Genes Controlled by DNA Methylation Are Involved in Wilms Tumor Progression

Guerra, João Victor da Silva; Pereira, Bruna Maria de Sá; Cruz, Jéssica Gonçalves Vieira da; Scherer, Nicole de Miranda; Furtado, Carolina; Azevedo, Rafaela Montalvão de; Oliveira, Paulo Sérgio Lopes de; Faria, Paulo; Boroni, Mariana; Maschietto, Mariana

doi:10.3390/cells8080921

Cited by 14 publications

(10 citation statements)

References 62 publications

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“…We observed that the WT cases with epimutations at more than one imprinted chromosome region correspond to more advanced tumor stages and have more frequent metastases with respect to the cases with single-locus defects or normal imprinting, suggesting that multiple imprinting defects arise mostly during the late stages of tumorigenesis. Consistent with these data, it has been recently proposed that 44 genes controlled by DNA methylation, including multiple imprinted genes, can be a signature for metastasis formation in WT [20].…”

Section: Discussionsupporting

confidence: 56%

Both Epimutations and Chromosome Aberrations Affect Multiple Imprinted Loci in Aggressive Wilms Tumors

Pignata

Palumbo

Cerrato

et al. 2020

Cancers

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The embryonal renal cancer Wilms tumor (WT) accounts for 7% of all children’s malignancies. Its most frequent molecular defect is represented by DNA methylation abnormalities at the imprinted 11p15.5 region. Multiple imprinted methylation alterations dictated by chromosome copy-number variations have been recently demonstrated in adult cancers, raising the question of whether multiple imprinted loci were also affected in WT. To address this issue, we analyzed DNA methylation and chromosome profiles of 7 imprinted loci in 48 WT samples. The results demonstrated that methylation abnormalities of multiple imprinted loci occurred in 35% of the cases, but that they were associated with either chromosome aberrations or normal chromosome profiles. Multiple imprinted methylation changes were correlated with tumor stage and presence of metastasis, indicating that these epimutations were more frequent in highly aggressive tumors. When chromosome profiles were affected, these alterations were extended to flanking cancer driver genes. Overall, this study demonstrates the presence of multiple imprinted methylation defects in aggressive WTs and suggests that the mechanism by which they arise in embryonal and adult cancers is different.

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Section: Discussionsupporting

confidence: 56%

Both Epimutations and Chromosome Aberrations Affect Multiple Imprinted Loci in Aggressive Wilms Tumors

Pignata

Palumbo

Cerrato

et al. 2020

Cancers

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“…WT is the most frequent kidney cancer. It has a prevalence rate of 8.33 per million children in Brazil [ 17 , 18 , 19 , 20 , 21 ]. Therefore, the investigated cohort of samples is small but significant in terms of the rarity of the disease.…”

Section: Resultsmentioning

confidence: 99%

A Metabonomic View on Wilms Tumor by High-Resolution Magic-Angle Spinning Nuclear Magnetic Resonance Spectroscopy

et al. 2022

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Pediatric cancer NMR-metabonomics might be a powerful tool to discover modified biochemical pathways in tumor development, improve cancer diagnosis, and, consequently, treatment. Wilms tumor (WT) is the most common kidney tumor in young children whose genetic and epigenetic abnormalities lead to cell metabolism alterations, but, so far, investigation of metabolic pathways in WT is scarce. We aimed to explore the high-resolution magic-angle spinning nuclear magnetic resonance (HR-MAS NMR) metabonomics of WT and normal kidney (NK) samples. For this study, 14 WT and 7 NK tissue samples were obtained from the same patients and analyzed. One-dimensional and two-dimensional HR-MAS NMR spectra were processed, and the one-dimensional NMR data were analyzed using chemometrics. Chemometrics enabled us to elucidate the most significant differences between the tumor and normal tissues and to discover intrinsic metabolite alterations in WT. The metabolic differences in WT tissues were revealed by a validated PLS-DA applied on HR-MAS T2-edited 1H-NMR and were assigned to 16 metabolites, such as lipids, glucose, and branched-chain amino acids (BCAAs), among others. The WT compared to NK samples showed 13 metabolites with increased concentrations and 3 metabolites with decreased concentrations. The relative BCAA concentrations were decreased in the WT while lipids, lactate, and glutamine/glutamate showed increased levels. Sixteen tissue metabolites distinguish the analyzed WT samples and point to altered glycolysis, glutaminolysis, TCA cycle, and lipid and BCAA metabolism in WT. Significant variation in the concentrations of metabolites, such as glutamine/glutamate, lipids, lactate, and BCAAs, was observed in WT and opened up a perspective for their further study and clinical validation.

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“…BRCA1 gene on 17q21.31 encodes a nuclear phosphoprotein that plays a role in maintaining genomic stability [33]. However, BRCA1, which demonstrates promoter hypomethylation, is over-expressed in Wilms tumor [34]. RARB2 gene on 3p24.2 encodes retinoic acid receptor beta that is a type of nuclear receptor activated by all-trans retinoic acid and 9-cis retinoic acid [35].…”

Section: Discussionmentioning

confidence: 99%

Identification of Molecular Biomarkers in Taiwanese Patients with Wilms Tumor Using a Methylation-Specific Multiplex Ligation-Dependent Probe Amplification (MS-MLPA)-Based Approach

Wang

Hou

et al. 2020

Preprint

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Background: Wilms tumor is a solid tumor that frequently occurs in children. Genetic or epigenetic aberrations in WT1 and WT2 loci are implicated in its etiology. Moreover, tumor suppressor genes are frequently silenced by methylation in this tumor. Methods: In the present study, we analyzed the methylation statuses of promoter regions of 24 different tumor suppressor genes using a methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA)-based approach in six Wilms tumors. Results: All six Wilms tumors showed methylation of RASSF1 specific to tumors, not in normal tissues. Moreover, methylated HIC1 was identified in stromal type Wilms tumors and methylated BRCA1 was identified in epithelial type Wilms tumors. Unmethylated CASP8, RARB, MLH1_167, APC, and CDKN2A were found only in blastemal predominant type Wilms tumors. Conclusions: Our results indicated that methylation of RASSF1 is the essential event in the tumorigenesis of Wilms tumor, which may inform its clinical and therapeutic management. In addition, mixed type Wilms tumors may be classified according to epithelial, stromal, and blastemal components via MS-MLPA-based approach.

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Genes Controlled by DNA Methylation Are Involved in Wilms Tumor Progression

Cited by 14 publications

References 62 publications

Both Epimutations and Chromosome Aberrations Affect Multiple Imprinted Loci in Aggressive Wilms Tumors

Both Epimutations and Chromosome Aberrations Affect Multiple Imprinted Loci in Aggressive Wilms Tumors

A Metabonomic View on Wilms Tumor by High-Resolution Magic-Angle Spinning Nuclear Magnetic Resonance Spectroscopy

Identification of Molecular Biomarkers in Taiwanese Patients with Wilms Tumor Using a Methylation-Specific Multiplex Ligation-Dependent Probe Amplification (MS-MLPA)-Based Approach

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