Pritchard-Jones, K. | bioRxiv Science

bioRxiv2024

Subtype-specific Patterns of Evolution and Clinically Relevant Genomic Instability in Wilms Tumour

BackgroundUnderstanding cancer evolution is fundamental to predicting cancer progression. However, the evolution of paediatric cancers is still under-researched. Large cohorts of patients are required to determine consistent evolutionary trajectories that shed light on key steps in cancer development and reveal underlying biology, especially in rare cancers. Additionally, well annotated clinical data is necessary for determining if evolutionary biomarkers are predictive of patient outcome. MethodsWe performed detailed evolutionary analysis of 64 paediatric kidney cancers, including 60 Wilms tumours (WT), using DNA microarrays and, in a subset of 30 patients, a WT-specific targeted sequencing assay, to detect copy number alterations (CNA) and mutations, respectively. By analysing multiple tissue samples in the majority of cases we could detect mutation heterogeneity in each tumour. We reconstructed clones across the cohort and described their phylogenetic histories, in addition to detecting mirrored subclonal allelic imbalance. ResultsOur results highlight pervasive evidence of parallel evolution in WTs affecting CNAs, and CTNNB1 and TP53 mutations. Furthermore, we demonstrate that stromal-type WTs often evolve from a consistent series of events (WT1 mutation, 11p uniparental disomy and CTNNB1 mutation) and we suggest that 19q uniparental disomy is an important ancestral event in both epithelial and diffuse anaplastic WTs. Finally, we propose the total number of evolutionary CNA events as a prognostic biomarker in WTs for event-free survival, particularly in high-risk WT. ConclusionsOverall, this study sheds light on the evolution of the most common paediatric kidney cancer and links evolutionary analysis to fundamental clinical and biological questions in a large cohort of WTs. We conclude that histological subtypes of WT are often defined by consistent evolutionary sequences. We present evidence that a key marker of evolvability, namely CNA diversity measured phylogenetically across multiple tumour sites, is prognostic of patient outcome and should be considered for clinical use to detect the most aggressive blastemal and diffuse anaplastic type WTs.

cancer biology↗

bioRxiv2020

The epithelial splicing regulator ESRP2 is epigenetically repressed by DNA hypermethylation in Wilms tumour and acts as a tumour suppressor

Wilms tumour (WT), a childhood kidney cancer with embryonal origins, has been extensively characterised for genetic and epigenetic alterations, but a proportion of WTs still lack identifiable abnormalities. To uncover DNA methylation changes critical for WT pathogenesis, we compared the epigenome of fetal kidney with two WT cell lines, using methyl-CpG immunoprecipitation. We filtered our results to remove common cancer-associated epigenetic changes, and to enrich for genes involved in early kidney development. This identified four candidate genes that were hypermethylated in WT cell lines compared to fetal kidney, of which ESRP2 (epithelial splicing regulatory protein 2), was the most promising gene for further study. ESRP2 was commonly repressed by DNA methylation in WT, and this was shown to occur early in WT development (in nephrogenic rests). ESRP2 expression could be reactivated by DNA methyltransferase inhibition in WT cell lines. When ESRP2 was overexpressed in WT cell lines, it acted as an inhibitor of cellular proliferation in vitro, and in vivo it suppressed tumour growth of orthotopic xenografts in nude mice. RNA-seq of the ESRP2-expressing WT cell lines identified several novel splicing targets, in addition to well-characterised targets of ESRP2. We propose a model in which the mesenchymal to epithelial transition that is essential for early kidney development, can be disrupted in to generate WT, either by genetic abnormalities such as WT1 mutations, or by epigenetic defects, such as ESRP2 methylation.

cancer biology↗