New research from Children’s Hospital of Philadelphia (CHOP) offers insight into how a rare genetic condition called Beckwith–Wiedemann syndrome (BWS) affects the liver and may raise cancer risk.
BWS occurs in approximately 1 in 11,000 births. Most children do not exhibit all characteristics of the syndrome, but some of the most common features include an enlarged tongue, low levels of sugar in the bloodstream, defects in the abdominal wall, overgrowth on one side or part of the body and an increased risk of developing certain cancers during childhood. Previously, CHOP researchers conducted a preliminary study and found cancer predisposition signatures in tumor adjacent livers in patients with BWS as well as in hepatoblastoma, a rare tumor that originates in liver cells. However, these findings were limited.
In this study, a more in-depth analysis of the liver in patients with BWS was conducted by examining specific liver cell populations at a single cell level. The goal was to generate a detailed map examining both the cell type composition differences and exploring gene expression changes in the affected BWS liver to better understand what drives its metabolic activity.
“Our findings build on past research and offer new insights into how BWS causes both tissue overgrowth and cancer risk,” said Jennifer M. Kalish, MD, PhD, a pediatric geneticist at CHOP, with a special interest in BWS and cancer predisposition. “We found that fat metabolism and cell stress are key factors in potential cancer predisposition.”
In the study, Kalish and her team took a multiomic approach, using single nucleus RNA sequencing (snRNA-seq) and single-nucleus chromatin accessibility profiling (snATAC-seq) to study liver tissue from children with and without BWS. Researchers analyzed samples from four patients with BWS and three matched patients without BWS. The tissue came from areas near tumors but not affected by them, allowing them to study baseline liver differences.
One of their major discoveries was the increased activity of a gene regulator, peroxisome proliferator-activated receptor alpha (PPARA), which controls how the liver breaks down fat. In BWS liver cells, PPARA was switched on more than usual. As a result, the cells broke down more fatty acids and stored less fat than healthy liver cells. That resulted in creating stress in the cells, leading to lipid peroxidation, which is caused by the buildup of damaging byproducts.
The harmful byproducts caused an increase in reactive oxygen species (ROS) – unstable molecules that can damage DNA. The researchers observed more oxidative DNA damage in BWS liver cells, which they noted could explain the increased risk of cancer in children with the condition. To confirm the results, researchers studied induced pluripotent stem cells modeling the cells of patients with BWS and turned them into liver cells. These lab-grown cells showed the same links between fat metabolism and DNA damage.
“Our hope is that ongoing research based on these findings will lead to more targeted therapies or preventative strategies for children with BWS to help reduce their risk of developing serious health complications,” said Kalish.
Patients and their families can partner with Kalish and her research team by opting to participate in the BWS registry, a program that collects clinical data and samples from patients to understand the various ways the condition affects patients and how to tailor treatments to patients’ needs.
This work was supported by NIH (CA193915), a Damon Runyon Clinical Investigator Award supported by the Damon Runyon Cancer Research Foundation (105-19), Alex’s Lemonade Stand Foundation, St. Baldrick’s Foundation Research Grant Award, Rally Foundation for Childhood Cancer Research Career Development Award, the Lorenzo “Turtle” Sartini, Jr. Endowed Chair in Beckwith-Wiedemann Syndrome Research and the Victoria Fertitta Fund through the Lorenzo “Turtle” Sartini Jr. Endowed Chair in Beckwith-Wiedemann Syndrome Research.
Nirgude et al. “Single-nucleus multiomic analysis of Beckwith-Wiedemann syndrome liver reveals PPARA signaling enrichment and metabolic dysfunction.” Commun Biol. Online March 26, 2025. DOI: 10.1038/s42003-025-07961-9.
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New research from Children’s Hospital of Philadelphia (CHOP) offers insight into how a rare genetic condition called Beckwith–Wiedemann syndrome (BWS) affects the liver and may raise cancer risk.
BWS occurs in approximately 1 in 11,000 births. Most children do not exhibit all characteristics of the syndrome, but some of the most common features include an enlarged tongue, low levels of sugar in the bloodstream, defects in the abdominal wall, overgrowth on one side or part of the body and an increased risk of developing certain cancers during childhood. Previously, CHOP researchers conducted a preliminary study and found cancer predisposition signatures in tumor adjacent livers in patients with BWS as well as in hepatoblastoma, a rare tumor that originates in liver cells. However, these findings were limited.
In this study, a more in-depth analysis of the liver in patients with BWS was conducted by examining specific liver cell populations at a single cell level. The goal was to generate a detailed map examining both the cell type composition differences and exploring gene expression changes in the affected BWS liver to better understand what drives its metabolic activity.
“Our findings build on past research and offer new insights into how BWS causes both tissue overgrowth and cancer risk,” said Jennifer M. Kalish, MD, PhD, a pediatric geneticist at CHOP, with a special interest in BWS and cancer predisposition. “We found that fat metabolism and cell stress are key factors in potential cancer predisposition.”
In the study, Kalish and her team took a multiomic approach, using single nucleus RNA sequencing (snRNA-seq) and single-nucleus chromatin accessibility profiling (snATAC-seq) to study liver tissue from children with and without BWS. Researchers analyzed samples from four patients with BWS and three matched patients without BWS. The tissue came from areas near tumors but not affected by them, allowing them to study baseline liver differences.
One of their major discoveries was the increased activity of a gene regulator, peroxisome proliferator-activated receptor alpha (PPARA), which controls how the liver breaks down fat. In BWS liver cells, PPARA was switched on more than usual. As a result, the cells broke down more fatty acids and stored less fat than healthy liver cells. That resulted in creating stress in the cells, leading to lipid peroxidation, which is caused by the buildup of damaging byproducts.
The harmful byproducts caused an increase in reactive oxygen species (ROS) – unstable molecules that can damage DNA. The researchers observed more oxidative DNA damage in BWS liver cells, which they noted could explain the increased risk of cancer in children with the condition. To confirm the results, researchers studied induced pluripotent stem cells modeling the cells of patients with BWS and turned them into liver cells. These lab-grown cells showed the same links between fat metabolism and DNA damage.
“Our hope is that ongoing research based on these findings will lead to more targeted therapies or preventative strategies for children with BWS to help reduce their risk of developing serious health complications,” said Kalish.
Patients and their families can partner with Kalish and her research team by opting to participate in the BWS registry, a program that collects clinical data and samples from patients to understand the various ways the condition affects patients and how to tailor treatments to patients’ needs.
This work was supported by NIH (CA193915), a Damon Runyon Clinical Investigator Award supported by the Damon Runyon Cancer Research Foundation (105-19), Alex’s Lemonade Stand Foundation, St. Baldrick’s Foundation Research Grant Award, Rally Foundation for Childhood Cancer Research Career Development Award, the Lorenzo “Turtle” Sartini, Jr. Endowed Chair in Beckwith-Wiedemann Syndrome Research and the Victoria Fertitta Fund through the Lorenzo “Turtle” Sartini Jr. Endowed Chair in Beckwith-Wiedemann Syndrome Research.
Nirgude et al. “Single-nucleus multiomic analysis of Beckwith-Wiedemann syndrome liver reveals PPARA signaling enrichment and metabolic dysfunction.” Commun Biol. Online March 26, 2025. DOI: 10.1038/s42003-025-07961-9.
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