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

Sullivan, Michael J.; Taniguchi, Tadatsugu; Jhee, Agnes; Kerr, Natalie; Reeve, Anthony E.

doi:10.1038/sj.onc.1203096

Cited by 85 publications

(80 citation statements)

References 50 publications

(65 reference statements)

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“…Thus, we propose the patterns of methylation of H19 in TGCTs as 'erasure of methylation' by contrast with 'gain of hypomethylation' in somatic neoplasms. The region between exons 2 and 3 of IGF2 has been suggested as a putative DMR (Sullivan et al, 1999). We confirmed this region is hemimethylated in normal PBLs.…”

Section: T Kawakami Et Alsupporting

confidence: 82%

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Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin

et al. 2006

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Genome-wide epigenetic modification plays a crucial role in regulating genome functions at critical stages of development. In particular, DNA methylation is known to be reprogrammed on a genome-wide level in germ cells and in preimplantation embryos, although it is relatively stable in somatic cells. In this reprogramming process, the genome becomes demethylated, and methylated de novo during later stages of development. Reprogramming of DNA methylation in male germ cells has not been fully investigated. Testicular germ cell tumors (TGCTs) possess a pluripotential nature and display protean histology from germ cells to embryonal and somatic cell differentiation. These properties make TGCT a unique model for studying germ cell development and gametogenesis in respect of DNA reprogramming. In order to obtain an insight into the epigenetic dynamics of TGCTs, we conducted a comprehensive analysis of differential methylated regions (DMRs) on H19 and IGF2 in TGCTs compared with testicular malignant lymphomas. In the present study, we show that methylation imprint at the promoter and CTCF-binding site upstream of H19 was completely erased in both seiminomatous and nonseminomatous TGCTs, whereas differential methylation was observed in testicular lymphomas. The erasure of methylation imprint was also observed in TGCTs with malignant transformation. We found biallelic unmethylation at the promoter and the CTCF-binding site upstream of H19 is required, but not sufficient for the biallelic expression of H19 in TGCTs. These data suggest that factors other than methylation contribute to transcriptional regulation of imprinted genes in TGCTs. The present data have shown that TGCTs carry distinctive epigenetic profiles at the core-imprinting domain of H19/ IGF2 from other neoplasms of somatic cell origin. The data also suggest that both seminomatous and nonseminomatous TGCTs carry methylation profiles similar to fetal germ cells, but not adult germ cells, indicating the origin of TGCTs as fetal germ cells.

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Section: T Kawakami Et Alsupporting

confidence: 82%

“…Based on the predominant unmethylation profile of H19 in TGCTs, we analysed IGF2 DMR located on exons 2 and 3 (Sullivan et al, 1999;Figure 3a). This region contained one polymorphic site and five of the 19 samples were informative for this site.…”

Section: Methylation Patterns Of Igf2 Is Mosaic In Tgctsmentioning

confidence: 99%

Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin

et al. 2006

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“…1) and is normally maternally methylated (IGF2 DMR; ref. 28), whereas another is located upstream of H19 and is paternally methylated (29). The latter region harbors sequences known to bind to the zinc finger protein CTCF in a methylation-sensitive manner (18,30).…”

Section: Resultsmentioning

confidence: 99%

“…This DMR normally carries a maternal methylation mark in both mouse and human, but this methylation is specifically reduced or lost in Wilms' tumors (28) and colorectal cancers (14)(15)(16) and this correlates with IGF2 LOI (14, 15).…”

Section: Introductionmentioning

confidence: 99%

Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer

Murphy

Huang

Wen

et al. 2006

Molecular Cancer Research

127

103

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Overexpression of the imprinted insulin-like growth factor-II (IGF2) is a prominent characteristic of gynecologic malignancies. The purpose of this study was to determine whether IGF2 loss of imprinting (LOI), aberrant H19 expression, and/or epigenetic deregulation of the IGF2/H19 imprinted domain contributes to elevated IGF2 expression in serous epithelial ovarian tumors. IGF2 LOI was observed in 5 of 23 informative serous epithelial ovarian cancers, but this did not correlate with elevated expression of IGF2 H19 RNA expression levels were also found not to correlate with IGF2 transcript levels. However, we identified positive correlations between elevated IGF2 expression and hypermethylation of CCCTC transcription factor binding sites 1 and 6 at the H19 proximal imprint center (P = 0.05 and 0.02, respectively). Hypermethylation of CCCTC transcription factor sites 1 and 6 was observed more frequently in cancer DNA compared with lymphocyte DNA obtained from women without malignancy (P < 0.0001 for both sites 1 and 6). Ovarian cancers were also more likely to exhibit maternal allele-specific hypomethylation upstream of the imprinted IGF2 promoters when compared with normal lymphocyte DNA (P = 0.004). This is the same region shown previously to be hypomethylated in colon cancers with IGF2 LOI, but this was not associated with LOI in ovarian cancers. Elevated IGF2 expression is a frequent event in serous ovarian cancer and this occurs in the absence of IGF2 LOI. These data indicate that the epigenetic changes observed in these cancers at the imprint center may contribute to IGF2 overexpression in a novel mechanistic manner. (Mol Cancer Res 2006;4(4):283 -92)

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“…CpG islands are normally unmethylated, but allele-specific methylation of CpG islands appears to mark both the inactive X chromosome (Yen et al 1984) and many imprinted genes, for example, H19, Snrpn, and Igf2r (Brandeis et al 1993;Shemer et al 1997;Wutz et al 1997). In addition, GC-rich sequences that are not CpG islands (i.e., they meet the first, but not the second criterion above) may also be differentially methylated (termed a differentially methylated region) in the vicinity of imprinted genes, for example Igf2 (Sullivan et al 1999) and a second site 2-4 kb upstream of the H19 CpG island (Thorvaldsen et al 1998). Therefore, one of our goals was to identify conserved CpG islands and GC-rich sequences that might serve as a substrate for future experiments to investigate allelespecific methylation.…”

Section: A Two-island Rule For Imprinted Genesmentioning

confidence: 99%

Sequence and Comparative Analysis of the Mouse 1-Megabase Region Orthologous to the Human 11p15 Imprinted Domain

et al. 2000

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A major barrier to conceptual advances in understanding the mechanisms and regulation of imprinting of a genomic region is our relatively poor understanding of the overall organization of genes and of the potentially important cis-acting regulatory sequences that lie in the nonexonic segments that make up 97% of the genome. Interspecies sequence comparison offers an effective approach to identify sequence from conserved functional elements. In this article we describe the successful use of this approach in comparing a ∼1-Mb imprinted genomic domain on mouse chromosome 7 to its orthologous region on human 11p15.5. Within the region, we identified 112 exons of known genes as well as a novel gene identified uniquely in the mouse region, termed Msuit, that was found to be imprinted. In addition to these coding elements, we identified 33 CpG islands and 49 orthologous nonexonic, nonisland sequences that met our criteria as being conserved, and making up 4.1% of the total sequence. These conserved noncoding sequence elements were generally clustered near imprinted genes and the majority were between Igf2 and H19 or within Kvlqt1.

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

Cited by 85 publications

References 50 publications

Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin

Erasure of methylation imprint at the promoter and CTCF-binding site upstream of H19 in human testicular germ cell tumors of adolescents indicate their fetal germ cell origin

Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer

Sequence and Comparative Analysis of the Mouse 1-Megabase Region Orthologous to the Human 11p15 Imprinted Domain

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