Microdeletion and IGF2 loss of imprinting in a cascade causing Beckwith-Wiedemann syndrome with Wilms' tumor

Prawitt, Dirk; Enklaar, Thorsten; Gärtner-Rupprecht, Barbara; Spangenberg, Christian; Lausch, Ekkehart; Reutzel, Dirk; Fees, Stephan; Korzon, Maria; Brożek, Izabela; Limon, Janusz; Housman, David E.; Zabel, Bernhard

doi:10.1038/ng0805-785

Cited by 38 publications

(22 citation statements)

References 7 publications

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“…In addition to 11p15 LOH/LOI, a role for IGF2 in WT tumorigenesis is strongly suggested by the observation that patients with the somatic overgrowth syndrome Beckwith-Wiedemann syndrome who develop WT often carry germline mutations in an IGF2 imprinting control region (43,44). IGF2 signals primarily through IGF-IR (39)(40)(41), and the increased expression of pIRS, a substrate for activated IGF-IR, in mouse tumors confirms that this is also true for the Wt1-Igf2 tumors.…”

Section: Discussionmentioning

confidence: 73%

Wt1 ablation and Igf2 upregulation in mice result in Wilms tumors with elevated ERK1/2 phosphorylation

Hu¹,

Gao²,

Tian³

et al. 2011

J. Clin. Invest.

106

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Wilms tumor (WT) is a genetically heterogeneous childhood kidney tumor. Several genetic alterations have been identified in WT patients, including inactivating mutations in WT1 and loss of heterozygosity or loss of imprinting at 11p15, which results in biallelic expression of IGF2. However, the mechanisms by which one or a combination of genetic alterations results in tumorigenesis has remained challenging to determine, given the lack of a mouse model of WT. Here, we engineered mice to sustain mosaic, somatic ablation of Wt1 and constitutional Igf2 upregulation, mimicking a subset of human tumors. Mice with this combination of genetic alterations developed tumors at an early age. Mechanistically, Wt1 ablation blocked mesenchyme differentiation, and increased Igf2 expression upregulated ERK1/2 phosphorylation. Importantly, a subset of human tumors similarly displayed upregulation of ERK1/2 phosphorylation, which suggests ERK signaling might contribute to WT development. Thus, we have generated a biologically relevant mouse model of WT and defined one combination of driver alterations for WT. This mouse model will provide a powerful tool to study the biology of WT initiation and progression and to investigate therapeutic strategies for cancers with IGF pathway dysregulation. IntroductionWilms tumor (WT) is a childhood kidney tumor that is thought to arise from undifferentiated metanephric mesenchyme. WT is genetically heterogeneous. Mutations that occur in tumors include inactivation of WT1 (~20% of tumors), somatic stabilizing CTNNB1 mutations (~15%), somatic deletion of WTX (~20%), and p53 mutations (~5%) that occur specifically in the subset of anaplastic WT (1-5). Overall, only one-third of tumors have mutations in 1 or more of these 4 genes (6). Additionally, loss of heterozygosity (LOH) or loss of imprinting (LOI) at the chromosomal region 11p15, which harbors a cluster of imprinted genes, is observed in approximately 70% of tumors (7,8), resulting in biallelic expression of IGF2. However, the mechanism by which one or a combination of alterations results in tumorigenesis is not known. Children heterozygous for germline WT1 mutations are predisposed to WT, and these tumors have invariably sustained mutation of the wild-type WT1 allele. However, inactivation of WT1 is also observed in premalignant lesions (9), which suggests that one or more additional, rate-limiting genetic alterations is required for progression to a malignant phenotype.The cellular pathways dysregulated in WTs as a result of WT1 ablation or IGF2 upregulation are unknown, and identifying such pathways in human tumors is challenging because of the genetic heterogeneity of the disease and the biologic complexity of primary human tumors. While animal models can be powerful tools for dissecting the biology of human tumors, the development of a mouse model for WT has been elusive. Wt1 -/-mice lack kidneys

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Section: Discussionmentioning

confidence: 73%

Wt1 ablation and Igf2 upregulation in mice result in Wilms tumors with elevated ERK1/2 phosphorylation

Hu¹,

Gao²,

Tian³

et al. 2011

J. Clin. Invest.

106

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“…There is extensive literature on the association of IGF2, hepatoblastomas and other tumors as part of the Beckwith-Wiedemann syndrome. 29,30 2. Mitogen inducible gene 6 (MIG6) (3.88X).…”

