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

Author:

Brzezinski Jack,Choufani Sanaa,Romao Rodrigo,Shuman Cheryl,Chen Haiying,Cunanan Joanna,Bagli Darius,Grant Ronald,Lorenzo Armando,Weksberg RosannaORCID

Abstract

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.

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology

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