptly and disappear with no transitional stages being observed. By analysis of incompatible changes i.e., genomic alterations that cannot be reversed, we show that almost all tumors from a single patient show such changes, thus the tumors cannot have originated from each other. As recurrent tumors share both genomic alterations and driver gene mutations, these must have been present in the histologically normal urothelium in periods with no tumor growth. We present a model that includes a growing and genomically evolving field of urothelial cells that occasionally, and locally, produce bursts of cellular growth leading to overt tumors. This gene expression data was used to check the molecular subtypes based on Lund taxonomy (LundTax) in the recurring urothelial carcinomas. Total RNA from fresh-frozen resection samples of urothelial carcinomas was hybridized to the Illumina HumanHT-12 V3.0/V4.0 expression beadchip arrays (Illumina Inc) at the SCIBLU Genomics Centre at Lund University Sweden (http://www.lth.se/sciblu).