A new study by The Children’s Hospital of Philadelphia’s Jennifer Kalish, MD, PhD, into a rare disease could broaden researchers’ understanding of how numerous cancers develop. Dr. Kalish recently received an award from Alex’s Lemonade Stand Foundation to investigate tumor development associated with the rare childhood overgrowth disease Beckwith-Wiedemann Syndrome.
A genetic disorder that is often associated with overgrowth of the tongue (macroglossia), or a condition called hemihypertrophy in which one side of the body is larger than the other, Beckwith-Wiedemann Syndrome (BWS) occurs in approximately 1 out of 13,700 births. BWS is associated with an increased risk of childhood cancers, in particular the kidney cancer Wilms tumor and hepatoblastoma, a form of liver cancer.
Currently working in the laboratory of the University of Pennsylvania’s Marisa S. Bartolomei, PhD, Dr. Kalish is also an attending physician in the Division of Genetics. In late 2013 Dr. Kalish received a “Young Investigator” grant from the Alex’s Lemonade Stand Foundation to support her BWS investigation. A large portion of Dr. Kalish’s funding has also come from The University of Pennsylvania’s Institute for Translational Medicine and Therapeutics.
In addition to studying the clinical characterization of BWS, a major focus of Dr. Kalish’s research has been working to understand why some children with BWS develop tumors. “Up to 25 percent of children with BWS develop tumors, but we do not have a good understanding of why they do,” she said.
Because of their elevated risk of tumor development, all patients with BWS face rigorous, frequent cancer screening tests. Until they are four years old, patients must have blood drawn every six weeks, and must undergo abdominal ultrasounds every three months until they are eight years old. Though the screening is “pretty intense,” Dr. Kalish said the testing remains necessary because doctors cannot yet tell which BWS patients will develop tumors and which ones will not.
In an attempt to understand why only some children with BWS develop tumors, and to work to develop better screening markers, Dr. Kalish is currently conducting a two-part study. She is simultaneously developing a mouse model of the disease, as well as deriving induced pluripotent stem cells (iPSCs) from BWS patients’ fibroblasts. Mature cells that have been “reprogrammed,” iPSCs are capable of developing into many cell types. Dr. Kalish will use the iPSCs she creates to form liver cells to study how the BWS patient cells can develop into liver tumor cells.
The focus of the mouse model, meanwhile, will be on the role particular genes play in BWS and tumor development. Dr. Kalish’s investigations will focus on chromosome 11, as several genes’ expression there is altered in BWS and other cancers, including neuroblastoma, a form of childhood cancer that is responsible for 10 to 15 percent of all childhood cancer-related deaths.
“This region is dysregulated in other cancers, outside of BWS cancers, so there is clearly something about this region that is leading to tumors,” Dr. Kalish said. “BWS is an example of a rare disease that allows us to study a more common mechanism of disease, i.e. some types of cancer. We know that BWS patients have this genetic change because there is a phenotype. We do not know in adult patients with these other tumors if the tumors resulted from initial genetic changes on chromosome 11. It is just unclear at this time.”
“Because BWS patients’ tumor screening ends at age eight, clinicians and researchers do not necessarily know what happens to those patients in later years,” Dr. Kalish said. While the literature indicates that BWS patients have normal development, Dr. Kalish pointed out that the new investigation, coupled with the fact that she has been receiving BWS referrals from all over the country and the world, could give researchers the ability to take a more comprehensive look at BWS patients’ long-term health and tumor risk, both before and after age eight.
“Ultimately, we would like to have better markers to screen for, a better understanding of why these children get tumors, but most importantly possible treatments,” Dr. Kalish said.
To learn more about Beckwith-Wiedemann Syndrome, see the Hospital’s site. For more information about the numerous investigations currently underway at The Children’s Hospital of Philadelphia Research Institute, see the Research Institute’s page.