On the Trail of a Cancer Predisposition Syndrome

Issue: 

Inside the cells of a developing human embryo is a little piece of “Alice in Wonderland.” While most of our bodies’ genes are expressed from both our mothers’ and fathers’ chromosomes, there is a particular growth-regulating region of chromosome 11 where Dad’s genes make you grow bigger, and Mom’s genes make you small. As in Alice’s adventure, there is potential for some difficult situations to occur when that growth process is not handled with exacting care.

With new grants awarded by the St. Baldrick’s Foundation and the National Cancer Institute, attending physician and geneticist Jennifer M. Kalish, MD, PhD, at The Children’s Hospital of Philadelphia, is going down the rabbit hole to try to set things right. She aims to answer key questions about cancer while helping children with Beckwith-Wiedemann Syndrome (BWS), an overgrowth disorder that can result when epigenetic regulation of growth-regulating regions of chromosome 11 goes awry.

Dr. Kalish’s current research builds on earlier work she conducted as a Young Investigator funded by the Alex’s Lemonade Stand Foundation.

Managing a Mosaic Syndrome

Ary Devlin was born in December 2013, seeming perfectly healthy in every way. But her mother, Alisha, was not so sure.

“I knew something was wrong,” Alisha said. “She never closed her mouth.”

After seeing multiple doctors seeking a cause for Ary’s macroglossia, or enlarged tongue, Ary eventually received a diagnosis of BWS, and Alisha and sought Dr. Kalish’s expertise at CHOP.

Part of Dr. Kalish’s challenge in both studying and treating children with BWS is that the syndrome’s manifestation is widely varied. Some children like Ary have subtle growth differences that are barely detectable, while others have more obvious growth differences.

Common features of BWS include omphaloceles (abdominal wall defects), hemihyperplasia (some body parts being larger than others, such as an enlarged arm or leg), enlarged organs, and increased risk of heptoblastoma (liver cancer) and Wilms tumor (kidney cancer). Treatment generally varies from child to child, as the focus is on managing an individual’s symptoms.

“Most of these changes happen as the embryo is developing,” said Dr. Kalish, who is also an instructor in pediatrics at the Perelman School of Medicine at the University of Pennsylvania. “Not every cell in their body has the genetic change, and therefore they end up being mosaic.”

One thing all children with BWS have in common is that their families face uncertainties about the future. Many of these unknowns have persisted because researchers have not yet compiled large-scale data to determine patterns of outcomes.

A Registry to Provide Answers

“One of the frustrating things, especially being at what I think is the greatest hospital in the world, where they know so much about BWS, is hearing, ‘Well, we don’t really have any data about this; there aren’t any studies,’” said Becky Feldman, whose 2-year-old son, Julian, has BWS.

To help other parents get more answers, both Becky and Alisha are advocates for a key piece of Dr. Kalish’s research: A clinical registry of patients with BWS, established at CHOP more than a year ago to build knowledge based on the hospital’s cohort of BWS patients, which is the largest in the country.

The registry is collecting longitudinal data on development and outcomes of interventions. Individuals of all ages with BWS or other forms of growth differences are welcome to participate in the registry, even if not treated at CHOP. Participants share their clinical data and biological samples remaining from clinical testing.

Biological samples are abundant because standard care for BWS includes regular blood tests every six weeks and ultrasounds every three months to catch liver and kidney cancers early if they develop. These screenings continue until ages 4 and 8, respectively, when the children’s risk drops off.

 Finding Cancer Mechanisms

As a physician-scientist, Dr. Kalish is taking her research beyond analysis of clinical data in the registry. She also is conducting basic research using BWS registry participants’ cells to better understand the mechanisms of cancer development. In the lab, she is converting these samples into induced pluripotent stem cells and developing them into the cancer-prone liver and kidney cell types.

By examining the functioning of these cells, she aims to better understand how cancer develops as a consequence of the growth dysregulation on chromosome 11 that causes BWS. She hopes this study will provide insight into nearby alterations believed to play a role in other cancers, too. And because BWS patients’ bodies are mosaic (including both normally developing cells and cells with altered growth-gene expression), she will be able to compare both types of cells from individual patients.

In another part of her study, Dr. Kalish is developing a new mouse model for BWS that demonstrates aspects of the condition’s development that existing models do not.

“By studying a syndrome where you have a confined molecular cause that you know the patients have, you can actually understand many other pathways about how tumors form in other kinds of cancer as well,” said Dr. Kalish.

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