Somatic overgrowth associated with overexpression of insulin–like growth factor II

Morison, Ian M.; Dm, Becroft; Taniguchi, Tadatsugu; Woods, C. G.; Ae, Reeve

doi:10.1038/nm0396-311

Cited by 133 publications

(79 citation statements)

References 41 publications

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“…The same phenomenon of relaxed IGF2 imprinting commonly occurs in Beckwith-Wiedemann syndrome (Weksberg et al, 1993;Reik et al, 1994), in children with the constitutional IGF2 overgrowth syndrome (Morison et al, 1996), and in the normal tissue adjacent to some cancers with relaxed imprinting (Okamoto et al, 1997;Cui et al, 1998).…”

Section: Introductionmentioning

confidence: 71%

Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation

et al. 1999

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Relaxation of IGF2 imprinting occurs in Wilms tumours and many other cancers, but the mechanism of loss of imprinting (LOI) remains unknown. To investigate the role of altered DNA methylation in LOI, we examined the pattern of methylation of the human insulin-IGF2 region in Wilms tumours and the normal kidney. The analysis included regions homologous to three`di erentially methylated regions' of the mouse Igf2 gene (dmrs 0, 1 and 2). In tumours displaying normal IGF2 imprinting, and in the normal kidney, maternal allelespeci®c DNA methylation was identi®ed spanning exons 2 and 3. This region is homologous to dmr 0, a site of maternal-speci®c di erential methylation in the mouse. In Wilms tumours with relaxed imprinting or 11p15.5 LOH this region was unmethylated. No other di erential methylation was identi®ed. In particular, two sites of paternal methylation in the mouse (dmrs 1 and 2), and all three imprinted IGF2 promoters were not methylated in the kidney or in Wilms tumours. We postulate that LOI in Wilms tumours is associated with loss of maternal allele-speci®c methylation from a region located upstream of the imprinted IGF2 promoters. This region may contain cis acting sequences that coordinately in¯uence imprinting.

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Section: Introductionmentioning

confidence: 71%

Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation

et al. 1999

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“…None of the patients had a family history of WT. Two patients (T13 and T25) had associated non-syndromic over-growth syndrome (Morison et al, 1996;Fukuzawa et al, 2008) and one patient (T7) had associated hemihyperplasia (Fukuzawa et al, 2008 …”

Section: Wt Samplesmentioning

confidence: 99%

Canonical WNT signalling determines lineage specificity in Wilms tumour

et al. 2009

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Wilms tumours (WTs) have two distinct types of histology with or without ectopic mesenchymal elements, suggesting that WTs arise from either the mesenchymal or epithelial nephrogenic lineages. Regardless of the presence or absence of CTNNB1 mutations, nuclear accumulation of b-catenin is often observed in WTs with ectopic mesenchymal elements. Here, we addressed the relationship between the WNT-signalling pathway and lineage in WTs by examining CTNNB1 and WT1 mutations, nuclear accumulation of b-catenin, tumour histology and gene expression profiles. In addition, we screened for mutations in WTX, which has been proposed to be a negative regulator of the canonical WNT-signalling pathway. Unsupervised clustering analysis identified two classes of tumours: mesenchymal lineage WNT-dependent tumours, and epithelial lineage WNT-independent tumours. In contrast to the mesenchymal lineage specificity of CTNNB1 mutations, WTX mutations were surprisingly observed in both lineages. WTX-mutant WTs with ectopic mesenchymal elements had nuclear accumulation of b-catenin, upregulation of WNT target genes and an association with CTNNB1 mutations in exon 7 or 8. However, epithelial lineage WTs with WTX mutations had no indications of active WNT signalling, suggesting that the involvement of WTX in the WNT-signalling pathway may be lineage dependent, and that WTX may have an alternative function to its role in the canonical WNT-signalling pathway.

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“…Clinically, it has to be distinguished from other overgrowth syndromes (OGS) such as Simpson ± Golabi ± Behmel syndrome and it must also be recognised in its incomplete or related forms such as nonsyndromic IGF2 overgrowth disorder 4 and isolated hemihyperplasia. 5 Molecular diagnosis is also difficult, mostly because of the large spectrum of genetic and epigenetic abnormalities.…”

Section: Introductionmentioning

confidence: 99%

Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith–Wiedemann syndrome

et al. 2001

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Beckwith ± Wiedemann syndrome (BWS) is an overgrowth disorder involving developmental abnormalities, tissue and organ hyperplasia and an increased risk of embryonal tumours (most commonly Wilms tumour). This multigenic disorder is caused by dysregulation of the expression of imprinted genes in the 11p15 chromosomal region. Molecular diagnosis of BWS is currently difficult, mostly due to the large spectrum of genetic and epigenetic abnormalities. The other difficulty in managing BWS is the identification of patients at risk of tumour. An imprinted antisense transcript within KCNQ1, called KCNQ1OT (also known as LIT1), was recently shown to be normally expressed from the paternal allele. A loss of imprinting of the KCNQ1OT gene, associated with the loss of maternal allele-specific methylation of the differentially methylated region KvDMR1 has been described in BWS patients. The principal aim of this study was to evaluate the usefulness of KvDMR1 methylation analysis of leukocyte DNA for the diagnosis of BWS. The allelic status of the 11p15 region and the methylation status of the KCNQ1OT and H19 genes were investigated in leukocyte DNA from 97 patients referred for BWS and classified into two groups according to clinical data: complete BWS (CBWS) (n=61) and incomplete BWS (IBWS) (n=36). Fifty-eight (60%) patients (39/61 CBWS and 19/36 IBWS) displayed abnormal demethylation of KvDMR1. In 11 of the 56 informative cases, demethylation of KvDMR1 was related to 11p15 uniparental disomy (UPD) (nine CBWS and two IBWS). Thirteen of the 39 patients with normal methylation of KvDMR1 displayed hypermethylation of the H19 gene. These 13 patients included two siblings with 11p15 trisomy. These results show that analysis of the methylation status of KvDMR1 and the H19 gene in leukocyte DNA is useful in the diagnosis of 11p15-related overgrowth syndromes, resulting in the diagnosis of BWS in more than 70% of investigated patients. We also evaluated clinical and molecular features as prognostic factors for tumour and showed that mosaicism for 11p15 UPD and hypermethylation of the H19 gene in blood cells were associated with an increased risk of tumour.

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Somatic overgrowth associated with overexpression of insulin–like growth factor II

Cited by 133 publications

References 41 publications

Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation

Relaxation of IGF2 imprinting in Wilms tumours associated with specific changes in IGF2 methylation

Canonical WNT signalling determines lineage specificity in Wilms tumour

Analysis of the methylation status of the KCNQ1OT and H19 genes in leukocyte DNA for the diagnosis and prognosis of Beckwith–Wiedemann syndrome

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