Analysis of the mutational status of SIX1/2 and microRNA processing genes in paired primary and relapsed Wilms tumors and association with relapse

Ciceri, Sara; Azevedo, Rafaela Montalvão de; Tajbakhsh, Amir; Bertolotti, Alessia; Spagnuolo, Rosalin Dolores; Boschetti, Luna; Capasso, Maria; D’Angelo, Paolo; Serra, Annalisa; Diomedi-Camassei, Francesca; Meli, Mariaclaudia; Nantron, Marilina; Quarello, Paola; Buccoliero, Anna Maria; Tamburini, Angela; Ciniselli, Chiara Maura; Verderio, Paolo; Collini, Paola; Radice, Paolo; Spreafico, Filippo; Perotti, Daniela

doi:10.1038/s41417-020-00268-3

Cited by 10 publications

(13 citation statements)

References 18 publications

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“…Observations highlighted by the current study, but certainly documented previously by others, 14 , 15 , 16 include the important role of copy number change in WTs. Although some of the regions gained or lost have some degree of data supporting the role of individual genes, most do not, despite a great deal of effort over the last decade.…”

Section: Discussionsupporting

confidence: 77%

“…Segmental copy number analysis for the relapse sample and the paired primary tumor sample (when available) was computed from WGS data by the GDC. Regions reported previously as gained or lost in WTs 14 , 15 , 16 were evaluated and are provided in Table 2 . These data confirm numerous gains and losses of entire chromosomes or chromosomal arms in WTs, particularly gain of 1q, 6, 7q, and 12 and loss of 1p, 16q, and 22.…”

Section: Resultsmentioning

confidence: 99%

“…This observation prompted analysis of high-resolution SNP arrays of large numbers of WTs to identify additional regions recurrently gained and lost. 14 , 15 , 16 This revealed several recurrent genetic regions of gain or loss, but the underlying pathogenetic genes and/or pathways remain elusive for most loci.…”

Section: Introductionmentioning

confidence: 99%

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Genetic changes associated with relapse in favorable histology Wilms tumor: A Children’s Oncology Group AREN03B2 study

Gadd

Huff

Skol

et al. 2022

Cell Reports Medicine

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Section: Discussionsupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

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Genetic changes associated with relapse in favorable histology Wilms tumor: A Children’s Oncology Group AREN03B2 study

Gadd

Huff

Skol

et al. 2022

Cell Reports Medicine

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“…This association was not found in tumors treated with pre-operative chemotherapy, but it was shown that SIX1/SIX2 and miRNAPG mutations were associated with blastemal-type WT, which is an adverse prognostic factor for recurrence [86,117]. The analysis of paired primary and recurrent tumors by AIEOP suggested that SIX1 and miRNAPG mutations may be involved in driving tumor recurrence, suggesting potential prognostic value that must be confirmed in future studies [118,119]. Rather than adhering to a single-sample strategy, AIEOP sampled multiple sections of the same tumors to avoid missing mutations that may be heterogeneously present.…”

Section: Somatic Mutationsmentioning

confidence: 99%

Prognostic Factors for Wilms Tumor Recurrence: A Review of the Literature

Groenendijk

Spreafico

Krijger

et al. 2021

Cancers

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In high-income countries, the overall survival of children with Wilms tumors (WT) is ~90%. However, overall, 15% of patients experience tumor recurrence. The adverse prognostic factors currently used for risk stratification (advanced stage, high risk histology, and combined loss of heterozygosity at 1p and 16q in chemotherapy-naïve WTs) are present in only one third of these cases, and the significance of these factors is prone to change with advancing knowledge and improved treatment regimens. Therefore, we present a comprehensive, updated overview of the published prognostic variables for WT recurrence, ranging from patient-, tumor- and treatment-related characteristics to geographic and socioeconomic factors. Improved first-line treatment regimens based on clinicopathological characteristics and advancing knowledge on copy number variations unveil the importance of further investigating the significance of biological markers for WT recurrence in international collaborations.

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“…Approximately 50% of patients with favorable histology who experience disease relapse die from their disease [ 8 , 9 ]. Adverse biological features of Wilms tumor associated with relapse include mutations in TP53 , SIX1 or SIX2 with concomitant microRNA processing gene mutations, and chromosomal copy number alterations including 1q gain and loss of heterozygosity of both 1p and 16q [ 7 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

TERT Expression in Wilms Tumor Is Regulated by Promoter Mutation or Hypermethylation, WT1, and N-MYC

Jablonowski

Gil

Pinto

et al. 2022

Cancers

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Increased TERT mRNA is associated with disease relapse in favorable histology Wilms tumor (WT). This study sought to understand the mechanism of increased TERT expression by determining the association between TERT and WT1 and N-MYC, two proteins important in Wilms tumor pathogenesis that have been shown to regulate TERT expression. Three out of 45 (6.7%) WTs and the corresponding patient-derived xenografts harbored canonical gain-of-function mutations in the TERT promoter. This study identified near ubiquitous hypermethylation of the TERT promoter region in WT compared to normal kidney. WTs with biallelic inactivating mutations in WT1 (7/45, 15.6%) were found to have lower TERT expression by RNA-seq and qRT-PCR and lower telomerase activity determined by the telomerase repeat amplification protocol. Anaplastic histology and increased percentage of blastema were positively correlated with higher TERT expression and telomerase activity. In vitro shRNA knockdown of WT1 resulted in decreased expression of TERT, reduced colony formation, and decreased proliferation of WiT49, an anaplastic WT cell line with wild-type WT1. CRISPR-Cas9-mediated knockout of WT1 resulted in decreased expression of telomere-related gene pathways. However, an inducible Wt1-knockout mouse model showed no relationship between Wt1 knockout and Tert expression in normal murine nephrogenesis, suggesting that WT1 and TERT are coupled in transformed cells but not in normal kidney tissues. N-MYC overexpression resulted in increased TERT promoter activity and TERT transcription. Thus, multiple mechanisms of TERT activation are involved in WT and are associated with anaplastic histology and increased blastema. This study is novel because it identifies potential mechanisms of TERT activation in Wilms tumor that could be of therapeutic interests.

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Analysis of the mutational status of SIX1/2 and microRNA processing genes in paired primary and relapsed Wilms tumors and association with relapse

Cited by 10 publications

References 18 publications

Genetic changes associated with relapse in favorable histology Wilms tumor: A Children’s Oncology Group AREN03B2 study

Genetic changes associated with relapse in favorable histology Wilms tumor: A Children’s Oncology Group AREN03B2 study

Prognostic Factors for Wilms Tumor Recurrence: A Review of the Literature

TERT Expression in Wilms Tumor Is Regulated by Promoter Mutation or Hypermethylation, WT1, and N-MYC

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