Epigenotyping as a tool for the prediction of tumor risk and tumor type in patients with Beckwith-Wiedemann syndrome (BWS)

Bliek, Jet; Gicquel, Christine; Maas, Saskia M.; Gaston, Véronique; Bouc, Yves Le; Mannens, Marcel M.A.M.

doi:10.1016/j.jpeds.2004.08.007

Cited by 89 publications

(66 citation statements)

References 24 publications

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“…First, gain of methylation in H19 upstream DNA sequences (as well as in the transcribed region of the H19 gene), which is the DNA counterpart of LOI that is scored in this and many other studies, can be seen in the nonneoplastic kidney parenchyma of a substantial group of sporadic Wilms' tumor patients (36,45). Second, IGF2 LOI associated with gain of methylation at the H19 5V DMR in various somatic tissues is the defining feature of the class of Beckwith-Wiedemann syndrome that is associated with a predisposition to Wilms' tumor (12,46,47). Recently, it has been suggested that rare cases of sporadic Wilms' tumor might have LOI secondary to LOH affecting the chromosome 16q CTCF gene (48).…”

Section: Stage Dependence and Timing Of Genetic And Epigenetic Eventssupporting

confidence: 56%

“…In another large group of sporadic Wilms' tumors, both parental alleles are retained, but the maternal allele of H19 and its upstream insulator sequences become hypermethylated at CpG sites, leading to the same end point of biallelic IGF2 expression [loss of imprinting (LOI)] and H19 silencing. In the Beckwith-Wiedemann syndrome, a subset of affected individuals show gain of methylation at H19 mat and LOI of IGF2 in their somatic tissues, leading to somatic overgrowth and a strong predisposition to Wilms' tumor (12). Recently, rare Beckwith-Wiedemann syndrome cases were identified with germ-line microdeletions in the H19 upstream sequences (13), a genetic finding that further supports the equivalence of WT2 and IGF2/H19.…”

Section: Introductionmentioning

confidence: 87%

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Genomic Profiling Maps Loss of Heterozygosity and Defines the Timing and Stage Dependence of Epigenetic and Genetic Events in Wilms' Tumors

Yuan

Yamashiro³

et al. 2005

Molecular Cancer Research

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To understand genetic and epigenetic pathways in Wilms' tumors, we carried out a genome scan for loss of heterozygosity (LOH) using Affymetrix 10K single nucleotide polymorphism (SNP) chips and supplemented the data with karyotype information. To score loss of imprinting (LOI) of the IGF2 gene, we assessed DNA methylation of the H19 5V differentially methylated region (DMR). Few chromosomal regions other than band 11p13 (WT1) were lost in Wilms' tumors from Denys-Drash and Wilms' tumor-aniridia syndromes, whereas sporadic Wilms' tumors showed LOH of several regions, most frequently 11p15 but also 1p, 4q, 7p, 11q, 14q, 16q, and 17p. LOI was common in the sporadic Wilms' tumors but absent in the syndromic cases. The SNP chips identified novel centers of LOH in the sporadic tumors, including a 2.4-Mb minimal region on chromosome 4q24-q25. Losses of chromosomes 1p, 14q, 16q, and 17p were more common in tumors presenting at an advanced stage; 11p15 LOH was seen at all stages, whereas LOI was associated with early-stage presentation. Wilms' tumors with LOI often completely lacked LOH in the genome-wide analysis, and in some tumors with concomitant 16q LOH and LOI, the loss of chromosome 16q was mosaic, whereas the H19 DMR methylation was complete. These findings confirm molecular differences between sporadic and syndromic Wilms' tumors, define regions of recurrent LOH, and indicate that gain of methylation at the H19 DMR is an early event in Wilms' tumorigenesis that is independent of chromosomal losses. The data further suggest a biological difference between sporadic Wilms' tumors with and without LOI. (Mol Cancer Res 2005;3(9):493 -502)

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Section: Stage Dependence and Timing Of Genetic And Epigenetic Eventssupporting

confidence: 56%

Section: Introductionmentioning

confidence: 87%

Genomic Profiling Maps Loss of Heterozygosity and Defines the Timing and Stage Dependence of Epigenetic and Genetic Events in Wilms' Tumors

Yuan

Yamashiro³

et al. 2005

Molecular Cancer Research

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“…4,[9][10][11]13,[27][28][29] In this study we further investigated these correlations providing data on a large cohort of fully characterized BWS patients with 11p15 region molecular defects. Our analysis evidences in the four BWS molecular subtypes differences in the incidence of many phenotypic traits, such as growth pattern, prevalence and severity of abdominal wall defects, macrosomia, nevus flammeus, ear signs, renal malformations, ureteral anomalies, organ enlargement, polyhydramnios, cancer incidence, and histotypes.…”

