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

Brown, Keith; Power, F. Clark; Moore, Bethany B.; Charles, Adrian; Malik, Karim

doi:10.1158/1541-7786.mcr-08-0002

Cited by 20 publications

(28 citation statements)

References 45 publications

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“…Genomic imprinting has been implicated in Beckwith-Wiedemann syndrome, which involves complicated genetic mechanisms. Genomic imprinting and epigenetic regulatory mechanisms of the WT1 gene region on kidney development and tumorigenesis of Wilms tumor has been studied extensively (Dallosso et al, 2004;Hancock et al, 2007;Brown et al, 2008). As shown by our data, some patients with deletions of both SLC1A2 and BDNF do not have autism whereas two patients with autism had deletion of neither SLC1A2 nor BDNF, suggesting implication of other genetic or epigenetic factors.…”

Section: Discussionmentioning

confidence: 53%

Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism

Xu¹,

Han²,

Morales³

et al. 2008

Cytogenet Genome Res

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WAGR (Wilms tumor, Aniridia, Genitourinary malformations and mental Retardation) syndrome is a rare genomic disorder caused by deletion of the 11p14-p12 chromosome region. The majority of WAGR patients have mental retardation and behavioral problems, and more than 20% of the patients also have features of autism. While the Wilms tumor/genitourinary anomalies and aniridia are caused by deletion of WT1 and PAX6 respectively, the genomic cause of mental retardation and autism in WAGR syndrome remains unknown. Using oligonucleotide arrays, we have characterized the 11p14-p12 deletions in 31 patients and identified all the genes involved in each deletion. The deletions had sizes ranging from 4.9 to 23 Mb that encompass 18–62 genes (40 on average). In addition to WT1 and PAX6, all the patients had deletion of PRRG4 (transmembrane gamma-carboxyglutamic acid protein 4). The majority of them had deletion of BDNF (brain-derived neurotrophic factor) and SLC1A2 [solute carrier family 1 (glial high affinity glutamate transporter) member 2]. Deletion of BDNF and SLC1A2 occurred in patients with autism more frequently than in those without autism. Literature review on the functions of the genes suggests that haploinsufficiency of SLC1A2, PRRG4, and BDNF may contribute to mental retardation and behavioral problems. In particular, BDNF may modulate the risk of autism in WAGR patients as suggested by its link with Rett syndrome as a target of MECP2. We observed that all the de novo deletions occurred in the chromosome 11 inherited from the father in the families genotyped, implying a predisposition for de novo mutations occurring in spermatogenesis and possible involvement of imprinting in cognitive impairment in WAGR patients.

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Section: Discussionmentioning

confidence: 53%

Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism

Xu¹,

Han²,

Morales³

et al. 2008

Cytogenet Genome Res

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“…It has been estimated that LOI of IGF2 occurs in 60-80% of Wilms' tumors [104,105]. Patients with LOI have a median age of 65 months at diagnosis (IQR 47-83 months), while those with normal imprinting are diagnosed much earlier, with a median age of 24 months (IQR 13-35 months)…”

Section: Wilms' Tumormentioning

confidence: 99%

Involvement of the IGF system in fetal growth and childhood cancer: an overview of potential mechanisms

Callan

Milne

2009

Cancer Causes Control

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Fetal growth is determined by a complex interplay of genetic, nutritional, environmental, and hormonal factors. Greater than expected fetal growth has been positively associated with the risk of the development of some cancers in childhood, particularly acute lymphoblastic leukemia, and the biological mechanisms underlying such associations are thought to involve insulin-like growth factors (IGFs). Circulating IGF levels are highly correlated with fetal growth, and IGFs are believed to play an important role in carcinogenesis; however, these two bodies of evidence have not been well integrated and, as a result, the potential underlying biological mechanisms linking the IGF system with the development of specific childhood cancers have not been elucidated. This review aims to draw together and summarize the literature linking the IGF system, rapidity of fetal growth, and risk of some specific childhood cancers; suggest explanations for some of the inconsistencies observed in previous studies of these associations; and propose an integrated framework for the putative involvement of the IGF system in the development of at least some childhood cancers. If the challenges involved in studying the complex IGF system can be overcome, this field presents an exciting opportunity to elucidate etiological pathways to childhood malignancies.

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“…Loss of IGF2 and WT1 imprinting in tumors typically results in up regulated expression levels (Brown et al 2008;Jacobs et al 2013), and our recent unpublished findings suggest that IGF2 imprinting may be lost in a subset of patients with DD. As both IGF2 and WT1 expression levels are up regulated in DD cells, we will include WT1 in these ongoing studies to determine if abnormal epigenetic regulation of expression contributes to the increased IGF2 and WT1 transcript levels in this fibrosis.…”

Section: Discussionmentioning

confidence: 67%

WT1 expression is increased in primary fibroblasts derived from Dupuytren’s disease tissues

Crawford

Raykha

Charles

et al. 2015

J. Cell Commun. Signal.

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Dupuytren's disease (DD) is a fibroproliferative and contractile fibrosis of the palmar fascia that, like all other heritable fibroses, is currently incurable. While DD is invariably benign, it exhibits some molecular similarities to malignant tumours, including increased levels of ß-catenin, oncofetal fibronectin, periostin and insulin-like growth factor (IGF)-II. To gain additional insights into the pathogenesis of DD, we have assessed the expression of WT1, encoding Wilm's tumour 1, an established tumour biomarker that is syntenic with IGF2, the gene encoding IGF-II in humans. We found that WT1 expression is robustly and consistently up regulated in primary fibroblasts derived from the fibrotic palmar fascia of patients with DD (DD cells), whereas syngeneic fibroblasts derived from the macroscopically unaffected palmar fascia in these patients and allogeneic fibroblasts derived from normal palmar fascia exhibited very low or undetectable WT1 transcript levels. WT1 immunoreactivity was evident in a subset of cells in the fibrotic palmar fascia of patients with DD, but not in macroscopically unaffected palmar fascia. These findings identify WT1 expression as a novel biomarker of fibrotic palmar fascia and are consistent with the hypothesis that the pathogeneses of DD and malignant tumours have molecular similarities.

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

Cited by 20 publications

References 45 publications

Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism

Characterization of 11p14-p12 deletion in WAGR syndrome by array CGH for identifying genes contributing to mental retardation and autism

Involvement of the IGF system in fetal growth and childhood cancer: an overview of potential mechanisms

WT1 expression is increased in primary fibroblasts derived from Dupuytren’s disease tissues

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