Allele loss at 16q defines poorer prognosis Wilms tumour irrespective of treatment approach in the UKW1–3 clinical trials: A Children’s Cancer and Leukaemia Group (CCLG) study

Messahel, Boo; Williams, Richard D.; Ridolfi, Antonia; A’Hern, Roger; Warren, William; Tinworth, Lorna; Hobson, Rachel; Al‐Saadi, Reem; Whyman, Gavin; Bründler, Marie-Anne; Kelsey, Anna; Sebire, Neil J.; Jones, Chris; Vujanić, Gordan; Pritchard‐Jones, Kathy

doi:10.1016/j.ejca.2009.01.005

Cited by 48 publications

(50 citation statements)

References 19 publications

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“…Previous studies in WT identified different regions of chromosomal gain/loss proposed as prognostic/predictive factors (Grundy et al, 1994(Grundy et al, , 2005Klamt et al, 1998;Messahel et al, 2009;Natrajan et al, 2006b;Wittmann et al, 2007). Among them, the only factor currently used in clinical practice to stratify WT patients and to treat them accordingly, is a combined LOH at 1p and 16q (Perlman, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Studies of loss of heterozygosity (LOH), performed using microsatellite markers, reported an association of LOH at chromosome arms 1p, 11q, 16q, and 22q with an adverse outcome (Grundy et al, 1994(Grundy et al, , 2005Klamt et al, 1998;Messahel et al, 2009;Wittmann et al, 2007). Comparative genomic hybridization (CGH) to metaphase chromosomes displayed an increased frequency of 1q gains in recurring tumors (Hing et al, 2001), an observation consistent with the overexpression of 1q genes assessed by comparative expressed sequence hybridization (CESH) (Lu et al, 2002).…”

Section: Introductionmentioning

confidence: 89%

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Genomic profiling by whole‐genome single nucleotide polymorphism arrays in Wilms tumor and association with relapse

Perotti

Spreafico

Torri

et al. 2012

Genes Chromosomes & Cancer

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Despite the excellent survival rate of Wilms tumor (WT) patients, only approximately one-half of children who suffer tumor recurrence reach second durable remission. This underlines the need for novel markers to optimize initial treatment. We investigated 77 tumors using Illumina 370CNV-QUAD genotyping BeadChip arrays and compared their genomic profiles to detect copy number (CN) abnormalities and allelic ratio anomalies associated with the following clinicopathological variables: relapse (yes vs. no), age at diagnosis (≤ 24 months vs. >24 months), and disease stage (low stage, I and II, vs. high stage, III and IV). We found that CN gains at chromosome region 1q21.1-q31.3 were significantly associated with relapse. Additional genetic events, including allelic imbalances at chromosome arms 1p, 1q, 3p, 3q, and 14q were also found to occur at higher frequency in relapsing tumors. Interestingly, allelic imbalances at 1p and 14q also showed a borderline association with higher tumor stages. No genetic events were found to be associated with age at diagnosis. This is the first genome wide analysis with single nucleotide polymorphism (SNP) arrays specifically investigating the role of genetic anomalies in predicting WT relapse on cases prospectively enrolled in the same clinical trial. Our study, besides confirming the role of 1q gains, identified a number of additional candidate genetic markers, warranting further molecular investigations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 89%

Genomic profiling by whole‐genome single nucleotide polymorphism arrays in Wilms tumor and association with relapse

Perotti

Spreafico

Torri

et al. 2012

Genes Chromosomes & Cancer

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“…Complex karyotypes with abnormalities affecting multiple loci have also been noted in three cases described in one study (Peres et al, 2004), and in three of five cases examined in another (Gow and Murphy, 2002). A number of groups have reported an association between loss of heterozygosity (LOH) on 16q and anaplasia or outcome (Klamt et al, 1998;Yeh et al, 2002;Grundy et al, 2005;Wittmann et al, 2007;Messahel et al, 2009). LOH events at 22q and 11q (Klamt et al, 1998;Wittmann et al, 2007) have also been linked to AH.…”

Section: Introductionmentioning

confidence: 88%

Molecular profiling reveals frequent gain of MYCN and anaplasia‐specific loss of 4q and 14q in wilms tumor

