Germline mutations in predisposition genes in pediatric cancer

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

Research output: Contribution to journalArticlepeer-review

812 Scopus citations


BACKGROUND The prevalence and spectrum of predisposing mutations among children and adolescents with cancer are largely unknown. Knowledge of such mutations may improve the understanding of tumorigenesis, direct patient care, and enable genetic counseling of patients and families. METHODS In 1120 patients younger than 20 years of age, we sequenced the whole genomes (in 595 patients), whole exomes (in 456), or both (in 69). We analyzed the DNA sequences of 565 genes, including 60 that have been associated with autosomal dominant cancerpredisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancerspecific and locus-specific genetic databases, the medical literature, computational predictions, and second hits identified in the tumor genome. The same approach was used to analyze data from 966 persons who did not have known cancer in the 1000 Genomes Project, and a similar approach was used to analyze data from an autism study (from 515 persons with autism and 208 persons without autism). RESULTS Mutations that were deemed to be pathogenic or probably pathogenic were identified in 95 patients with cancer (8.5%), as compared with 1.1% of the persons in the 1000 Genomes Project and 0.6% of the participants in the autism study. The most commonly mutated genes in the affected patients were TP53 (in 50 patients), APC (in 6), BRCA2 (in 6), NF1 (in 4), PMS2 (in 4), RB1 (in 3), and RUNX1 (in 3). A total of 18 additional patients had protein-truncating mutations in tumor-suppressor genes. Of the 58 patients with a predisposing mutation and available information on family history, 23 (40%) had a family history of cancer. CONCLUSIONS Germline mutations in cancer-predisposing genes were identified in 8.5% of the children and adolescents with cancer. Family history did not predict the presence of an underlying predisposition syndrome in most patients.

Original languageEnglish (US)
Pages (from-to)2336-2346
Number of pages11
JournalNew England Journal of Medicine
Issue number24
StatePublished - Dec 10 2015
Externally publishedYes

ASJC Scopus subject areas

  • General Medicine


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