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DNA methylation and transcriptomic profiles of Wilms tumour reveal new deregulated genes and epigenetic processes relevant for tumour stratification and management

ABSTRACT: Wilms tumour (WT), the most common kidney cancer in children, presents features of altered kidney development and frequently exhibits molecular alterations at the 11p15.5 imprinted locus, affecting the IGF2 and H19 genes, which contribute to tumour growth and may also act as predisposing events that require additional hits for tumour initiation. The epigenetic landscape beyond 11p15.5 suggests diagnostic and prognostic potential, but its link to transcriptomic changes is largely unexplored. We integrated methylomic and transcriptomic datasets of 27 primary tumours and matched non-neoplastic kidneys. DNA methylation profiling identified around 9,000 differentially methylated CpG sites distinguishing neoplastic from non-neoplastic tissue and other pediatric cancers, thus representing a novel WT-specific epigenetic signature. We found that cases with Imprinting Centre 1 (IC1) gain of methylation exhibited the most extensive epigenetic alterations, LOH tumours showed intermediate changes, whereas regressive tumours with largely normal 11p15.5 status displayed limited methylation abnormalities. Three methylation clusters corresponding to transcriptomic subtypes were identified, characterised by distinct tumour microenvironment and chemosensitivity predictions: a regressive-enriched group with high immune infiltration and predicted susceptibility to paclitaxel, a proliferative group with high tumour purity and predicted sensitivity to doxorubicin, and a stromal-like group with intermediate predicted sensitivity to both drugs. Combined analysis of methylation and expression data revealed more than 900 genes under epigenetic control, which contributed to defining the WT subtypes. Analysis of the IGF2/H19 locus uncovered multiple regulatory mechanisms underlying IGF2 activation, including imprinting defects at IC1, methylation changes at DMR0, differential promoter usage, and transcriptional modulation by PLAG1 and BAHD1. These findings define the epigenetic architecture of WT, encompassing genome-wide methylation changes, subtype-specific patterns, and their integration with gene expression, supporting stratification of cases for improved prognosis and therapeutic approaches.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303967 | GEO | 2026/06/23

REPOSITORIES: GEO

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Project description:Wilms tumour (WT), the most common kidney cancer in children, presents features of altered kidney development and frequently exhibits molecular alterations at the 11p15.5 imprinted locus, affecting the IGF2 and H19 genes, which contribute to tumour growth and may also act as predisposing events that require additional hits for tumour initiation. The epigenetic landscape beyond 11p15.5 suggests diagnostic and prognostic potential, but its link to transcriptomic changes is largely unexplored. We integrated methylomic and transcriptomic datasets of 27 primary tumours and matched non-neoplastic kidneys. DNA methylation profiling identified around 9,000 differentially methylated CpG sites distinguishing neoplastic from non-neoplastic tissue and other pediatric cancers, thus representing a novel WT-specific epigenetic signature. We found that cases with Imprinting Centre 1 (IC1) gain of methylation exhibited the most extensive epigenetic alterations, LOH tumours showed intermediate changes, whereas regressive tumours with largely normal 11p15.5 status displayed limited methylation abnormalities. Three methylation clusters corresponding to transcriptomic subtypes were identified, characterised by distinct tumour microenvironment and chemosensitivity predictions: a regressive-enriched group with high immune infiltration and predicted susceptibility to paclitaxel, a proliferative group with high tumour purity and predicted sensitivity to doxorubicin, and a stromal-like group with intermediate predicted sensitivity to both drugs. Combined analysis of methylation and expression data revealed more than 900 genes under epigenetic control, which contributed to defining the WT subtypes. Analysis of the IGF2/H19 locus uncovered multiple regulatory mechanisms underlying IGF2 activation, including imprinting defects at IC1, methylation changes at DMR0, differential promoter usage, and transcriptional modulation by PLAG1 and BAHD1. These findings define the epigenetic architecture of WT, encompassing genome-wide methylation changes, subtype-specific patterns, and their integration with gene expression, supporting stratification of cases for improved prognosis and therapeutic approaches.

Project description:Abstract: Dysregulation of the imprinted H19/IGF2 locus can lead to Silver-Russell Syndrome (SRS) in humans. However, the mechanism of how abnormal H19/IGF2 expression contributes to various SRS phenotypes remains unclear, largely due to incomplete understanding of the developmental functions of these two genes. We previously generated a mouse model with humanized H19/IGF2 ICR (hIC1) on the paternal allele that exhibited H19/Igf2 dysregulation together with SRS-like growth restriction and perinatal lethality. Here we dissect the role of H19 and Igf2 in cardiac and placental development utilizing multiple mouse models with varying levels of H19 and Igf2. We report severe cardiac defects such as ventricular septal defects (VSDs) and thinned myocardium, placental anomalies including thrombosis and vascular malformations, together with growth restriction in mouse embryos that correlated with the extent of H19/Igf2 dysregulation. Transcriptomic analysis using cardiac endothelial cells of these mouse models shows that H19/Igf2 dysregulation disrupts pathways related to extracellular matrix (ECM) and proliferation of endothelial cells. Our work links the heart and placenta through regulation by H19 and Igf2, demonstrating that accurate dosage of both H19 and Igf2 is critical for normal embryonic development, especially related to the cardiac-placental axis. Methods: E12.5 hearts were lysed with Collagenase, Dispase II, and DNase I. Cardiac endothelial cells were collected using MACS CD31 microbeads and RNA was isolated using RNeasy Micro kit. After confirming RNA integrity using Bioanalyzer, mRNA library was generated from 25ng RNA using NEBNext Poly(A) mRNA Magnetic Isolation Module and Ultra II RNA Library Prep Kit. Library quality was assessed by Bioanalyzer and TapeStation. Sequencing was performed on NovaSeq 6000. Quality of raw fastq reads was assessed using FastQC version 0.11.5. Reads were aligned to the GRCm38/mm10 reference using STAR version 2.4.0i with default parameters and maximum fragment size of 2000 bp. Properly paired primary alignments were retained for downstream analysis using Samtools version 1.9. Count matrices were generated using FeatureCounts version 1.6.2 against RefSeq gene annotation and read into DESeq2 to perform normalization and statistical analysis.

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DNA methylation and transcriptomic profiles of Wilms tumour reveal new deregulated genes and epigenetic processes relevant for tumour stratification and management

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