Molecular Basis of Beckwith-Wiedemann Syndrome Spectrum with Associated Tumors and Consequences for Clinical Practice

Abstract

Beckwith-Wiedemann syndrome (BWS, OMIM 130650) is a congenital imprinting condition with a heterogenous clinical presentation of overgrowth and an increased childhood cancer risk (mainly nephroblastoma, hepatoblastoma or neuroblastoma). Due to the varying clinical presentation encompassing classical, clinical BWS without a molecular diagnosis and BWS-related phenotypes with an 11p15.5 molecular anomaly, the syndromic entity was extended to the Beckwith-Wiedemann spectrum (BWSp). The tumor risk of up to 30% depends on the molecular subtype of BWSp with causative genetic or epigenetic alterations in the chromosomal region 11p15.5. The molecular diagnosis of BWSp can be challenging for several reasons, including the range of causative molecular mechanisms which are frequently mosaic. The molecular basis of tumor formation appears to relate to stalled cellular differentiation in certain organs that predisposes persisting embryonic cells to accumulate additional molecular defects, which then results in a range of embryonal tumors. The molecular subtype of BWSp not only influences the overall risk of neoplasia, but also the likelihood of specific embryonal tumors.

Keywords: Beckwith–Wiedemann syndrome spectrum; genomic imprinting; tumor.

Figure 1

Schematic representation of genetic and epigenetic defects causing BWSp and tumor types associated with the specific defects. Upper Panel: Schematic delineation of the chromosomal region 11p15.5 with the two imprinting clusters IC1 and IC2, the allele-specific methylation of the respective DMRs and the consequent expression of imprinted genes on the maternal (red) and paternal (blue) allele. Middle Panel: Defects observed in BWSp patients with resulting transcriptional consequences, leading to a maturation block in cells of susceptible organs. These cells may persist after birth and then either terminate their differentiation, regress or progress to form hyperplastic and tumorigenic cells. Lower Panel: Tumor types and histological subclasses that occur with certain risk due to typical secondary mutations in the cells that were stalled in development.