Germline Genes Mutations Associated with Pediatric Cancer Predisposition

The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown, but knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families.

A detailed analysis of the role germline mutations in genes associated with cancer predisposition play in the development of childhood cancer suggests that comprehensive genomic screening may be warranted on all pediatric cancer patients, not just those with a family history of cancer.


A large team of scientists led by those at St. Jude Children's Research Hospital (Memphis, TN, USA) enrolled 1,120 patients in a study which represented the major subtypes of pediatric cancer. Whole-genome, whole-exome, or both types of sequencing data were generated with the use of germline DNA for 595, 456, and 69 patients, respectively. To verify predictions of aberrant splicing caused by variants affecting splice junctions, they sequenced the ribonucleic acid (RNA) transcripts extracted from 522 samples of tumor tissue obtained from 522 patients. Paired end nucleotide reads (209 cycles) were acquired for all library types on the HiSeq 2000 sequencing platform or normalized on the MiSeq (Illumina, San Diego, CA, USA).

In the study the team revealed that 95 patients, or 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. The frequency of germline mutations in cancer predisposition genes varied by the type of cancer the child had. 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%.

The most commonly mutated genes in the affected patients were TP53, APC, BRCA2, NF1, PMS2, and RB1. Many of these genes have been previously associated with rare families with multiple children who develop cancer. 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.

Richard K. Wilson, PhD, a coauthor of the study, said, “We've suspected for some time that many pediatric cancers could be traced to an inherited genetic predisposition. Now, using genome sequencing, we can see the contribution of germline mutations to pediatric cancer risk. Our results explain why children, who have not lived long enough to accumulate a critical number of cancer-causing mutations can still develop cancer.” The study was published on November19, 2015, in the journal the New England Journal of Medicine.

Related Links:
St. Jude Children's Research Hospital 
Illumina