Rare Disease Study Could Broaden Tumor Development Understanding

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 the 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.

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. In late 2013 Dr. Kalish, an attending physician in the Division of Genetics, received a “Young Investigator” grant from the Alex’s Lemonade Stand Foundation to support her BWS investigation.

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.

Working to Improve Screening, Treatments

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 developing an animal 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.

Dr. Kalish plans to look at the role particular genes play in BWS and tumor development. In particular, she will focus on chromosome 11, as several genes’ expression there is altered in BWS and other cancers.

“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.”

While previous research indicates BWS patients develop normally, Dr. Kalish pointed out that her new investigation, coupled with the BWS referrals she has been receiving 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.

“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.