• 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 Patel, Jared 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, and James R Downing.
• Departments of Computational Biology (J.Z., G.W., M.N.E., D.H., X.M., X.Z., M.R.W., X.C., M.R., A.P., J.B.B., S.W.), Oncology (M.F.W., T.A.G., R.B.M., S.H.-D., R.N., E.Q., A.G., A.S.P., C.-H.P., K.E.N.), and Pathology (T.A.G., M.R.W., S.A.S., D.W.E., C.-H.P., J.R.D.) and the Pediatric Cancer Genome Project (J.Z., M.F.W., G.W., M.N.E., T.A.G., J.E., X.M., D.A.Y., B.V., X.C., R.B.M., S.H.-D., R.N., E.Q., S.A.S., M.R., A.P., J.B.B., S.W., M.S.W., A.G., D.W.E., A.S.P., C.-H.P., K.E.N., J.R.D.), St. Jude Children's Research Hospital, Memphis, TN; and the Department of Genetics and McDonnell Genome Institute, Washington University School of Medicine in St. Louis, St. Louis (L.D., E.R.M., R.K.W.).
• N. Engl. J. Med. 2015 Dec 10; 373 (24): 2336-2346.

BackgroundThe 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.MethodsIn 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 cancer-predisposition syndromes, for the presence of germline mutations. The pathogenicity of the mutations was determined by a panel of medical experts with the use of cancer-specific 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).ResultsMutations 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.ConclusionsGermline 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. (Funded by the American Lebanese Syrian Associated Charities and the National Cancer Institute.).

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