Anaplastic Wilms' tumour, a subtype displaying poor prognosis, harbours p53 gene mutations

Bardeesy, Nabeel; Falkoff, David L.; Petruzzi, Mary-Jane; Nowak, Norma J.; Zabel, Bernhard; Adam, Mohammed; Aguiar, Maria Cássia Ferreira de; Grundy, Paul E.; Shows, Tom; Pelletier, Jerry

doi:10.1038/ng0594-91

Cited by 286 publications

(161 citation statements)

References 31 publications

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“…It has been clearly shown that p53 mutations are associated with anaplasia of Wilms tumors (Bardeesy et al, 1994(Bardeesy et al, , 1995Malkin et al, 1994;Lahoti et al, 1996). It is likely that they also occur in the anaplastic Wilms tumors we have analysed.…”

Section: An Expression Signature For Anaplastic Wilms Tumormentioning

confidence: 99%

“…Although it is relatively rare (3.2-7.3% of all Wilms tumors), this subset of tumors is clinically important since anaplastic tumors are typically resistant to therapy and have poor prognosis (Beckwith and Palmer, 1978;Bonadio et al, 1985). The molecular basis for the anaplastic phenotype is unknown; however, unlike Wilms tumors with favorable histology (FH), most anaplastic tumors contain somatic p53 mutations (Bardeesy et al, 1994(Bardeesy et al, , 1995. In the present study, we utilized a custom cDNA array containing 4900 Unigenes or unclustered ESTs (9240 clones) relevant to cancer biology and/or kidney development to examine gene expression profiles of 54 Wilms tumors, and established a gene expression connection between Wilms tumor and kidney morphogenesis, as well as identified a gene expression signature that differentiates anaplastic Wilms tumors from those with FH.…”

Section: Introductionmentioning

confidence: 99%

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Transcript profiling of Wilms tumors reveals connections to kidney morphogenesis and expression patterns associated with anaplasia

Kessler

Williams

2004

Oncogene

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Anaplasia (unfavorable histology) is associated with therapy resistance and poor prognosis of Wilms tumor, but the molecular basis for this phenotype is unclear. Here, we used a cDNA array with 9240 clones relevant to cancer biology and/or kidney development to examine the expression profiles of 54 Wilms tumors, five normal kidneys and fetal kidney. By linking genes differentially expressed between fetal kidney and Wilms tumors to kidney morphogenesis, we found that genes expressed at a higher level in Wilms tumors tend to be expressed more in uninduced metanephrogenic mesenchyme or blastema than in their differentiated structures. Conversely, genes expressed at a lower level in Wilms tumors tend to be expressed less in uninduced metanephrogenic mesenchyme or blastema. We also identified 97 clones representing 76 Unigenes or unclustered ESTs that clearly separate anaplastic Wilms tumors from tumors with favorable histology. Genes in this set provide insight into the nature of the abnormal nuclear morphology of anaplastic tumors and may facilitate identification of molecular targets to improve their responsiveness to treatment.

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Section: An Expression Signature For Anaplastic Wilms Tumormentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Transcript profiling of Wilms tumors reveals connections to kidney morphogenesis and expression patterns associated with anaplasia

Kessler

Williams

2004

Oncogene

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“…A likely target of the 17p LOH is the TP53 tumor suppressor gene, a locus that shows a well-known association with tumor progression in other systems and that has been implicated previously as mutated in some anaplastic Wilms' tumors (35). We sequenced several of the most frequently mutated exons of TP53 (exons 5-9) in six of the Wilms' tumors with 17p LOH and found a single case (a stage IV tumor) with a loss-of-function mutation: a 4-bp insertion in exon 5 that produced a frameshift and premature STOP codon (data not shown).…”

Section: The Number Of Chromosomes Affected By Loh In Sporadic Wilms'mentioning

confidence: 99%

Genomic Profiling Maps Loss of Heterozygosity and Defines the Timing and Stage Dependence of Epigenetic and Genetic Events in Wilms' Tumors

