Cancer Predisposition in Children: Increasing Awareness

Most cancers in children are thought to result from genetic mutations that occur in growing tissues. However, it is now clear that at least 10-20% of children who develop cancer are genetically predisposed to do so, and that percentage continues to grow as we learn more. Identifying children who have a high risk of developing specific cancers is important not only for them, but also for family members such as parents and siblings who may be affected. If someone is at increased risk for certain cancers, surveillance testing can be done to detect cancers early, when they are more easily cured. Treating a tumor the size of a grape is much easier, less likely to be metastatic, and has a better prognosis than a tumor the size of a grapefruit. Surgical removal is easier, less therapy is required, radiation can usually be avoided, and side effects are dramatically reduced. Thus, early detection is the goal.

A comprehensive, multifaceted program

To harness the growing understanding of hereditary factors in childhood cancer, CHOP created the Cancer Predisposition Program in 2005. Currently led by Garrett M. Brodeur, MD, it is one of the most comprehensive programs of its kind in the country. The Cancer Predisposition Program sees children with over 100 different syndromes, each with its own unique cancer risk. Some of these patients are seen by syndrome-specific multidisciplinary clinics.  For example, CHOP is fortunate to have a Neurofibromatosis Program, a Bone Marrow Failure Clinic, a Thyroid Center, and a Comprehensive Gastrointestinal Cancer Predisposition Program (Polyposis Clinic) to follow patients with syndrome-specific needs. Our Beckwith-Wiedemann Spectrum Program and our retinoblastoma programs are each perhaps the largest in the country, if not the world.

The Cancer Predisposition Program works closely with the team in the Division of Genomic Diagnostics, who perform much of the genetic testing and have developed specific testing panels that can be tailored to individual patients. Colleagues at the University of Pennsylvania/Perelman School of Medicine Cancer Risk Evaluation Program and the Basser Center for BRCA Research assist with testing parents or adult family members, and they assume care of CHOP patients when they reach adulthood.

The CHOP Cancer Predisposition Program is expanding rapidly and has recently hired a program coordinator, an additional genetic counselor, and an access/insurance coordinator, with plans to hire a nurse navigator. A psychologist will also be added to help patients and their families cope with the psychosocial stressors of their diagnosis. Our program will be a medical home for patients at risk for childhood cancer, providing coordination of surveillance imaging, lab testing, and multidisciplinary care. The CHOP Cancer Predisposition Program is also conducting research focused on identifying new cancer predisposition genes, and testing novel methods of early detection in predisposed individuals.

New gene discovery

The genetic factors responsible for many cancer predisposition syndromes are known, but for many children there is no known genetic cause despite clear indicators of cancer predisposition. This includes patients who meet clinical criteria for a disease but have negative genetic testing, as well as patients and families with a strong family history of specific cancers, but for which no predisposition gene is known. Our program is focused on several such individuals and families to identify novel predisposition genes that lead to childhood cancer.

Current surveillance techniques

Current surveillance depends on the specific cancer predisposition syndrome, as each puts a child at risk for particular cancers. The Cancer Predisposition Program follows accepted pediatric syndrome-specific surveillance guidelines and is diligent in working with other predisposition programs nationally and internationally to provide families with the most up-to-date and evidence-based recommendations. The techniques used include physical exam, blood tests, ultrasound, magnetic resonance imaging (MRI), endoscopy and colonoscopy, detailed eye exams and other surveillance tests as needed. These tests are performed on a regular basis, usually every 3 months to every 1-2 years, and may change based on the child’s age and medical history. Although current techniques are effective in most cases, some tumors can be missed or develop between assessments. Also, incidental findings can lead to unnecessary studies, and some exams in young children require sedation or general anesthesia.

On the horizon: enhanced surveillance techniques

Our program is doing research to evaluate novel surveillance techniques that may be more specific or sensitive, such as enhanced imaging (contrast-enhanced ultrasound, PET-MRI), as well as testing blood for tumor-specific biomarkers or circulating tumor DNA (ctDNA). The microbiome (the type and relative number of specific bacteria in stool), as well as evidence of tumor DNA in stool can be monitored for surveillance or modified to reduce cancer risk. The microbiome composition has been shown to be predictive of cancer development in animal models of colon cancer predisposition. The GI tract can also influence immune responses and possibly cancer development in other parts of the body.

The goal: cancer prevention

Can childhood cancers ever be prevented? Once considered impossible, current thinking is that the prevention of childhood cancer may be possible in the near future, at least in high-risk individuals. Proving that cancer can be prevented will take a collaborative approach by a large consortium of institutions. Since each individual syndrome is relatively rare, and the cancer incidence in each individual can change over time, a large number of patients must be followed over a number of years to determine the efficacy of a specific screening or prevention approach. The collaboration that the CHOP Cancer Predisposition Program has developed with other centers will be crucial in conducting such studies.

Nevertheless, in certain cases cancer prevention is already being done, such as prophylactic surgery (thyroidectomy, or colectomy), or vaccinations (against HPV or other oncogenic viruses). For many cancer predisposition syndromes, the genes, proteins and pathways are known that are defective and that put these individuals at increased risk, and there are medications that can modulate these pathways and restore function. Although there may be side effects of long-term use of these drugs, even at low doses, clinical trials can be done to optimize the drugs, doses and schedules. There are other approaches that could be studied, such as regulating the microbiome to maintain a favorable profile. Cancer prevention in children once seemed like a pipe dream, but this may soon become a reality, at least for some of the high-risk individuals.