title: Comparative methylome analysis identifies new tumour subtypes and biomarkers for transformation of nephrogenic rests into Wilms tumour.
abstract: 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.
authors.affiliation: UCL Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH UK.
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Charlton
authors.affiliation: UCL Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH UK.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Williams
authors.affiliation: UCL Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH UK.
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Sebire
authors.affiliation: The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG UK.
authors.forename: Sergey
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authors.lastname: Popov
authors.affiliation: Department of Pathology, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN UK.
authors.forename: Gordan
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authors.lastname: Vujanic
authors.affiliation: UCL Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH UK.
authors.forename: Tasnim
authors.initials: T
authors.lastname: Chagtai
authors.affiliation: UCL Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH UK.
authors.forename: Marisa
authors.initials: M
authors.lastname: Alcaide-German
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT UK.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Morris
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT UK.
authors.forename: Lee M
authors.initials: LM
authors.lastname: Butcher
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Guilhamon
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London, WC1E 6BT UK.
authors.forename: Stephan
authors.initials: S
authors.lastname: Beck
authors.affiliation: UCL Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH UK.
authors.forename: Kathy
authors.initials: K
authors.lastname: Pritchard-Jones