Yuan

Yamashiro³

et al. 2005

Molecular Cancer Research

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To understand genetic and epigenetic pathways in Wilms' tumors, we carried out a genome scan for loss of heterozygosity (LOH) using Affymetrix 10K single nucleotide polymorphism (SNP) chips and supplemented the data with karyotype information. To score loss of imprinting (LOI) of the IGF2 gene, we assessed DNA methylation of the H19 5V differentially methylated region (DMR). Few chromosomal regions other than band 11p13 (WT1) were lost in Wilms' tumors from Denys-Drash and Wilms' tumor-aniridia syndromes, whereas sporadic Wilms' tumors showed LOH of several regions, most frequently 11p15 but also 1p, 4q, 7p, 11q, 14q, 16q, and 17p. LOI was common in the sporadic Wilms' tumors but absent in the syndromic cases. The SNP chips identified novel centers of LOH in the sporadic tumors, including a 2.4-Mb minimal region on chromosome 4q24-q25. Losses of chromosomes 1p, 14q, 16q, and 17p were more common in tumors presenting at an advanced stage; 11p15 LOH was seen at all stages, whereas LOI was associated with early-stage presentation. Wilms' tumors with LOI often completely lacked LOH in the genome-wide analysis, and in some tumors with concomitant 16q LOH and LOI, the loss of chromosome 16q was mosaic, whereas the H19 DMR methylation was complete. These findings confirm molecular differences between sporadic and syndromic Wilms' tumors, define regions of recurrent LOH, and indicate that gain of methylation at the H19 DMR is an early event in Wilms' tumorigenesis that is independent of chromosomal losses. The data further suggest a biological difference between sporadic Wilms' tumors with and without LOI. (Mol Cancer Res 2005;3(9):493 -502)

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“…It is associated with several well-characterized genetic defects, including the mutational inactivation of the WT1 (2) or WTX (3) tumor suppressor genes. TP53 is also sometimes mutated in a rare aggressive subset of WTs (4). Activating CTNNB1 proto-oncogene mutations have been found in WT, often in conjunction with WT1 mutation in the same tumor (5).…”

Section: Introductionmentioning

confidence: 99%

Frequency and Timing of Loss of Imprinting at 11p13 and 11p15 in Wilms' Tumor Development

Brown

Power

Moore

et al. 2008

Molecular Cancer Research

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Epigenetic changes occur frequently in Wilms' tumor (WT), especially loss of imprinting (LOI) of IGF2/H19 at 11p15. Our previous results have identified imprinted transcripts (WT1-AS and AWT1) from the WT1 locus at 11p13 and showed LOI of these in some WTs. In this article, we set out to test the relationship between LOI at 11p13 and 11p15 and their timing in WT progression relative to other genetic changes. We found a higher level (83%) of 11p13 LOI in WT than of 11p15 LOI (71%). There was no correlation between methylation levels at the 11p13 and 11p15 differentially methylated regions or between allelic expression of WT1-AS/AWT1 and IGF2. Interestingly, retention of normal imprinting at 11p13 was associated with a small group of relatively late-onset, high-stage WTs. An examination of genetic and epigenetic alterations in nephrogenic rests, which are premalignant WT precursors, showed that LOI at both 11p13 and 11p15 occurred before either 16q loss of heterozygosity (LOH) or 7p LOH. This suggests that these LOH events are very unlikely to be a cause of LOI but that LOH may act by potentiating the effects of overexpression of IGF2 and/or WT1-AS/AWT1 that

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Anaplastic Wilms' tumour, a subtype displaying poor prognosis, harbours p53 gene mutations

Cited by 286 publications

References 31 publications

Transcript profiling of Wilms tumors reveals connections to kidney morphogenesis and expression patterns associated with anaplasia

Transcript profiling of Wilms tumors reveals connections to kidney morphogenesis and expression patterns associated with anaplasia

Genomic Profiling Maps Loss of Heterozygosity and Defines the Timing and Stage Dependence of Epigenetic and Genetic Events in Wilms' Tumors

Frequency and Timing of Loss of Imprinting at 11p13 and 11p15 in Wilms' Tumor Development

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