East Montgomery Times

Researchers at the Children’s Hospital of Philadelphia (CHOP) have made significant findings regarding Beckwith–Wiedemann syndrome (BWS), a rare genetic condition affecting approximately 1 in 11,000 births. This study investigates how BWS impacts the liver and may increase cancer risk in affected children.

Previously, CHOP researchers identified cancer predisposition signatures within tumor-adjacent liver tissues in BWS patients, as well as within a rare liver tumor, hepatoblastoma. The new study built upon this preliminary work by examining specific liver cell populations at a single-cell level. This in-depth analysis aims to understand the cell type differences and gene expression changes within the BWS-affected liver.

Dr. Jennifer M. Kalish, a pediatric geneticist at CHOP, stated, “Our findings build on past research and offer new insights into how BWS causes both tissue overgrowth and cancer risk.” One crucial discovery was the increased activity of the gene regulator, peroxisome proliferator-activated receptor alpha (PPARA). This increase results in higher fatty acid breakdown and reduced fat storage in BWS liver cells compared to healthy liver cells. Subsequently, this creates cellular stress and lipid peroxidation, leading to a rise in reactive oxygen species (ROS), unstable molecules that damage DNA.

The researchers observed significant oxidative DNA damage in BWS liver cells, suggesting this could explain the increased cancer risk. The study utilized advanced techniques, including single nucleus RNA sequencing (snRNA-seq) and single-nucleus chromatin accessibility profiling (snATAC-seq), on liver tissues from both BWS patients and those without the syndrome.

To validate their findings, the team created induced pluripotent stem cells simulating BWS patient liver cells. These lab-grown cells demonstrated similar links between fat metabolism and DNA damage. Dr. Kalish expressed hope that continued research could lead to targeted therapies or prevention strategies for children with BWS to reduce their risk of serious health issues.

Families of individuals with BWS can contribute to ongoing research by participating in the BWS registry, aiding in the collection of clinical data and samples to better tailor treatments.

This research was supported by various organizations, including the NIH, Damon Runyon Cancer Research Foundation, Alex’s Lemonade Stand Foundation, and St. Baldrick’s Foundation, among others. The study is detailed in the paper by Nirgude et al., titled “Single-nucleus multiomic analysis of Beckwith-Wiedemann syndrome liver reveals PPARAsignaling enrichment and metabolic dysfunction," published in Commun Biol.