Abstract B04: Three distinct subgroups of Wilms’ tumors with novel molecular features and important clinical implications are defined by genome-wide DNA methylation profiles

Abstract Introduction: Wilms’ tumor (WT) is the most common childhood renal cancer. Although many children are cured with standard therapy, survivors frequently suffer chronic diseases as a result of their treatment. Historical evidence suggests that a number of children could be cured with surgery alone; however, many of these children are currently difficult to identify. Although the majority of mutations described in this disease are not prognostic, the commonest single molecular alteration in WT is epigenetic—loss of imprinting at chromosome 11p15. We therefore examined genome-wide patterns of DNA methylation in WTs to identify groups of patients with low risk of relapse. Methods: We enrolled two cohorts of patients: a discovery cohort consisting of 32 tumors and 21 matched kidneys was recruited at the time of surgery at our hospital. A validation cohort included 40 tumor-normal pairs from the Children’s Oncology Group (COG) biobank and an additional 11 pairs from our hospital. All samples had genome-wide DNA methylation and copy number variation data generated. The samples from COG additionally had whole-exome sequencing while 22 local tumors had RNA sequencing. Results: Unsupervised clustering of DNA methylation data demonstrated three DNA methylation subgroups that could be reproduced in the validation cohort using a “signature” of selected differentially methylated sites. One group (“PRO”) had genome-wide loss of methylation with specific gain of methylation at renal development genes and tumor-suppressor genes. This group also had increased expression of genes related to cell proliferation. Mutations in microRNA processing genes were found exclusively in this group and were associated with dysregulation of microRNA expression. All known cases of relapse were found in this group. A second group (“DIFF”) had a DNA methylation profile similar to normal kidney, no copy number alterations, reduced expression of genes associated with early renal development, and mutations only in WT1 or CTNNB1. No relapses were known in this group, but there was an increased incidence of bilateral disease. A third group (“INT”) had intermediate methylation values at all signature sites, a gene expression profile similar to the DIFF group, and increased microRNA dysregulation. All tumors in the INT group had either mutations in TRIM28, epithelial histology, or both. Discussion: Genome-wide DNA methylation profiling demonstrates three subgroups of WT with distinct molecular and clinical characteristics. The DIFF group has molecular features consistent with a differentiation process occurring. These patients may be candidates for therapy reduction. The INT group suggests that some patients with wild-type TRIM28 share features with tumors with mutations in the gene—known to be associated with low risk of relapse. This group may also be a candidate for therapy reduction. We are now investigating the features that drive increased proliferation in the PRO group as these may be targets of future therapy for these higher-risk patients. Citation Format: Jack Brzezinski, Sanaa Choufani, Rodrigo Romao, Cheryl Shuman, Haiying Chen, Ronald Grant, Armando Lorenzo, Rosanna Weksberg. Three distinct subgroups of Wilms’ tumors with novel molecular features and important clinical implications are defined by genome-wide DNA methylation profiles [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B04.

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