Dataset Information

Wilms tumour in Beckwith-Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines.

ABSTRACT: Beckwith-Wiedemann Syndrome (BWS) is an overgrowth syndrome caused by a variety of molecular changes on chromosome 11p15.5. Children with BWS have a significant risk of developing Wilms tumours with the degree of risk being dependent on the underlying molecular mechanism. In particular, only a relatively small number of children with loss of methylation at the centromeric imprinting centre (IC2) were reported to have developed Wilms tumour. Discontinuation of tumour surveillance for children with BWS and loss of methylation at IC2 has been proposed in several recent publications. We report here three children with BWS reported to have loss of methylation at IC2 on clinical testing who developed Wilms tumour or precursor lesions. Using multiple molecular approaches and multiple tissues, we reclassified one of these cases to paternal uniparental disomy for chromosome 11p15.5. These cases highlight the current challenges in definitively assigning tumour risk based on molecular classification in BWS. The confirmed cases of loss of methylation at IC2 also suggest that the risk of Wilms tumour in this population is not as low as previously thought. Therefore, we recommend that for now, all children with a clinical or molecular diagnosis of BWS be screened for Wilms tumour by abdominal ultrasonography until the age of eight years regardless of the molecular classification.

SUBMITTER: Brzezinski J

PROVIDER: S-EPMC5558170 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Wilms tumour in Beckwith-Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines.

Brzezinski Jack J Shuman Cheryl C Choufani Sanaa S Ray Peter P Stavropoulos Dmitiri J DJ Basran Raveen R Steele Leslie L Parkinson Nicole N Grant Ronald R Thorner Paul P Lorenzo Armando A Weksberg Rosanna R

European journal of human genetics : EJHG 20170712 9

Beckwith-Wiedemann Syndrome (BWS) is an overgrowth syndrome caused by a variety of molecular changes on chromosome 11p15.5. Children with BWS have a significant risk of developing Wilms tumours with the degree of risk being dependent on the underlying molecular mechanism. In particular, only a relatively small number of children with loss of methylation at the centromeric imprinting centre (IC2) were reported to have developed Wilms tumour. Discontinuation of tumour surveillance for children wit ...[more]

PMID: 28699632

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Project description:BackgroundBeckwith-Wiedemann syndrome (BWS) is an imprinting disorder with a population frequency of approximately 1 in 10,000. The most common epigenetic defect in BWS is a loss of methylation (LOM) at the 11p15.5 imprinting centre, KCNQ1OT1 TSS-DMR, and affects 50% of cases. We hypothesised that genetic factors linked to folate metabolism may play a role in BWS predisposition via effects on methylation maintenance at KCNQ1OT1 TSS-DMR.ResultsSingle nucleotide variants (SNVs) in the folate pathway affecting methylenetetrahydrofolate reductase (MTHFR), methionine synthase reductase (MTRR), 5-methyltetrahydrofolate-homocysteine S-methyltransferase (MTR), cystathionine beta-synthase (CBS) and methionine adenosyltransferase (MAT1A) were examined in 55 BWS patients with KCNQ1OT1 TSS-DMR LOM and in 100 unaffected cases. MTHFR rs1801133: C>T was more prevalent in BWS with KCNQ1OT1 TSS-DMR LOM (p < 0.017); however, the relationship was not significant when the Bonferroni correction for multiple testing was applied (significance, p = 0.0036). None of the remaining 13 SNVs were significantly different in the two populations tested. The DNMT1 locus was screened in 53 BWS cases, and three rare missense variants were identified in each of three patients: rs138841970: C>T, rs150331990: A>G and rs757460628: G>A encoding NP_001124295 p.Arg136Cys, p.His1118Arg and p.Arg1223His, respectively. These variants have population frequencies of less than 1 in 1000 and were absent from 100 control cases. Functional characterization using a hemimethylated DNA trapping assay revealed a reduced methyltransferase activity relative to wild-type DNMT1 for each variant ranging from 40 to 70% reduction in activity.ConclusionsThis study is the first to examine folate pathway genetics in BWS and to identify rare DNMT1 missense variants in affected individuals. Our data suggests that reduced DNMT1 activity could affect maintenance of methylation at KCNQ1OT1 TSS-DMR in some cases of BWS, possibly via a maternal effect in the early embryo. Larger cohort studies are warranted to further interrogate the relationship between impaired MTHFR enzymatic activity attributable to MTHFR rs1801133: C>T, dietary folate intake and BWS.

Dataset Information

Wilms tumour in Beckwith-Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines.

Publications

Wilms tumour in Beckwith-Wiedemann Syndrome and loss of methylation at imprinting centre 2: revisiting tumour surveillance guidelines.

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