Each year, about 16,000 children are diagnosed with cancer. To learn more about , underlying genetic risks for cancer in children, researchers from Memorial Sloan Kettering’s pediatric program tested 751 pediatric patients treated for solid tumors for inherited cancer-associated mutations, or germline mutations. In a paper published in Nature Cancer, they report on identifying germline genomic sequencing details and that many children harbored pathogenic and likely pathogenic variants. Specifically, one more of these variants were found in 18% (138/751) of individuals when including variants in low-, moderate- and high-penetrance dominant or recessive genes or in 13% (99/751) of individuals in moderate- and high-penetrance dominant genes.
The team was surprised to find that 34% of the high- or moderate-penetrance variants were found in children whose diagnosis and previous history would not indicate increased risk. As a result of this study, the authors recommend that germline testing should be considered for all children with cancer and recommend genetic testing o parents, siblings, and other closely related family members.
Using its own MSK-IMPACT (Integrated Mutation Profiling of Actionable Cancer Targets) test, the team screened each child for mutations in more than 500 genes and compared that with patients’ normal germline cells. MSK-IMPACT is a targeted tumor-sequencing test available to MSK patients. With the MSK-IMPACT test, doctors can quickly find out whether a tumor has changes that make the cancer vulnerable to particular drugs. In this case, the MSK team used MSK-IMPACT to identify the hereditary factors associated with children’s cancers.
The study revealed that pathogenic/likely pathogenic variants were reported in 49% (34/70) of patients with retinoblastoma, 21% (30/143) of patients with CNS tumors, 15% (28/182) of patients with neuroblastoma, 12% (28/229) of patients with sarcoma and 19% (27/143) of patients with other tumor types.
“Many of the associations we are learning about with this kind of testing were not previously known and have broadened our understanding of how inherited genes may be related to a predisposition to pediatric cancers,” says genetic counselor Elise Fiala, the paper’s first author.
“This study shows that the criteria we currently use to determine who should receive germline testing are flawed,” added physician-scientist Michael Walsh, the paper’s senior author, who leads research on inherited pediatric cancer genomics within MSK’s Robert and Kate Niehaus Center for Inherited Cancer Genomics.
The results showed that in about half of the patients in whom an inherited predisposition was found, scientists would not have predicted it and therefore would not have screened the children. These findings included mutations in the BRCA genes; the genes associated with Lynch syndrome; the gene TP53, which is linked to Li-Fraumeni syndrome; and others. They also discovered a previously unknown link between loss of function of the CDKN2A gene and osteosarcoma, the most common form of bone cancer in children and young adults.
Other family members, including siblings, parents, and perhaps others maybe want to have genetic testing to see if they also harbor the gene mutation. If found, closer monitoring, screening, or preventive measures would then be reasonable over time. In this study, testing in family members revealed 27 were mutation carriers who were not previously aware of their status. And parents wishing to have more children might want to consider IVF and preimplantation diagnosis to prevent passing on the mutation to future children.
“The potential for cancer predisposition should be considered for every child with cancer,” the authors write. “Outside of guidelines-based testing, the potential additional utility of broader germline testing needs to be considered in the context of the patient’s clinical condition as well as the patient and family’s desire for information that could primarily be used for other family members in the immediate future.”