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.

Figure 1

Map of chromosome 11p15 region: (a) Schematic representation of imprinting regulation in the chromosome 11p15 region. Orange represents maternally derived chromosomes while green represents paternally derived chromosomes. Typically, IC1 is methylated on the paternally derived chromosome resulting in IGF2 expression and silencing of H19 while on the maternally derived chromosome IC2 is methylated resulting in silencing of KCNQ1OT1 and expression of KCNQ1 and CDKN1C. (b) Map of KCNQ1OT1 (DMR (IC2) indicating the coverage of pyrosequencing, MS-MLPA, and the Infinium methylation array. IC2 overlaps the CpG island indicated by a green bar. Genome maps are adapted from the UCSC Genome Browser. (c) Map of H19 (DMR (IC1) indicating coverage of pyrosequencing, methylation-specific MLPA probes (MS-MLPA), copy-number specific MLPA probes (CN-MLPA), and the Infinium methylation array. CTCF target sites are indicated.

Figure 2

Clinical photographs of patients reported in this case series. (a) Case 1; (b) Case 2; and (c) Case 3.

Figure 3

SNP Array data from the 3 cases in this series at 11p15.5 and 11p15.4. For each case the first set of data represents the B allele frequency (BAF, green) and the second set of data represents the log R ratio (LRR, blue). In the bottom panel, a red arrow marks IC1 (chr11:2019627-2024297) while a purple arrow marks IC2 (chr11:2720411-2722087).

Figure 4

Pathology findings from partial nephrectomy. (a–d) Treated WT. (a) Macroscopic appearance of the tumour measuring only 0.5 cm in diameter. (b) The central portion of the specimen is mainly necrotic with isolated differentiated epithelial elements. (c) The more peripheral portion consists of blastema (lower left corner) with differentiated tubules in a fibrotic stroma. (d) Intra-renal vein (vessel wall marked by arrow) containing a tumour thrombus composed of fibrous stroma and rare differentiated tubules. (e and f) perilobar nephrogenic rest showing a well circumscribed rest surrounded by normal renal parenchyma. The rest is composed of nests of tubules separated by varying amounts of fibrous stroma. (original magnifications: a × 1, b, c × 200, d × 100, e × 10, and f × 100).