Comparative methylome analysis identifies new tumour subtypes and biomarkers for transformation of nephrogenic rests into Wilms tumour
| Autor: | Marisa Alcaide-German, Stephan Beck, Neil J. Sebire, Tasnim Chagtai, Jocelyn Charlton, Paul Guilhamon, Richard D. Williams, Kathy Pritchard-Jones, Tiffany Morris, Lee M. Butcher, Gordan M. Vujanic, Sergey Popov |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Pathology
medicine.medical_specialty Biology 03 medical and health sciences 0302 clinical medicine Gene expression medicine Genetics Genetics(clinical) Gene Molecular Biology Genetics (clinical) 030304 developmental biology 0303 health sciences Research fungi Methylation Embryonic Tissue Human genetics 3. Good health Differentially methylated regions TSPAN32 030220 oncology & carcinogenesis DNA methylation Cancer research Molecular Medicine |
| Zdroj: | Genome Medicine |
| ISSN: | 1756-994X |
| Popis: | Background Wilms tumours (WTs) are characterised by several hallmarks that suggest epimutations such as aberrant DNA methylation are involved in tumour progression: loss of imprinting at 11p15, lack of recurrent mutations and formation of nephrogenic rests (NRs), which are lesions of retained undifferentiated embryonic tissue that can give rise to WTs. Methods To identify such epimutations, we performed a comprehensive methylome analysis on 20 matched trios of micro-dissected WTs, NRs and surrounding normal kidneys (NKs) using Illumina Infinium HumanMethylation450 Bead Chips and functionally validated findings using RNA sequencing. Results Comparison of NRs with NK revealed prominent tissue biomarkers: 629 differentially methylated regions, of which 55% were hypermethylated and enriched for domains that are bivalent in embryonic stem cells and for genes expressed during development (P = 2.49 × 10-5). Comparison of WTs with NRs revealed two WT subgroups; group-2 WTs and NRs were epigenetically indistinguishable whereas group-1 WTs showed an increase in methylation variability, hypomethylation of renal development genes, hypermethylation and relative loss of expression of cell adhesion genes and known and potential new WT tumour suppressor genes (CASP8, H19, MIR195, RB1 and TSPAN32) and was strongly associated with bilateral disease (P = 0.032). Comparison of WTs and NRs to embryonic kidney highlighted the significance of polycomb target methylation in Wilms tumourigenesis. Conclusions Methylation levels vary during cancer evolution. We have described biomarkers related to WT evolution from its precursor NRs which may be useful to differentiate between these tissues for patients with bilateral disease. Electronic supplementary material The online version of this article (doi:10.1186/s13073-015-0136-4) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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