Study co-author Kim Nichols, MD, who is a member the St. Jude Children’s Research Hospital Department of Oncology and director of the St. Jude Hereditary Cancer Predisposition Clinic, Memphis, TN, said this study lays the groundwork to understand the spectrum of cancers and age-specific cancer risks associated with germline mutations in predisposition genes. It also may help guide clinicians on how best to monitor at-risk patients and families.

This study involved sequencing the whole genome, whole exome, or both of patients enrolled in the Pediatric Cancer Genome Project to check for germline mutations in 565 genes associated with cancer.

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In-depth data analysis was performed on 60 of the genes associated with autosomal dominant hereditary cancer predisposition syndromes. Mutations in these genes are known to increase cancer risk when one of the two copies of the gene is altered.

In this study, 95 patients (8.5%) had germline mutations in 21 of the 60 genes. Investigators checked whole-exome sequencing data of a comparison group without cancer and found that only 1.1% of 966 adults enrolled in the 1000 Genomes Project (an international collaboration to map human genetic variation) had alterations in the same genes. In this study, the frequency of germline mutations in cancer predisposition genes varied by tumor type. The highest frequency (16.7%) was found in children with non-central nervous system (CNS) solid tumors, followed by CNS tumors (9%), and leukemia (4.4%).

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The most commonly mutated genes in the affected patients were TP53, APC, BRCA2, NF1, PMS2, and RB1. An unexpected finding was the identification of mutations in the breast and ovarian cancer genes BRCA1 and BRCA2 in a number of the pediatric cancer patients.

These genes are not currently included in pediatric cancer genetic screening. The prevalence of mutations in these genes in this pediatric cancer cohort suggests that the role of these genes in pediatric cancer needs to be further studied.

Dr. Nichols said another surprising finding to emerge from this study was the prevalence of germline mutations in 6 patients with Ewing sarcoma. Until now, it was thought that Ewing sarcoma was not part of any cancer predisposition syndrome.


  1. Zhang J, Walsh MF, Wu G, et al. Germline mutations in predisposition genes in pediatric cancer [published online ahead of print November 18, 2015]. N Engl J Med. doi: 10.1056/NEJMoa1508054.