Somatic Mosaicism for Partial Paternal Isodisomy in Wiedemann-Beckwith Syndrome: A Post-Fertilization Event

Henry, Isabelle; Puech, Anne; Riesewijk, A.; Ahnine, L; Mannens, Marcel; Beldjord, Chérif; Bitoun, Pierre; Tournade, M F; Landrieu, P.; Junien, Claudine

doi:10.1159/000472384

Cited by 125 publications

(79 citation statements)

References 22 publications

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“…In principle, loss of 11p15 maternal alleles in pediatric tumors have the same consequence as GOI in HCCs of inactivating imprinted, maternally expressed genes. Furthermore, this mechanism recalls BWS cases with paternal uniparental disomy (31,32), and suggests a unifying common picture, in which loss of function of 11p15 maternal alleles, through various different mechanisms, may be the critical event associating this chromosomal region with tumorigenesis and BWS. The loss of maternal specific methylation of KvDMR1, not only in HCCs but also in BWS (9,10), supports this hypothesis.…”

Section: Discussionmentioning

confidence: 76%

Gain of imprinting at chromosome 11p15: A pathogenetic mechanism identified in human hepatocarcinomas

Schwienbacher

Gramantieri

Scelfo

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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Genomic imprinting is a reversible condition that causes parentalspecific silencing of maternally or paternally inherited genes. Analysis of DNA and RNA from 52 human hepatocarcinoma samples revealed abnormal imprinting of genes located at chromosome 11p15 in 51% of 37 informative samples. The most frequently detected abnormality was gain of imprinting, which led to loss of expression of genes present on the maternal chromosome. As compared with matched normal liver tissue, hepatocellular carcinomas showed extinction or significant reduction of expression of one of the alleles of the CDKN1C, SLC22A1L, and IGF2 genes. Loss of maternal-specific methylation at the KvDMR1 locus in hepatocarcinoma correlated with abnormal expression of CDKN1C and IGF2, suggesting a function for KvDMR1 as a long-range imprinting center active in adult tissues. These results point to the role of epigenetic mechanisms leading to loss of expression of imprinted genes at chromosome region 11p15 in human tumors.

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Section: Discussionmentioning

confidence: 76%

Gain of imprinting at chromosome 11p15: A pathogenetic mechanism identified in human hepatocarcinomas

Schwienbacher

Gramantieri

Scelfo

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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“…18,19 In these patients, in addition to the effects of IGF2 overexpression, a decreased level of the maternally expressed gene CDKN1C may contribute to the BWS phenotype. 9,12,20 It has been demonstrated that BWS patients with paternal UPD always show mosaicisms, suggesting that all cases had arisen as a postzygotic event 19,21,22 ; a possible explanation is that lack of one or more chromosome 11 maternally expressed genes may lead to embryonic lethality. 23 It was also suggested that the degree of mosaicism and the location of the genetic abnormality in different tissue is strongly associated with the pathological phenotype.…”

Section: Beckwith-wiedemann Syndrome (Bws (Mim 130650)mentioning

confidence: 99%

“…26 Clinically, a clear association between mosaic UPD and hemihyperplasia exists. 15,19,22,27 In addition, it was noted that neoplasias and Wilms' tumours are more frequent in BWS patients with pUPD or H19DMR hypermethylation than in BWS patients with other molecular defect. [27][28][29] Moreover, it has been hypothesized that extremely high levels of UPD might drive severe phenotypic expression of BWS; 30 but it is often difficult to determine if levels of UPD correlate with severity of the phenotype especially when the tissues/organs involved are not usually directly tested.…”

Section: Beckwith-wiedemann Syndrome (Bws (Mim 130650)mentioning

confidence: 99%

Beckwith–Wiedemann syndrome and uniparental disomy 11p: fine mapping of the recombination breakpoints and evaluation of several techniques

et al. 2011

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Beckwith-Wiedemann syndrome (BWS) is a phenotypically and genotypically heterogeneous overgrowth syndrome characterized by somatic overgrowth, macroglossia and abdominal wall defects. Other usual findings are hemihyperplasia, embryonal tumours, adrenocortical cytomegaly, ear anomalies, visceromegaly, renal abnormalities, neonatal hypoglycaemia, cleft palate, polydactyly and a positive family history. BWS is a complex, multigenic disorder associated, in up to 90% of patients, with alteration in the expression or function of one or more genes in the 11p15.5 imprinted gene cluster. There are several molecular anomalies associated with BWS and the large proportion of cases, about 85%, is sporadic and karyotypically normal. One of the major categories of BWS molecular alteration (10-20% of cases) is represented by mosaic paternal uniparental disomy (pUPD), namely patients with two paternally derived copies of chromosome 11p15 and no maternal contribution for that. In these patients, in addition to the effects of IGF2 overexpression, a decreased level of the maternally expressed gene CDKN1C may contribute to the BWS phenotype. In this paper, we reviewed a series of nine patients with BWS because of pUPD using several methods with the aim to evaluate the percentage of mosaicism, the methylation status at both loci, the extension of the pUPD at the short arm and the breakpoints of recombination. Fine mapping of mitotic recombination breakpoints by singlenucleotide polymorphism-array in individuals with UPD and fine estimation of epigenetic defects will provide a basis for understanding the aetiology of BWS, allowing more accurate prognostic predictions and facilitating management and surveillance of individuals with this disorder.

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“…Hemihyperplasia and organomegaly (in particular kidneys) have been shown to be clinical features associated with an increase in the relative risk of cancer. 3,14 ± 16 It was also suggested that patients with 11p15 UPD have an increased risk of tumour, 17,18 but subsequent studies on larger series of patients did not confirm these data. 3 This work had two aims: (1) to evaluate the usefulness of KvDMR1 methylation analysis of leukocyte DNA, in addition to tests for the presence of 11p15 UPD and methylation analysis of the H19 gene, for the diagnosis of BWS in a large series of 97 patients; (2) to determine whether clinical and/or molecular features are associated with an increased risk of tumour.…”

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 Mosaicism for Partial Paternal Isodisomy in Wiedemann-Beckwith Syndrome: A Post-Fertilization Event

Cited by 125 publications

References 22 publications

Gain of imprinting at chromosome 11p15: A pathogenetic mechanism identified in human hepatocarcinomas

Gain of imprinting at chromosome 11p15: A pathogenetic mechanism identified in human hepatocarcinomas

Beckwith–Wiedemann syndrome and uniparental disomy 11p: fine mapping of the recombination breakpoints and evaluation of several techniques

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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