Abstract 3755: DNA methylation patterns, but not genetic sequence alterations, are concordant across multiply sampled sites within individuals with unilateral and bilateral Wilms tumors

Abstract

Abstract Wilms tumor, the most common renal malignancy of childhood, is a disease marked by heterogeneity. One tumor can harbor multiple histologic subtypes and multifocal or bilateral disease is common occurring in up to 10% of patients. Several molecular features have been associated with Wilms tumors and some are used for risk stratification. However, it is unclear which, if any, features are consistent throughout a single tumor or shared between tumors in cases of bilateral disease. To answer this question, we generated genomic and epigenomic data from multiply sampled Wilms tumors from 10 patients - 3 with unilateral disease and 7 with bilateral disease. Multiple samples from each tumor as well as matched normal tissues were included when available. All tumors and matched normal tissues had DNA methylation array data available. Segmental chromosomal aberrations (SCAs) were inferred from methylation array data. Sequencing data were available for all bilateral patients but not for unilateral patients. We found that SCAs were discordant both between pairs of bilateral tumors and within multiply sampled unilateral tumors. This discordance included SCAs used for clinical risk stratification (chromosome 1q gain, 1p loss). Sequence variants were also rarely shared between pairs of bilateral tumors. On the other hand, DNA methylation patterns were concordant across all samples for each individual. We previously described 3 distinct DNA methylation patterns in Wilms tumors and found that all samples from each patient classified into the same subgroup. Furthermore, DNA methylation at Wilms tumor-specific and subgroup-specific differentially methylated regions had high (>0.8) correlation in all samples from all cases. Our data demonstrate that, in contrast to genomic changes such as SCAs and sequence alterations, DNA methylation patterns in Wilms tumors are frequently shared between paired tumors in bilateral disease and in multiple regions within individual tumors. This is consistent with earlier studies demonstrating that gain of methylation at the H19 imprinted region is often the earliest event in Wilms tumors and in some cases likely occurs in the embryonic intermediate mesoderm prior to the development of individual kidneys. Our findings demonstrate the utility of Wilms tumor DNA methylation patterns in overcoming tumor heterogeneity for risk stratification in cases of bilateral or multifocal Wilms tumors. Citation Format: Jack Brzezinski, Sanaa Choufani, Cheryl Shuman, Rodrigo Romao, Armando Lorenzo, Rosanna Weksberg. DNA methylation patterns, but not genetic sequence alterations, are concordant across multiply sampled sites within individuals with unilateral and bilateral Wilms tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3755.