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

Brzezinski, Jack; Choufani, Sanaa; Romao, Rodrigo; Shuman, Cheryl; Chen, Haiying; Cunanan, Joanna; Bägli, Darius; Grant, Ronald; Lorenzo, Armando J.; Weksberg, Rosanna

doi:10.1038/s41416-020-01102-1

Cited by 15 publications

(21 citation statements)

References 48 publications

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“…HOXA5 is a tumor suppressor gene dysregulated in expression and methylation in several types of cancer [ 39 ]. Our DNAm studies in Wilms tumor tissues identified hypermethylation of HOXA5 CpG sites [ 40 , 41 ]. This finding is of interest since BOS individuals appear to have an increased risk for Wilms tumor [ 4 ].…”

Section: Discussionmentioning

confidence: 99%

DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes

et al. 2022

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The additional sex combs-like (ASXL) gene family—encoded by ASXL1, ASXL2, and ASXL3—is crucial for mammalian development. Pathogenic variants in the ASXL gene family are associated with three phenotypically distinct neurodevelopmental syndromes. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show consistent patterns of genome-wide DNA methylation (DNAm) alterations, i.e., DNAm signatures in peripheral blood. Given the role of ASXL1 in chromatin modification, we hypothesized that pathogenic ASXL1 variants underlying Bohring-Opitz syndrome (BOS) have a unique DNAm signature. We profiled whole-blood DNAm for 17 ASXL1 variants, and 35 sex- and age-matched typically developing individuals, using Illumina’s Infinium EPIC array. We identified 763 differentially methylated CpG sites in individuals with BOS. Differentially methylated sites overlapped 323 unique genes, including HOXA5 and HOXB4, supporting the functional relevance of DNAm signatures. We used a machine-learning classification model based on the BOS DNAm signature to classify variants of uncertain significance in ASXL1, as well as pathogenic ASXL2 and ASXL3 variants. The DNAm profile of one individual with the ASXL2 variant was BOS-like, whereas the DNAm profiles of three individuals with ASXL3 variants were control-like. We also used Horvath’s epigenetic clock, which showed acceleration in DNAm age in individuals with pathogenic ASXL1 variants, and the individual with the pathogenic ASXL2 variant, but not in individuals with ASXL3 variants. These studies enhance our understanding of the epigenetic dysregulation underpinning ASXL gene family-associated syndromes.

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Section: Discussionmentioning

confidence: 99%

DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes

et al. 2022

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“…Recently, Brzezinski et al observed that TRIM28‐ mutated tumours belong to a subgroup of WT with genome‐wide dysregulation of DNA methylation [22] and display a very distinct and recognizable DNA methylation pattern (Brzezinski, personal communication).…”

Section: Trim28 Variants In Patients With Wtmentioning

confidence: 99%

“…Additionally, global hypomethylation of TEs has been associated with genomic instability in various adult cancer types [51]. Although WTs generally harbour few mutations or copy number changes compared with adult cancer, TRIM28‐ mutated WTs were recently shown to be part of a subgroup of WTs which are less stable genomically [22].…”

Section: Biological Functions Of Trim28mentioning

confidence: 99%

TRIM28 variants and Wilms' tumour predisposition

Hol

Diets

Krijger

et al. 2021

The Journal of Pathology

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TRIM28 was recently identified as a Wilms' tumour (WT) predisposition gene, with germline pathogenic variants identified in around 1% of isolated and 8% of familial WT cases. TRIM28 variants are associated with epithelial WT, but the presence of other tumour components or anaplasia does not exclude the presence of a germline or somatic TRIM28 variant. In children with WT, TRIM28 acts as a classical tumour suppressor gene, with both alleles generally disrupted in the tumour. Therefore, loss of TRIM28 (KAP1/TIF1beta) protein expression in tumour tissue by immunohistochemistry is an effective strategy to identify patients carrying pathogenic TRIM28 variants. TRIM28 is a ubiquitously expressed corepressor that binds transcription factors in a context‐, species‐, and cell‐type‐specific manner to control the expression of genes and transposable elements during embryogenesis and cellular differentiation. In this review, we describe the inheritance patterns, histopathological and clinical features of TRIM28‐associated WT, as well as potential underlying mechanisms of tumourigenesis during embryonic kidney development. Recognizing germline TRIM28 variants in patients with WT can enable counselling, genetic testing, and potential early detection of WT in other children in the family. A further exploration of TRIM28‐associated WT will help to unravel the diverse and complex mechanisms underlying WT development. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

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“…Moreover, patients who present with the genome-wide dysregulation of DNA methylation have been associated with high-risk histology tumors and the occurrence of relapse (Foster et al, 2021), indicating that abnormal DNA methylation, either alone or in combination with the existing surveillance methods, may serve as a potential epigenetic biomarker or therapeutic target for WT patients. Currently, CpG sites that have been shown to be associated with potential WT pathogenesis include Wilms tumor 1 (WT1) (Brzezinski et al, 2021), WTX (Pelletier et al, 1991), TP53 (Rivera et al, 2007), and 11p15 (Andrade et al, 2014), and the methylation of some of these genes can be detected in peripheral blood (Fiala et al, 2020). In recent studies, methylation patterns have been studied and recommended as a potential method for disease classification and prognostic assessment.…”

Section: Discussionmentioning

confidence: 99%

“…To date, DNA methylation has been demonstrated to be involved in the pathogenesis of many diseases, including tumor development. Previous studies have shown that genome-wide dysregulation of DNA methylation is associated with WT patients who display high-risk histology (Brzezinski et al, 2021). The early and prevalent events in WT are associated with DNA methylation changes affected many common cellular functions, most of which are involved in the epigenetic regulation of early renal development or transcription.…”

Section: Introductionmentioning

confidence: 99%

DNA Methylation Data-Based Classification and Identification of Prognostic Signature of Children With Wilms Tumor

Tang

Lei

et al. 2021

Front. Cell Dev. Biol.

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Background: As an epigenetic alteration, DNA methylation plays an important role in early Wilms tumorigenesis and is possibly used as marker to improve the diagnosis and classification of tumor heterogeneity.Methods: Methylation data, RNA-sequencing (RNA-seq) data, and corresponding clinical information were downloaded from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) database. The prognostic values of DNA methylation subtypes in Wilms tumor were identified.Results: Four prognostic subtypes of Wilms tumor patients were identified by consensus cluster analysis performed on 312 independent prognostic CpG sites. Cluster one showed the best prognosis, whereas Cluster two represented the worst prognosis. Unique CpG sites identified in Cluster one that were not identified in other subtypes were assessed to construct a prognostic signature. The prognostic methylation risk score was closely related to prognosis, and the area under the curve (AUC) was 0.802. Furthermore, the risk score based on prognostic signature was identified as an independent prognostic factor for Wilms tumor in univariate and multivariate Cox regression analyses. Finally, the abundance of B cell infiltration was higher in the low-risk group than in the high-risk group, based on the methylation data.Conclusion: Collectively, we divided Wilms tumor cases into four prognostic subtypes, which could efficiently identify high-risk Wilms tumor patients. Prognostic methylation risk scores that were significantly associated with the adverse clinical outcomes were established, and this prognostic signature was able to predict the prognosis of Wilms tumor in children, which may be useful in guiding clinicians in therapeutic decision-making. Further independent studies are needed to validate and advance this hypothesis.

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

Cited by 15 publications

References 48 publications

DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes

DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes

TRIM28 variants and Wilms' tumour predisposition

DNA Methylation Data-Based Classification and Identification of Prognostic Signature of Children With Wilms Tumor

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