Abstract B36: DNA methylation profiling describes Wilms tumor evolution from its precursor lesion

Abstract

Abstract Wilms tumor (WT) is the most common pediatric renal cancer and represents a model of disruption in kidney development with observed lesions of undifferentiated embryonic kidney termed nephrogenic rests (NR) which are considered precursor lesions. Epigenetic dysregulation plays a large part in Wilms tumorigenesis as dysregulation of IGF2/H19 is the most common aberration observed in ~70% WT. To provide new insights into the molecular evolution of WT from its precursor lesions, genome-wide CpG methylation, which has frequently been shown to alter gene expression in cancer, was studied using the Illumina HumanMethylation 450 BeadChip array. Matched normal kidney (NK), NR and WT were sampled from 30 patient nephrectomies. To ensure precise microdissection, DNA was extracted from formalin-fixed paraffin embedded tissue after histological analysis. Analysis of methylation β-values revealed an increase in methylation variability in both the NR and WT tissue. Linear modeling further supported the role of NR as a precursor lesion however showed that, although morphologically similar to embryonic kidney, the NR tissue is a unique entity. Furthermore, drastic epigenetic restructuring is observed in NR tissue including large regions of hyper- and hypomethylation previously associated with cancer tissue. This novel data suggests the NR has a cancer-like methylome. Further changes in DNA methylation were observed upon evolution of NR to WT. These ‘late event' methylation variable positions have the potential to be developed into an assay for differential detection of NR or WT in diagnostically challenging cases. These results lead us to propose that during Wilms tumorigenesis, NR are prevented from completing nephrogenesis and continue divergent evolution into a separate entity distinct from the embryonic kidney. These NR are precancerous lesions that then evolve into WT. Citation Format: Jocelyn Charlton, Richard Williams, Marisa Alcaide-German, Neil Sebire, Sergey Popov, Kathy Pritchard-Jones, Stephan Beck. DNA methylation profiling describes Wilms tumor evolution from its precursor lesion. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr B36.