Clinically and biologically relevant subgroups of Wilms tumour defined by genomic and epigenomic analyses

Br J Cancer. 2021 Jan;124(2):437-446. doi: 10.1038/s41416-020-01102-1. Epub 2020 Oct 5.

Abstract

Background: Although cure rates for Wilms tumours (WT) are high, many patients receive therapy with attendant long-term complications. Our goal was to stratify WT using genome-wide analyses to identify candidate molecular features for patients who would benefit from a reduction in therapy.

Methods: We generated DNA methylation and exome sequencing data on WT-kidney pairs (n = 57) and unpaired tumours (n = 27) collected either at our centre or by the Children's Oncology Group. Samples were divided into a discovery set (n = 32) and validation set (n = 52).

Results: Analysis of DNA methylation revealed two subgroups of WT with distinct features. Subgroup A has a similar DNA methylation profile to mature kidney, while Subgroup B has genome-wide dysregulation of DNA methylation. The rate of non-synonymous missense mutations and segmental chromosomal aberrations was higher in Subgroup B tumours, suggesting that this group has genome instability related to its epigenetic state. Subgroup A had a higher proportion of cases of bilateral disease. Tumours with high-risk histology or from patients who relapsed were only found in Subgroup B.

Conclusion: We have identified subgroup-specific molecular events that could inform future work supporting more targeted therapeutic approaches and patient stratification. We propose a novel developmental tumour model based on these findings.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Child
  • Chromosome Aberrations
  • DNA Methylation / genetics
  • Female
  • Gene Expression Profiling / methods
  • Genes, Wilms Tumor
  • Humans
  • Kidney Neoplasms / classification
  • Kidney Neoplasms / genetics*
  • Male
  • Mutation
  • Whole Exome Sequencing
  • Wilms Tumor / classification
  • Wilms Tumor / genetics*