Williams

Al‐Saadi

Natrajan

et al. 2011

Genes Chromosomes & Cancer

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Anaplasia in Wilms tumor, a distinctive histology characterized by abnormal mitoses, is associated with poor patient outcome. While anaplastic tumors frequently harbour TP53 mutations, little is otherwise known about their molecular biology. We have used array comparative genomic hybridization (aCGH) and cDNA microarray expression profiling to compare anaplastic and favorable histology Wilms tumors to determine their common and differentiating features. In addition to changes on 17p, consistent with TP53 deletion, recurrent anaplasia-specific genomic loss and under-expression were noted in several other regions, most strikingly 4q and 14q. Further aberrations, including gain of 1q and loss of 16q were common to both histologies. Focal gain of MYCN, initially detected by high resolution aCGH profiling in 6/61 anaplastic samples, was confirmed in a significant proportion of both tumor types by a genomic quantitative PCR survey of over 400 tumors. Overall, these results are consistent with a model where anaplasia, rather than forming an entirely distinct molecular entity, arises from the general continuum of Wilms tumor by the acquisition of additional genomic changes at multiple loci.

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“…In total, genomic abnormalities were found in 29/38 tumors using this approach. Eight tumors with segmental 16q loss of heterozygosity due to deletion were detected (patients 4,7,13,14,20,21,26, and 27 in Table 1). In addition, one tumor (patient 28) exhibited copy-number neutral imbalance of the entire chromosome 16.…”

Section: Q Deletions Are Confined To Immature Tumor Tissue Elementsmentioning

confidence: 99%

Deletions of 16q in Wilms Tumors Localize to Blastemal-Anaplastic Cells and Are Associated with Reduced Expression of the IRXB Renal Tubulogenesis Gene Cluster

Mengelbier

Karlsson

Lindgren

et al. 2010

The American Journal of Pathology

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Wilms tumor is the most common pediatric renal neoplasm, but few molecular prognostic markers have been identified for this tumor. Somatic deletion in the long arm of chromosome 16 (16q) is known to predict a less favorable outcome in Wilms tumor, but the underlying molecular mechanisms are not known. We show that 16q deletions are typically confined to immature anaplastic-blastic tumor elements, while deletions are absent in maturing tumor components. The smallest region of deletion overlap mapped to a 1.8-Mb segment containing the IRXB gene cluster including IRX3, IRX5, and IRX6, of which IRX3 is a recently identified regulator of tubular maturation during nephrogenesis. Tumors with 16q deletion showed a lower overall mRNA expression of IRXB genes, and 16q-deleted tumor cells failed to express IRX3 while it was expressed in differentiating tubular tumor elements with intact 16q. Consistent with a role for IRX3 in tubular differentiation, gene sets linked to Notch signaling, Rho signaling, and ion channel activity were enriched in tumors with high IRX3 expression, while WTs with low expression were enriched for gene sets linked to cell cycle progression. Wilms tumor accounts for more than 95% of kidney tumors in children. The majority of patients receiving modern multimodal therapy are cured, but 10 to 15% still die of disease.1 Histologically, most WTs mimic the fetal developing kidney in which immature cells of the metanephric mesenchyme differentiate into stromal and epithelial elements, the latter of which ultimately give rise to the nephronic tubules and glomeruli.2 The notion that Wilms tumor originates from pluripotent immature cells is supported by its characteristic triphasic histology, including blastemal, epithelial, and stromal components. The blastema consists of undifferentiated mesenchymal cells, resembling the metanephric mesenchyme, while the epithelial component might show different degrees of differentiation, including primitive tubular and glomeruloid formations. Gene expression studies have provided additional evidence for the hypothesis that Wilms tumor results from a differentiation block in embryonic kidney formation; genes overexpressed in Wilms tumor are also

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Allele loss at 16q defines poorer prognosis Wilms tumour irrespective of treatment approach in the UKW1–3 clinical trials: A Children’s Cancer and Leukaemia Group (CCLG) study

Cited by 48 publications

References 19 publications

Genomic profiling by whole‐genome single nucleotide polymorphism arrays in Wilms tumor and association with relapse

Genomic profiling by whole‐genome single nucleotide polymorphism arrays in Wilms tumor and association with relapse

Molecular profiling reveals frequent gain of MYCN and anaplasia‐specific loss of 4q and 14q in wilms tumor

Deletions of 16q in Wilms Tumors Localize to Blastemal-Anaplastic Cells and Are Associated with Reduced Expression of the IRXB Renal Tubulogenesis Gene Cluster

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