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Discovering the causes of cancer and the means of prevention

Douglas Stewart Uncovers Genetic Variation in Rare Hereditary Cancers

by Victoria Fisher, M.P.H.

Douglas Stewart

Tenure-track investigator Douglas Stewart, M.D., searches for rare germline genetic variation that increases the risk for cancer. He utilizes data from both family-based studies and cohorts.

“In clinical genetics, we say that when you hear hoof beats, don’t think horses, think zebras,” Dr. Stewart said. “I’ve always been interested in the zebras of the world.”

From Chemistry to Clinical Genetics

Dr. Stewart’s love of science began in childhood. These early interests led to a bachelor’s degree in chemistry, followed by a Fulbright year in New Zealand to study natural products chemistry, including synthesis of a compound with anticancer properties.

“I enjoyed the chemistry, but I was more intrigued about what could be done with this compound,” Dr. Stewart recalled. “At the end of the day, I liked the idea of doing something with an impact on human health.”

That experience led him to pursue a medical degree from the University of Pennsylvania School of Medicine. While at Penn, he attended a neurology lecture on muscular dystrophy. The speaker described a gene therapy project to transplant a mutated dystrophin gene from a patient with a mild form of the disease into children with the full-blown disease.

“I was just so taken by this idea, using a quirky version of dystrophin to try and help these kids,” Dr. Stewart said. “I remember thinking, ‘that is the coolest thing I’ve ever heard in my life’.”

“There’s something thrilling about seeing a child or family that is one of only a handful in the world, and perhaps you have knowledge that can help them in some way.”

As Dr. Stewart continued through medical school, he pursued work that fit his evolving interests. He credits a summer laboratory position with teaching him genetics, and later a rotation at the Children’s Hospital of Philadelphia (CHOP) with introducing him to the world of clinical genetics. After completing a residency in internal medicine, Dr. Stewart again returned to CHOP for a clinical genetics fellowship in 2001. 

“I came upon this career path sort of by serendipity,” Dr. Stewart said. “Looking back, it all makes sense. There’s a joke that in medicine you pick the field that suits your own pathology. I’d always been interested in trivia, rare facts, and unusual things. There’s something thrilling about seeing a child or family that is one of only a handful in the world, and perhaps you have knowledge that can help them in some way.”

After his CHOP fellowship in clinical genetics, Dr. Stewart joined the Physician Scientist Development Program at the National Human Genome Research Institute (NHGRI) in 2004. There, his research focused on neurofibromatosis type 1 (NF1), a genetic disorder that features the growth of multiple cutaneous or subcutaneous tumors of peripheral nerves. In recognition for his work in NF1, he was named one of NIH’s first Earl Stadtman Investigators and joined DCEG’s Clinical Genetics Branch in the summer of 2010.

Neurofibromatosis Type 1 (NF1)

During his time at NHGRI, Dr. Stewart worked to identify genes that influenced or modified the severity of NF1.

“NF1 is a disease that’s been well known in medical science since the 1880s,” Dr. Stewart said. “Despite that, I’ve been pleasantly surprised to see what other discoveries could be made, especially in adults.”

Dr. Stewart and his colleague Dr. Eric Legius of Catholic University in Leuven, Belgium, published the first genetic, functional, and clinical evidence of an association between NF1 and painful tumors in the finger-tips known as glomus tumors.

Infant with café-au-lait macules - flat, pigmented spots that are a clinical feature of NF1

Analyses of this cohort of 135 patients have yielded other novel insights, such as the identification of candidate modifier genes influencing the number of café-au-lait macules (flat, pigmented spots that are a clinical feature of NF1); the first genome-wide association study in NF1; and characterization of novel clinical features (phenotypes) in NF1, including its association with pulmonary hypertension.

Dr. Stewart has continued his NF1 research as a tenure-track investigator in DCEG and has several projects underway. Currently, the cohort is contributing to larger consortia efforts to find genetic modifiers of skin tumors and a type of brain tumor called optic pathway glioma.

In addition, Dr. Stewart is collaborating with Brigitte Widemann, M.D., of the NCI Center for Cancer Research, to sequence DNA from NF1 tumor biopsies to see how tumors differ in children who respond to certain drugs compared to those who do not.  

“We’re excited because Dr. Widemann has found a drug that seems to work in a phase I trial to control the growth of plexiforms, which are precursor lesions,” Dr. Stewart said. “We’re now helping with the genomic component of the phase II trial.”

Pleuropulmonary Blastoma (PPB)

PPB is a rare tumor of the lung. Research has shown that PPB may be part of an inherited cancer predisposition syndrome caused by changes in a gene known as DICER1. Since 2011, Dr. Stewart and colleagues have recruited families to participate in a study to characterize the disorder. Recently, the research team developed a new PPB study website to recruit new patients and families. 

“I had never heard of PPB until I came to DCEG and started working with Dr. Christian Kratz, who initiated the study” Dr. Stewart said. “The DICER1 gene had only been discovered a few years before; I was excited to utilize all of the wonderful tools that we have at NCI to bring to bear on such a rare disease.”

About two or three PPB families visit the Clinical Center each month to undergo a complete history, physical exam, lab work, imaging, and a variety of consultations. This gives investigators a complete picture of phenotypic and epidemiologic data of the PPB patients. 

After a few years of recruiting, the study finally has enough participants for the investigators to do meaningful analyses. Ultimately, Dr. Stewart hopes to identify all of the variety of tumors associated with PPB and related medical problems. “We know something about the pediatric manifestations of people who have mutations in DICER1, but we don’t know much about the adults.”

Opening up Genetic Cold Cases

Over the past several decades, NCI has recruited families to the Clinical Center that appear to have an increased risk of cancer. In many cases, no underlying gene could be identified as the cause.

“Now, with the advent of exome sequencing, we can go back and see if we can find a gene in those families,” Dr. Stewart said. “I call these cold cases; they haven’t been fully solved (like in police detective work) and they’ve been sitting in the freezer for decades.”

Dr. Stewart and colleagues have been investigating a handful of families that first came to the Clinical Center in the 1970s. Because of NCI’s extensive records, investigators are able to put together 45 years of follow-up on these families and have successfully identified some genetic factors associated with risk.

“With the advent of exome sequencing, we can go back and see if we can find a gene in those families. I call these cold cases; they haven’t been fully solved (like in police detective work) and they’ve been sitting in the freezer for decades.”

“I would love to go through the NCI repository and comprehensively characterize more of these cold cases,” Dr. Stewart said. “It’s been a lot of fun to dig through the records and find photographs from the 70s, with 70s haircuts and clothing, all right there in the medical chart.”

Whether he’s looking at families or cohorts, studying rare childhood tumors or cold cases from the 1970s, Dr. Stewart is committed to characterizing rare variants that increase the risk for cancer.

“The gene hunting is the best part of the job,” Dr. Stewart said. “It’s a thrill to sit down with data that no one else has looked at, pick it apart, and find variants in genes that underlie some of these cancer susceptibility syndromes.”

Read other articles in the Summer 2015 issue of Linkage newsletter.