Imprinting cluster regions (ICRs) on chromosome 11p15 (WT2) and Beckwith-Wiedemann syndrome

A second Wilms tumor locus, WT2, maps to an imprinted region of chromosome 11p15.5. When it is a germline pathogenic variant, it causes Beckwith-Wiedemann syndrome. About 3% of children with Wilms tumor have germline epigenetic or genetic changes at the 11p15.5 growth regulatory locus without any clinical manifestations of overgrowth. Like children with Beckwith-Wiedemann syndrome, these children have an increased incidence of bilateral Wilms tumor or familial Wilms tumor.[32]

Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, and metachronous bilateral disease is also observed.[29,41,42] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the National Wilms Tumor Study (NWTS).[42,43]

Approximately 80% of patients with Beckwith-Wiedemann syndrome have a molecular defect of the 11p15 domain.[44] Various molecular mechanisms underlying Beckwith-Wiedemann syndrome have been identified. Some of these abnormalities are genetic (germline pathogenic variants of the maternal allele of CDKN1C, paternal uniparental isodisomy of 11p15, or duplication of part of the 11p15 domain) but are more frequently epigenetic (loss of methylation of the maternal ICR2 [CDKN1C and KCNQ1OT1 genes] or gain of methylation of the maternal ICR1 [IGF2 and H19 genes]).[32,45]

Several candidate genes at the WT2 locus comprise the two independent imprinted domains: IGF2 and H19; and CDKN1C and KCNQ1OT1.[45] LOH, which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally active ones. A loss or switch of the imprint for genes (change in methylation status) in this region has also been frequently observed and results in the same functional aberrations.[32,44,45]

A relationship between epigenotype and phenotype has been shown in Beckwith-Wiedemann syndrome, with a different rate of cancer in Beckwith-Wiedemann syndrome according to the type of alteration of the 11p15 region.[46]

The following four main molecular subtypes of Beckwith-Wiedemann syndrome are characterized by specific genotype-phenotype correlations:

Other tumors such as neuroblastoma or hepatoblastoma were reported in patients with paternal 11p15 isodisomy.[48-50] For patients with Beckwith-Wiedemann syndrome, the relative risk of developing hepatoblastoma is 2,280 times that of the general population.[42]

Loss of imprinting or gene methylation is rarely found at other loci, supporting the specificity of loss of imprinting at 11p15.5.[51] Interestingly, Wilms tumor in Japanese and East Asian children, which occurs at a lower incidence than in White children, is not associated with either nephrogenic rests or IGF2 loss of imprinting.[52]