Characterization of translocations in mesenchymal hamartoma and undifferentiated embryonal sarcoma of the liver

Mathews, James; Duncavage, Eric J.; Pfeifer, John D.

doi:10.1016/j.yexmp.2013.09.006

Cited by 38 publications

(45 citation statements)

References 40 publications

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“…Androgenetic cells may have been present below the threshold of the STR assay but at sufficient density to resolve placenta-like levels of C19MC miRNA. This seems unlikely because the histologic sections from the paraffin blocks used for all the analyses had a similar proportion of stromal and nonstromal cells to other cases in the series, and multiple studies have implicated stroma as the principal genetically altered cell type in HMH [4,5], Alternatively, C19MC promoter demethylation because of a mechanism other than ABM may be responsible for this subset of HMHs. Somatic loss of imprinting of other genes is well established in the pathogenesis of neoplasms associated with BeckwithWiedemann syndrome and other tumors [16].…”

Section: C19mc Promoter Demethylation In Sporadic Hmh [N = 2)mentioning

confidence: 99%

“…The latter retain features normally only found in placental blood vessels, including expression of Glutl and other antigens. In an analogous manner, placental stromal cells or their progenitors might disseminate to the liver and proliferate to form mesenchyme-rich hamartomas, which retain the unmethylated paternal C19MC promoter status and miRNA expression of normal placental stroma [4,5,14], According to this model, grafting of otherwise normal placental stroma could produce HMH with C19MC demethylation but no detectable ABM. Proliferative abnormalities in ABM-associated PMD might enhance the likelihood of dissemination, accounting for the frequent association of HMH and ABM/PMD (Table 3).…”

Section: C19mc Promoter Demethylation In Sporadic Hmh [N = 2)mentioning

confidence: 99%

“…Including those in this study, at least 19 examples of HMH with structural alterations affecting chromosome 19ql3.4 in HMH have been published [4], A subset have been characterized in more detail, and in each case, a translocation or other type of rearrangement disrupts the C19MC promoter ± 5' exons in a manner likely to place C19MC miRNA expression under the regulation of a heterologous promoter/enhancer (Fig. 5).…”

Section: C19mc Gene Locus Rearrangements In Sporadic Hmh (N = 3)mentioning

confidence: 99%

“…As discussed previously [5], possible explanations include selective expression of one or more miRNA in the [7 ], s tr u c tu r a l r e a r r a n g e m e n ts r e p o r t e d in H M H (B-E) [4 ,5 ], a n d u n d if f e r e n t ia t e d e m b r y o n a l s a rc o m a (UES) o f t h e liv e r (F) [4 ]. A ll o f t h e re a r r a n g e m e n ts a p p e a r lik e ly t o C19MC cluster other than the small subset assessed by our RT-qPCR assay.…”

Section: Hmh Without C19mc Expression (N = 2)mentioning

confidence: 99%

“…Expression correlates inversely with methylation of the promoter; the paternal promoter is selectively demethyl ated in the placenta, whereas both alleles are methylated in other tissues. The chromosomal rearrangements characterized in sporadic HMH disrupt the promoter ± 5'-end of C19MC and appear to bring intact 3' portions of the gene under control of the MALAT1 promoter or other heterologous regulatory elements, which presumably promote hepatic expression [4,5]. A subset of HMH cases lacks a chromosomal rearrangement but exhibits another genetic abnormality, androgenetic-biparental mosaicism (ABM) [13,14], In ABM, all cells are diploid, but in a fraction of the cell population, both haploid sets of chromosomes are paternally derived and likely lack genome-wide maternal imprints [15].…”

Section: Introductionmentioning

confidence: 99%

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Methylation Status of the Chromosome Arm 19q MicroRNA Cluster in Sporadic and Androgenetic-Biparental Mosaicism–Associated Hepatic Mesenchymal Hamartoma

et al. 2015

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The C19MC gene on chromosome band 19q13.4 encodes a cluster of 46 microRNAs; those microRNAs are normally only expressed from the paternal allele and in the placenta. Placental expression correlates with selective demethylation of the paternal C19MC promoter, in contrast to methylation of both maternal and paternal alleles in nonplacental tissues. Prior investigations demonstrated "ectopic" activation of this gene in most hepatic mesenchymal hamartomas, including sporadic tumors and others with androgenetic-biparental mosaicism (subset of cells are diploid, but contain only paternally derived chromosomes). In the present investigation of C19MC promoter methylation status in a series of 14 mesenchymal hamartomas, a demethylated allele was identified in 6 tumors, including all 4 with androgenetic-biparental mosaicism. Conversely, only methylated alleles were cloned from sporadic hamartomas, including 3 tumors with chromosomal rearrangements thought likely to activate C19MC expression independent of the native promoter. In conjunction with published data, the findings suggest multiple molecular mechanisms for C19MC activation in hepatic mesenchymal hamartoma, including the existence of a normal placental imprinting pattern in mesenchymal cells in a subset of cases. Some or all of the latter hamartomas may result from placental "grafting," a hypothesis supported by endothelial expression of the placental vascular marker, glucose transporter-1, in 1 of the 6 cases with a demethylated allele.

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Section: C19mc Promoter Demethylation In Sporadic Hmh [N = 2)mentioning

confidence: 99%

Section: C19mc Promoter Demethylation In Sporadic Hmh [N = 2)mentioning

confidence: 99%

Section: C19mc Gene Locus Rearrangements In Sporadic Hmh (N = 3)mentioning

confidence: 99%