Section: Biologic Significance Of Genes Differentially Expressed Betwmentioning

confidence: 99%

Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas†

et al. 2006

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H epatocellular carcinomas (HCC) and hepatoblastomas of childhood (HPBL) are two types of liver cancer with high mortality and morbidity and international prevalence. There have been several recent studies of patterns of gene expression and molecular classification of HCC. [1][2][3][4] The studies demonstrated that HCC can be clustered in subgroups of gene expression patterns that have different prognostic and clinical behavior. Other recent studies also examined similarities between HCC precursor lesions (low and high grade liver nodules) and demonstrated significant similarities but also differences between HCC and precursor lesions. 5 In this study, we also focused on gene expression of HCC and HPBL, but from a different perspective than previous studies. We utilized a set of tissues from normal liver (NL), HCC, HPBL and tumor adjacent (AT) tissues and determined gene expression patterns not as a ratio of tumor vs. normal, but rather as absolute separate values for each unique tissue. This allowed standard but stringent statistical analysis not feasible when gene expression is only viewed as a fold change over normal tissues. Identification of gene expression patterns of liver tumors from this perspective allows identification of the main differences between the tumor subtypes and the adjacent nontumor (but often cirrhotic) liver; it also offers the potential of defining new therapeutic and diagnostic modalities. Our findings include some genes already shown to increase in HCC, thus validating our overall approach. Our results also revealed many other genes, not so far involved with biology of liver tumors. In addition, we carried a whole genome analysis of 27 HCC and determined chromosomal loci with genetic abnormalities common to most of the HCC. Materials and MethodsSee Supplemental information at the HEPATOLOGY

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“…On the paternal allele the ICR is methylated, CTCF cannot bind to it, and the enhancer is instead recruited by threedimensional looping to activate the Igf2 promoter. Thus, differential insulator activity leads to differences in gene activity, and malfunction of this insulator contributes to Beckwith-Wiedemann syndrome (prenatal overgrowth) (Prawitt et al, 2005), a paradigm of insulator malfunction.…”

Section: Introductionmentioning

confidence: 99%

ISWI contributes to ArsI insulator function in development of the sea urchin

2012

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SUMMARYInsulators are genomic elements that regulate transcriptional activity by forming chromatin boundaries. Various DNA insulators have been identified or are postulated in many organisms, and the paradigmatic CTCF-dependent insulators are perhaps the best understood and most widespread in function. The diversity of DNA insulators is, however, understudied, especially in the context of embryonic development, when many new gene territories undergo transitions in functionality. Here we report the functional analysis of the arylsulfatase insulator (ArsI) derived from the sea urchin, which has conserved insulator activity throughout the many metazoans tested, but for which the molecular mechanism of function is unknown. Using a rapid in vivo assay system and a highthroughput mega-shift assay, we identified a minimal region in ArsI that is responsible for its insulator function. We discovered a small set of proteins specifically bound to the minimal ArsI region, including ISWI, a known chromatin-remodeling protein. During embryogenesis, ISWI was found to interact with select ArsI sites throughout the genome, and when inactivated led to misregulation of select gene expression, loss of insulator activity and aberrant morphogenesis. These studies reveal a mechanistic basis for ArsI function in the gene regulatory network of early development. KEY WORDS: Sea urchin, Insulator, ISWI, Embryogenesis, Gene regulation, Strongylocentrotus purpuratus ISWI contributes to ArsI insulator function in development of the sea urchinMamiko Yajima*, William G. Fairbrother and Gary M. Wessel* DEVELOPMENT 3614 Watanabe et al., 2006;Tajima et al., 2006). It is not known how this DNA element functions as an insulator, nor what proteins are associated with its activity. We sought to expand our understanding of diverse insulators and their functions and report here that the ArsI sequence is found throughout the genome and interacts with a small cohort of nuclear proteins responsible for its insulator activity. One of the ArsI-associated proteins discovered here, an ortholog of the chromatin-remodeling protein ISWI, was found to function in ArsI activities in vivo and to associate with ArsI sites differentially during the course of embryonic development. These results demonstrate in vivo important regulation of early embryonic development by a DNA insulator and document another essential element in our understanding of GRNs during embryonic development. MATERIALS AND METHODS Mega-shift assay, cloning and sequencingA high-throughput binding assay called mega-shift (microarray evaluation of genomic aptamers by shift) was used to narrow down the exact location(s) of the ArsI sequence-protein complexes. For detailed methods, see Tantin et al. (Tantin et al., 2008). Briefly, a previously identified 573 bp region of ArsI sequence and its adjacent 1.4 kb sequence from the genomic loci of the Strongylocentrotus purpuratus arylsulfatase ortholog (Sp-Ars; accession number NW_001468620) were synthesized as a pool of tiled 30-mers with a common flankin...

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Microdeletion and IGF2 loss of imprinting in a cascade causing Beckwith-Wiedemann syndrome with Wilms' tumor

Cited by 38 publications

References 7 publications

Wt1 ablation and Igf2 upregulation in mice result in Wilms tumors with elevated ERK1/2 phosphorylation

Wt1 ablation and Igf2 upregulation in mice result in Wilms tumors with elevated ERK1/2 phosphorylation

Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas†

ISWI contributes to ArsI insulator function in development of the sea urchin

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