Study Sheds Light on Role of Inherited Mutations in Childhood Cancer

December 8, 2015, by NCI Staff

In the most comprehensive study of its kind conducted to date, more than 8 percent of children with cancer were found to have inherited genetic mutations associated with a predisposition to the disease.

In addition to providing the most accurate assessment yet available of the possible role of inherited, or germline, mutations in childhood cancers, the authors said, the study also suggests that several inherited genetic mutations typically associated with some adult cancers may play a role in pediatric cancer.

The study was published November 18 in the New England Journal of Medicine.

A Deep Dive

To conduct the study, researchers from the St. Jude Children’s Research Hospital and Washington University School of Medicine in St. Louis isolated DNA from samples of both healthy and tumor tissue from more than 1,100 children with cancer. The researchers used a variety of approaches to analyze the DNA, and focused their analyses on 60 genes that are associated with inherited cancer-predisposition syndromes.

Harmful or potentially harmful mutations in genes from this 60-gene set were found in the healthy tissue from 95 (8.5 percent) of the children, the researchers reported. By comparison, when they looked at normal tissue samples from nearly 1,000 adults enrolled in a separate genomics study, only 1.1 percent had such mutations.

The prevalence of mutations in these 60 genes varied across cancer types. For example, nearly 17 percent of children with noncentral nervous system tumors (such as sarcomas and neuroblastoma) had mutations in this group of genes, but only 4.4 percent of children with leukemia did.

Overall, harmful mutations were seen in 21 of the 60 genes, more than half of them in the tumor-suppressor gene TP53, which is often called the “guardian of the genome” because of the critical role it plays in preventing cancer-causing changes in cells.

The 60 genes included three that are associated with substantially increased breast cancer risk in adults. Eight patients had a mutation in one of these genes, including six patients with mutations in the BRCA2 gene, and one each with a mutation in the BRCA1 and PALB2 genes. However, in this small group of patients the presence of these mutations was not associated with any single cancer.

The research team also found that only 40 percent of patients who had a mutation in one of the 60 cancer predisposition genes had a family history of the disease. This finding was based on a subset of 58 of the 95 patients, those for whom the research team had information on family history of cancer.

The researchers noted that, based on several factors—including that many of the children in the study had younger parents who, due to their age, are less likely to have developed cancer—this figure may be an underestimate.

Even if it is an underestimate, the finding is important, wrote John Maris, M.D., of the Children’s Research Hospital of Philadelphia, in an accompanying editorial.

“At a minimum, this work highlights the fact that family history alone is an unreliable guide to the likelihood of a cancer-predisposition syndrome in any patient with a newly diagnosed cancer,” he wrote.

Influence on Care and Research

The study’s results potentially could have an immediate influence on how clinicians approach caring for patients and providing guidance to their families, the study authors noted.

“For many pediatric cancer patients, comprehensive next-generation DNA sequencing of both their tumor and normal tissue may provide valuable information that will not only influence their clinical management, but also lead to genetic counseling and testing of their parents and siblings who may be at risk and would benefit from ongoing surveillance,” said the study’s senior author, James Downing, M.D., of St. Jude, in a news release.

If clinicians or families wish to pursue further genetic tests, the type of genetic testing may be important. Four of the mutations seen in the study were mosaic, meaning that they were found in only some of the normal cells tested, Dr. Maris wrote. That means that they “probably would have been missed by standard genetic-testing strategies," he explained.

Although the findings “shed important light” on the potential contribution of germline mutations in some children with cancer, Malcolm Smith, M.D., Ph.D., associate branch chief of pediatrics in NCI’s Cancer Therapy Evaluation Program, stressed that they should be interpreted with caution.

For example, children with cancers with a known genetic predisposition, such as adrenocortical cancer, were over-represented in the study, which Dr. Smith said could have artificially inflated the number of germline mutations found.

Nevertheless, Dr. Smith concluded, “this study contributes important evidence for more effectively managing cancer care, guiding genetic testing of relatives, and instituting appropriate measures for cancer prevention and surveillance for patients and families afflicted by childhood cancer.”