Heritable Mutations in Pediatric Cancer

Abstract

Research Article| April 01 2016 Heritable Mutations in Pediatric Cancer AAP Grand Rounds (2016) 35 (4): 43. https://doi.org/10.1542/gr.35-4-43 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Heritable Mutations in Pediatric Cancer. AAP Grand Rounds April 2016; 35 (4): 43. https://doi.org/10.1542/gr.35-4-43 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search toolbar search search input Search input auto suggest filter your search All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: cancer, childhood cancer, mutation Source: Zhang J, Walsh M, Wu G, et al. Germline mutations in predisposition genes in pediatric cancer. N Engl J Med. 2015; 373(24): 2336– 2346; doi: https://doi.org/10.1056/NEJMoa1508054Google Scholar Investigators from St. Jude Children’s Research Hospital and Washington University in St. Louis assessed the frequency of mutations among cancer-associated genes in children and adolescents with a wide variety of cancers. Whole-genome or whole-exome (coding regions only) sequencing data (or both) were generated for 565 cancer-associated genes, including a subset of 60 autosomal dominant cancer-related genes, as part of the Pediatric Cancer Genome Project. Cases for the study, patients <20 years of age with cancer, were compared to 2 control cohorts without cancer: unrelated adults from the 1000 Genomes Project, and persons (median age 6 years; range 1–37 years) with and without autism from the National Database for Autism Research. Medical records of cases with and without cancer-related heritable mutations were reviewed for a family history of cancer. The pathogenicity of mutations was classified after review by experts. Rates of “pathogenic” or “probably pathogenic” mutations among case and control groups were compared. The rates of a family history of cancer among cases with or without mutations were also compared. Data were analyzed on 1,120 case participants (median age 6.9 years), 996 unrelated adult controls, 515 persons with autism, and 208 without autism. Case diagnoses included 52.5% with leukemia, 21.9% with central nervous system (CNS) tumors, and 25.6% with non-CNS solid tumors. There was an 8.5% prevalence of pathogenic or probably pathogenic mutations in cases compared with a prevalence of 1.1% and 0.6% in controls from the 1000 Genome Project and the autism study, respectively. The prevalence of mutations in cases with non-CNS tumors was 16.7%, with CNS tumors 8.6%, and with leukemia 4.4%. Among 58 case participants with pathogenic or probably pathogenic mutations and medical record availability, 40% had a family history of cancer. Conversely, in a randomly selected group of 100 case participants who did not have mutations identified, 42% had a family history of cancer. The authors conclude that genetic childhood cancer susceptibility is complex and family history alone is an unreliable guide to predicting an underlying cancer-predisposition syndrome. Dr Hogan has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device. Prior to this study, the prevalence of children and adolescents with cancer who have a familial cancer-predisposition syndrome was difficult to determine.1 Recognized inherited syndromes have been associated with high-penetrance DNA mutations (eg, Li-Fraumeni syndrome with sarcomas, adrenocortical carcinoma, and others), chromosomal aneuploidy (eg, Down syndrome with leukemia), and epigenetic disorders (eg, Beckwith-Weidemann syndrome with Wilms tumor, hepatoblastoma, and others).2 Criteria for identifying children with cancer and their family members with inherited cancer susceptibility have included the presence of rare tumors, bilateral or multifocal tumors, cancer at a younger than expected age, multiple synchronous or metachronous tumors, other features of... You do not currently have access to this content.