Epigenetic Specificity of Loss of Imprinting of the IGF2 Gene in Wilms Tumors

Björnsson, Hans T.; Brown, Lindsey J.; Fallin, M. Danielle; Rongione, Michael; Bibikova, Marina; Wickham, Eliza; Fan, Jie; Feinberg, Andrew P.

doi:10.1093/jnci/djm069

Cited by 96 publications

(60 citation statements)

References 21 publications

(30 reference statements)

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“…However, there is evidence to suggest that alterations in DMR methylation are specific for the IGF2/H19 locus in case of WTs (14,15,29). Nevertheless, our data broadens this concept by clearly documenting that transcriptional activation of imprinted genes is a common finding in WTs and imprinted genes are activated as functional units.…”

Section: B Dsupporting

confidence: 50%

“…To see whether widespread activation of imprinted genes in WTs depends on epigenetic changes, we analyzed the methylation status of H19DMR and made correlations with the expression level of imprinted genes. H19DMR has been chosen, as deregulation of the IGF2/H19 cluster is a wellknown mechanism described in many embryonal cancers (12,14,29). By using a quantitative real-time PCR-based method (14) we depicted that two-thirds of all WTs displayed alterations at this locus.…”

Section: ------------------------------------------------------------mentioning

confidence: 99%

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Altered expression of imprinted genes in Wilms tumors

Hubertus

Lacher²,

Rottenkolber³

et al. 2011

Oncol Rep

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Abstract. Overexpression of insulin-like growth factor 2 (IGF2), an imprinted gene located on chromosome 11p15, has been reported as a characteristic feature in various embryonal tumors, including Wilms tumor (WT). Recent studies specified loss of imprinting (LOI) in a differential methylated region (DMR) of the IGF2/H19 cluster or loss of heterozygosity (LOH), respectively, uniparental disomy (UPD) being responsible for this overexpression. However, the role of other imprinted genes in the genesis of WT is still unknown. In the current study, we analyzed transcriptional activity of the imprinted genes IGF2, H19, NNAT, DLK1, RTL1, MEG3, and MEST as well as the methylation status of the DMR of the IGF2/H19 cluster in a panel of 32 WTs. Except for H19, we detected massive overexpression of all genes in the majority of WTs compared to normal renal tissue, which was most prominent for the paternally expressed genes IGF2, NNAT, and MEST. Alterations of the H19DMR were found in two-thirds of the WTs. Moreover, we have seen a strong correlation between the transcriptional activity of IGF2, NNAT and MEST and LOI/LOH of H19DMR, which was inverse for H19. Expression of DLK1, RTL1 and MEG3 does not correlate with LOI/LOH of H19DMR. Altogether, our findings suggest that over-expression of imprinted genes is common in WTs and correlates at least for some imprinted genes with LOI of H19DMR. Thus, it may be speculated that alterations of the DNA modification machinery drive erroneous setting of methylation marks in imprinting regions throughout the genome, which leads to the concomitant activation of imprinted genes in blastomagenesis.

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Section: B Dsupporting

confidence: 50%

Section: ------------------------------------------------------------mentioning

confidence: 99%

Altered expression of imprinted genes in Wilms tumors

Hubertus

Lacher²,

Rottenkolber³

et al. 2011

Oncol Rep

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“…These include reports that have excluded imprinting defects in the 14q DLK1/GTL2 imprinting cluster in WT (45,46) and a study of allele-specific expression and methylation of imprinted genes in 11p15 LOI WTs, which showed that the only major alterations were confined to the IGF2/H19 region (47). However, the study we report here represents the first to directly compare two different loci that each show LOI in WT.…”

Section: Loi At 11p15mentioning

confidence: 86%

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

Brown

Power

Moore

et al. 2008

Molecular Cancer Research

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Epigenetic changes occur frequently in Wilms' tumor (WT), especially loss of imprinting (LOI) of IGF2/H19 at 11p15. Our previous results have identified imprinted transcripts (WT1-AS and AWT1) from the WT1 locus at 11p13 and showed LOI of these in some WTs. In this article, we set out to test the relationship between LOI at 11p13 and 11p15 and their timing in WT progression relative to other genetic changes. We found a higher level (83%) of 11p13 LOI in WT than of 11p15 LOI (71%). There was no correlation between methylation levels at the 11p13 and 11p15 differentially methylated regions or between allelic expression of WT1-AS/AWT1 and IGF2. Interestingly, retention of normal imprinting at 11p13 was associated with a small group of relatively late-onset, high-stage WTs. An examination of genetic and epigenetic alterations in nephrogenic rests, which are premalignant WT precursors, showed that LOI at both 11p13 and 11p15 occurred before either 16q loss of heterozygosity (LOH) or 7p LOH. This suggests that these LOH events are very unlikely to be a cause of LOI but that LOH may act by potentiating the effects of overexpression of IGF2 and/or WT1-AS/AWT1 that

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“…Through proliferation, this clone became the only hemopoietic cell in the bone marrow and peripheral blood and resulted in the β-thalassemia major phenotype, a phenomenon found in a variety of malignancies. 16,17 We conclude that the patient's β-thalassemia major involved inheritance of paternal uniparental isodisomy of chromosome 11p15 harboring the HBB [c.52A>T] allele, which was mixed with β-thalassemia minor mosaicism caused by normal biparental inheritance. Though homozygosity of autosomal recessive gene mutations was described in uniparental disomy of other chromosomes, homozygosity of HBB gene mutations associated with paternal uniparental isodisomy of 11p15 is reported here for the first time.…”

Section: Resultsmentioning

confidence: 94%