Section: Phenotypes In Beckwith-wiedemann Syndromementioning

confidence: 99%

“…4,[9][10][11]13,[27][28][29] Some aspects emerge as new: in particular, the significant association between hepatoblastoma and UPD may have relevant implications for cancer screening, the association between IC2-GoM and uretheral defects and polyhydramnios may have implications for the neonatal nephrourological management, the higher incidence of benign neoplasm paralleling the distribution of the malignant ones should be taken into considerations during patients' follow-up. Finally, IC2-LoM/CDKN1C variant patients display a higher rate of postnatal overgrowth, poorly studied before; as in these molecular subgroups neonatal macrosomia is rarer than in UPD/IC1-GoM ones 13 clinicians should be aware that these molecular subtypes of BWS may display specific growth patterns after the neonatal period.…”

Section: Phenotypes In Beckwith-wiedemann Syndromementioning

confidence: 99%

(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome

et al. 2015

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Beckwith-Wiedemann syndrome (BWS) is characterized by cancer predisposition, overgrowth and highly variable association of macroglossia, abdominal wall defects, nephrourological anomalies, nevus flammeus, ear malformations, hypoglycemia, hemihyperplasia, and organomegaly. BWS molecular defects, causing alteration of expression or activity of the genes regulated by two imprinting centres (IC) in the 11p15 chromosomal region, are also heterogeneous. In this paper we define (epi)genotype-phenotype correlations in molecularly confirmed BWS patients. The characteristics of 318 BWS patients with proven molecular defect were compared among the main four molecular subclasses: IC2 loss of methylation (IC2-LoM, n = 190), IC1 gain of methylation (IC1-GoM, n = 31), chromosome 11p15 paternal uniparental disomy (UPD, n = 87), and cyclin-dependent kinase inhibitor 1C gene (CDKN1C) variants (n = 10). A characteristic growth pattern was found in each group; neonatal macrosomia was almost constant in IC1-GoM, postnatal overgrowth in IC2-LoM, and hemihyperplasia more common in UPD (Po0.001). Exomphalos was more common in IC2/CDKN1C patients (Po0.001). Renal defects were typical of UPD/IC1 patients, uretheral malformations of IC1-GoM cases (Po0.001). Ear anomalies and nevus flammeus were associated with IC2/CDKN1C genotype (Po0.001). Macroglossia was less common among UPD patients (Po0.001). Wilms' tumor was associated with IC1-GoM or UPD and never observed in IC2-LoM patients (Po0.001). Hepatoblastoma occurred only in UPD cases. Cancer risk was lower in IC2/CDKN1C, intermediate in UPD, and very high in IC1 cases (P = 0.009).In conclusion, (epi)genotype-phenotype correlations define four different phenotypic BWS profiles with some degree of clinical overlap. These observations impact clinical care allowing to move toward (epi) genotype-based follow-up and cancer screening.

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“…3,[10][11][12]13,[15][16][17] Clinical findings associated with higher risks of tumor development include hemihyperplasia, nephromegaly, and nephrogenic rests. 10,18 Although different molecular subgroups have been shown to be associated with different tumor rates and tumor profiles, 19,[20][21][22][23][24] further clinical studies are needed to validate these data before implementing stratified surveillance protocols.…”

Section: Introductionmentioning

confidence: 99%

Beckwith–Wiedemann syndrome

2009

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In association withBeckwith-Wiedemann syndrome Beckwith-Wiedemann syndrome (BWS) is a model disorder for the study of imprinting, growth dysregulation, and tumorigenesis. Unique observations in this disorder point to an important embryonic developmental window relevant to the observations of increased monozygotic twinning and an increased rate of epigenetic errors after subfertility/assisted reproduction.

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Epigenotyping as a tool for the prediction of tumor risk and tumor type in patients with Beckwith-Wiedemann syndrome (BWS)

Cited by 89 publications

References 24 publications

Genomic Profiling Maps Loss of Heterozygosity and Defines the Timing and Stage Dependence of Epigenetic and Genetic Events in Wilms' Tumors

Genomic Profiling Maps Loss of Heterozygosity and Defines the Timing and Stage Dependence of Epigenetic and Genetic Events in Wilms' Tumors

(Epi)genotype–phenotype correlations in Beckwith–Wiedemann syndrome

Beckwith–Wiedemann syndrome

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