Array comparative genomic hybridization reveals unbalanced gain of the MYCN region in Wilms tumors

Schaub, Rahel; Burger, Alexa; Bausch, Damaris; Niggli, Felix; Schäfer, Beat W.; Betts, David R.

doi:10.1016/j.cancergencyto.2006.08.010

Cited by 25 publications

(12 citation statements)

References 23 publications

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“…11 Notably, both SNPs are located within a region of 2p24 that shows somatic copy number gain or amplification in many childhood cancers, most notably neuroblastoma, but also occasionally in Wilms tumor. 12,13 It is generally assumed that a neighboring gene in the amplicon, MYCN , is the primary target in promoting oncogenesis. Whilst it is possible that the association we identified is mediated through a long-range effect on MYCN , DDX1 seems the more likely target.…”

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confidence: 99%

A genome-wide association study identifies susceptibility loci for Wilms tumor

et al. 2012

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Wilms tumor is the most common renal malignancy of childhood. To identify common variants that confer susceptibility to Wilms tumor we conducted a genome-wide association study in 757 cases and 1,879 controls. We evaluated ten SNPs in regions significant at P<5×10−5 in two independent replication series from the UK (769 cases and 2,814 controls) and the US (719 cases and 1,037 controls). We identified clear significant associations at two loci, 2p24 (rs3755132, P=1.03×10−14 and rs807624, P=1.32×10−14) and 11q14 (rs790356, P=4.25 ×10−15). Both regions contain genes that are plausibly related to Wilms tumorigenesis. We also identified candidate signals at 5q14, 22q12 and Xp22.

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confidence: 99%

A genome-wide association study identifies susceptibility loci for Wilms tumor

et al. 2012

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“…Although isolated cases have been described previously (Norris et al, 1988;McQuaid and O'Meara, 1990;Mares et al, 1996;Schaub et al, 2007), this has generally been viewed as a rare aberration. However, overexpression of MYCN, a phenotype of potential prognostic significance (Zirn et al, 2006;Wittmann et al, 2008), is common in WT even in the absence of chromosomal gain (Nisen et al, 1986;Shaw et al, 1988;Williams et al, 2004), suggesting that other mechanisms may operate to increase levels of the transcript in a broader range of Wilms tumors.…”

Section: Discussionmentioning

confidence: 94%

“…Genomic amplification of the MYCN gene on 2p24.1 is a rarely described aberration in Wilms tumor (Norris et al, 1988;McQuaid and O'Meara, 1990;Mares et al, 1996;Schaub et al, 2007). We have recently described genomic MYCN gains associated with anaplasia in WTs pretreated with neoadjuvant chemotherapy (Williams et al, 2010).…”

Section: Mycn Copy Number Gainmentioning

confidence: 97%

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 parallel epidemiologic studies of this patient registry, we have reported that Kenyan children present with WT at an age typical for this disease, as documented in other populations (i.e., between 3 and 4 years); as a result, delayed presentation at a later stage in disease progression is not solely explanatory of these observed alterations in TP53 . Copy number gain of MYCN is another feature of treatment‐resistant WT (Schaub et al, ; Williams et al, ). A recent article describes a similar frequency of MYCN alterations (18.5%) in a cohort of European WT and reports the same P44L mutation that was detected in two of these KWT (Wegert et al, ).…”

Section: Discussionmentioning

confidence: 99%

Genetic and chromosomal alterations in Kenyan Wilms Tumor

Lovvorn

Pierce

Libes

et al. 2015

Genes Chromosomes & Cancer

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Wilms tumor (WT) is the most common childhood kidney cancer worldwide and poses a cancer health disparity to black children of sub-Saharan African ancestry. Although overall survival from WT at 5 years exceeds 90% in developed countries, this pediatric cancer is alarmingly lethal in sub-Saharan Africa and specifically in Kenya (36% survival at 2 years). Although multiple barriers to adequate WT therapy contribute to this dismal outcome, we hypothesized that a uniquely aggressive and treatment-resistant biology compromises survival further. To explore the biologic composition of Kenyan WT (KWT), we completed a next generation sequencing analysis targeting 10 WT-associated genes and evaluated whole-genome copy number variation. The study cohort was comprised of 44 KWT patients and their specimens. Fourteen children are confirmed dead at 2 years and 11 remain lost to follow up despite multiple tracing attempts. TP53 was mutated most commonly in 11 KWT specimens (25%), CTNNB1 in 10 (23%), MYCN in 8 (18%), AMER1 in 5 (11%), WT1 and TOP2A in 4 (9%), and IGF2 in 3 (7%). Loss of heterozygosity (LOH) at 17p, which covers TP53, was detected in 18% of specimens examined. Copy number gain at 1q, a poor prognostic indicator of WT biology in developed countries, was detected in 32% of KWT analyzed, and 89% of these children are deceased. Similarly, LOH at 11q was detected in 32% of KWT, and 80% of these patients are deceased. From this genomic analysis, KWT biology appears uniquely aggressive and treatment-resistant.

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Array comparative genomic hybridization reveals unbalanced gain of the MYCN region in Wilms tumors

Cited by 25 publications

References 23 publications

A genome-wide association study identifies susceptibility loci for Wilms tumor

A genome-wide association study identifies susceptibility loci for Wilms tumor

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

Genetic and chromosomal alterations in Kenyan Wilms Tumor

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