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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146870 | GEO | 2020/03/13

REPOSITORIES: GEO

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Project description:We assessed DNA methylation and copy number status of 27,000 CpGs in 149 urothelial carcinomas and integrated the findings with gene expression and mutation data. Methylation was associated with gene expression for 1,332 CpGs, of which 26% showed positive correlation with expression, i.e., high methylation and high gene expression levels. These positively correlated CpGs were part of specific transcription factor binding sites, such as sites for MYC and CREBP1, or located in gene bodies. Furthermore, we found genes with copy number gains, low expression and high methylation levels, revealing an association between methylation and copy number levels. This phenomenon was typically observed for developmental genes, such as HOX genes and tumor suppressor genes. In contrast, we also identified genes with copy number gains, high expression and low methylation levels. This was for instance observed for some keratin genes. Tumor cases could be grouped into four subgroups, termed epitypes, by their DNA methylation profiles. One epitype was influenced by the presence of infiltrating immune cells, two epitypes were mainly composed of non-muscle invasive tumors, and the remaining epitype of muscle invasive tumors. The polycomb complex protein EZH2 that blocks differentiation in embryonic stem cells showed increased expression both at the mRNA and protein levels in the muscle invasive epitype, together with methylation of polycomb target genes and HOX genes. Our data highlights HOX gene silencing and EZH2 expression as mechanisms to promote a more undifferentiated and aggressive state in UC. The study was conducted on genomic DNA from 150 primary fresh-frozen urothelial carcinoma tumors selected to have equal representation of stages Ta, T1 and T2>. The design also included four fully methylated and four unmethylated hybridization controls as well as 7 Normal urothelium samples. One tumor sample (UC_0556_1) was included as a technical replicate in each of four bisulfite treatment batches. The samples were bisulfite treated and hybridized to Illumina Human Methylation27 Bead Chip arrays according to manufacturers instructions at the SCIBLU Genomics Centre at Lund University, Sweden. Note: Illumina methylation data set comprises total of 168 samples (raw data), but 156 samples (processed data), derived from primary urothelial carcinoma samples. See README.txt for details of the 12 samples not included in the final, processed data.

Project description:Peroxisome Proliferator-Activated Receptor-gamma (PPARG) is a nuclear hormone receptor that was originally described as a master regulator of adipogenesis but could also promote cellular differentiation in a number of epithelium. PPARG also serves as an important regulator in anti-inflammatory activity after a variety of injuries, acting in part by antagonizing the NF-kB pathway. Moreover, the expression of PPARG is strongly down regulated in the basal subtype of bladder cancer, suggesting that its removal might be essential in tumorigenesis. In urothelial cells, it has been shown that PPARG promotes urothelial differentiation in vitro, but its function in vivo remains unexplored. The urothelium is a stratified epithelium that serves as a barrier between the urinary tract and blood. It consists of terminally differentiated umbrella cells, intermediate cells which serve as umbrella cell progenitors; and unipotent basal cells. To determine the role of PPARG in vivo, we used Cre-Lox recombination to conditionally delete the Pparg gene in the mouse urothelium using the ShhCre driver, which drives recombination in basal and intermediate cells, and their respective daughters. Interestingly, ShhCre;Ppargfl/fl mutants lack umbrella and intermediate cells, but have an abnormal cell population negative for classical urothelial markers instead. Furthermore, we observed an increase of KRT14+ population in the basal compartment and squamous features in the mutant urothelium. Expression profile analysis suggested PPARG regulates metabolism, urothelial differentiation and innate immune response. We further challenged the Pparg mutant urothelium with acute injury. In wild type animals, urinary tract infection (UTI) with uropathogenic E.coli results in a transient innate immune response, followed by a completed regernation within 2 weeks. When ShhCre;Ppargfl/fl mutants were challenged with urinary tract infection, the innate immune response was not resolved even after several weeks and the Pparg ablated urothelium exhibited squamous metaplasia. RNAseq data suggested that PPARG plays a role in regulating squmous differentiation and NFkB signial pathway. Together these findings suggest that PPARG is essential for the normal differentiation of the urothelium and is a potent regulator of the inflammatory response after UTI. Understanding the link between the loss of PPARG, chronic inflammation and tumorigenesis in the urothelium could shed light on the urothelial differentiation network and pave the way for the development of therapeutic approaches to various urinary diseases.

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

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