Germline Mutations in Predisposition Genes in Pediatric Cancer

The most detailed analysis yet 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.

N Engl J Med. 2015 Nov 18; DOI: 10.1056/NEJMoa1508054


The frequency of germline mutations in cancer-predisposition genes in children and adolescents with cancer and the implications of such mutations are largely unknown. Previous studies have relied mainly on candidate-gene approaches, which are, by design, limited. To better determine the contribution of germline predisposition mutations to childhood cancer, we used next-generation sequencing, including whole-genome and whole-exome sequencing, to analyze the genomes of 1120 children and adolescents with cancer. We describe the prevalence and spectrum of germline variants among 565 cancer-associated genes, with an emphasis on the analysis of 60 genes that have been associated with autosomal dominant cancer-predisposition syndromes. We also reviewed records of patients with mutations and those without mutations in these 60 genes for information on family history of cancer.


Jinghui Zhang, Ph.D., Michael F. Walsh, M.D., Gang Wu, Ph.D., Michael N. Edmonson, B.A., Tanja A. Gruber, M.D., Ph.D., John Easton, Ph.D., Dale Hedges, Ph.D., Xiaotu Ma, Ph.D., Xin Zhou, Ph.D., Donald A. Yergeau, Ph.D., Mark R. Wilkinson, B.S., Bhavin Vadodaria, B.A., Xiang Chen, Ph.D., Rose B. McGee, M.S., Stacy Hines-Dowell, D.N.P., Regina Nuccio, M.S., Emily Quinn, M.S., Sheila A. Shurtleff, Ph.D., Michael Rusch, B.A., Aman Patel, M.S., Jared B. Becksfort, M.S., Shuoguo Wang, Ph.D., Meaghann S. Weaver, M.D., Li Ding, Ph.D., Elaine R. Mardis, Ph.D., Richard K. Wilson, Ph.D., Amar Gajjar, M.D., David W. Ellison, M.D., Ph.D., Alberto S. Pappo, M.D., Ching-Hon Pui, M.D., Kim E. Nichols, M.D., and James R. Downing, M.D.

Institute Authors

Li Ding, Ph.D.