Navigating the risks of childhood cancer predispositions

While most childhood cancers occur without any hereditary factors, around 10% of childhood cancers are associated with a cancer predisposition syndrome caused by mutations to genes that prevent tumor growth, known as tumor suppressor genes, or that drive cell growth and division, known as oncogenes, both of which play a critical role in cancer development.

Genetic predispositions can be inherited from a parent, or a new mutation can arise during conception without any family history. Although not every child with a predisposition will develop cancer, their risk is significantly higher. Through active surveillance and tailored interventions based on a patient’s unique genetic profile, we can identify tumors early and reduce the mortality and morbidity in these at-risk children.

Pediatric Cancer Predisposition Program?

Stanford Children's Health | Lucile Packard Children's Hospital Stanford has a long history of treating cancer predisposition syndromes. With the recent launch of its Pediatric Cancer Predisposition Program, patients receive fully integrated care through a multidisciplinary team of experts in pediatric oncology, genetic counseling, and psychology for a comprehensive, personalized medicine approach. The team evaluates children's risks of developing both primary and secondary cancers through proactive screening to detect cancer early when treatment is most effective. Patients receive timely and effective treatment through early diagnosis while keeping them and their families well-informed throughout the process. The program also offers patients and families the chance to participate in clinical research aimed at advancing treatments.

“Identifying a predisposition can impact how we should best treat the cancer that the patient has because some of those genetic predispositions put the child at a higher risk of second cancers as well. Secondary cancers can be caused by specific types of chemotherapy or radiation, which we use to treat cancer regularly. So, in some of those cases, we might need to alter the treatment approach to the child's primary cancer because we know that they have that genetic predisposition to other types of cancers later on,” explains Stanford Cancer Institute member Raya Saab , MD, the Lindhard Family Professor of Pediatric Cancer Biology and director of the Pediatric Cancer Predisposition Program.

Depending on the specific cancer predisposition syndrome, the team will collaborate and provide bridging services with additional subspecialties, including endocrinology, surgery, and gastroenterology, among others For instance, children with familial adenomatous polyposis (FAP) may need regular gastrointestinal evaluations, such as endoscopies and colonoscopies, requiring close collaboration with gastroenterologists. Similarly, for endocrine tumors linked to conditions like thyroid or adrenal cancers, endocrinologists become integral to the care team.

“Our team engages with other disciplinary groups to make sure the child and family are integrated with all the services that they need for appropriate surveillance for early detection of the tumor type that they're predisposed to,” explains Saab.

Early detection and active surveillance

Saab highlights how early detection and timely interventions have translated into better outcomes for her patients.?

“We have several patients who, through early intervention, we were able to identify tumors at a time where the tumor is small enough that you would be able to simply surgically resect it and obviate the need for chemotherapy or radiation.”

Saab recounts how an eight-year-old girl was initially treated for thyroid cancer and later diagnosed with a rare ovarian tumor by age 12. Through genetic testing by the team, she was diagnosed with a genetic cancer predisposition. Thanks to active surveillance, two more tumors were detected early elsewhere in her body, allowing for timely and successful treatment. In another case, a one-year-old child with a family history of cancer was found to have a rare abdominal tumor and was treated early without the need for chemotherapy. Today, she is thriving and continues to be monitored for new cancers.

“Without active surveillance, it is certain that these tumors would have been identified only when they became much larger and likely spread, and the chance for a cure would have been greatly reduced,” remarks Saab.

When to reach out to the Pediatric Cancer Predisposition team?

Children diagnosed with cancer are often referred to the Stanford Childhood Predisposition Program by their oncologist when their specific cancer type is known to have a genetic link. There are several genetic predisposition disorders linked to cancer, and the number continues to grow as genetic research uncovers new connections between genetic mutations and cancer susceptibility.

“The cancer risks depend on the syndromes themselves. Some of the ones that we see commonly in pediatric cancer are Li-Fraumeni syndrome and familial adenomatous polyposis,” explains Molly McGuinness, MS, CGC , a board-certified genetic counselor and member of the Pediatric Cancer Disposition Program Care Team.

The program offers genetic testing to determine if the cancer originates from a genetic syndrome present from birth. Some children present with cancer without any obvious family history or signs of a genetic predisposition that would have gone unnoticed without genetic testing. If a genetic predisposition is identified, the program will provide resources for testing the child's family members, including parents and siblings, to pinpoint others who may be at elevated risk and could benefit from targeted screening.

Saab explains, “About 10 to 15% of children with cancer harbor a genetic predisposition. Identifying those patients will not only help us recommend surveillance for other types of cancers later on but also help us identify whether their siblings or their parents need testing.”

If a parent has a known genetic predisposition to cancer, there's a 50% chance their child may have inherited the same risk. In such cases, it’s important to evaluate the child to determine whether they, too, carry a genetic predisposition. Healthy children are evaluated if they have a significant family history of cancer.?

"A significant cancer family history includes multiple relatives on the same side of the family having cancer, typically at earlier ages," notes McGuinness. “If there are other relatives in the family who have a diagnosis of cancer or had cancer and are living and can access genetic testing, then they would be the best people in the family to start the genetic testing process.”?

Certain clinical features or syndromes can indicate a genetic abnormality linked to cancer. These may include dysmorphism, cardiac defects, or congenital issues like overgrowth syndromes, which involve abnormal growth of limbs or large umbilical hernias.

Advances in diagnosis

Advances in genetic testing and technology have significantly improved the identification of genes associated with childhood cancer predisposition. This includes a broader range of genes in testing panels and improvements in the sensitivity of mutation detection.?

“We're now routinely incorporating newer and larger panels, especially for patients who were tested ten years ago or who have never undergone testing,” states McGuinness.

Current surveillance for childhood cancers predominantly relies on imaging techniques. Some tumors are monitored by the specific proteins they produce that are detectable in blood or urine. Ongoing research aims to enhance surveillance by detecting tumor DNA or RNA in the blood through liquid biopsies. Liquid biopsies, which analyze circulating tumor DNA (ctDNA) in the blood, promise to offer a minimally invasive tool for early cancer detection and monitoring treatment response.

“We're optimistic that over the next decade, advancements will enable blood tests for tumor DNA markers to become a standard part of surveillance for children's genetic predispositions. This would significantly reduce the need for invasive procedures, including anesthesia, which is needed during imaging tests for children,” Saab remarks.

As research continues to advance, the hope is that identifying and managing cancer predispositions will become even more effective through catching cancers earlier and treating them with greater precision.

By Sarah Pelta

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