Abstract 5169: Diagnostic yield of clinical tumor and germline exome sequencing for newly diagnosed children with solid tumors
Authors: Parsons Donald W. , Roy Angshumoy , Monzon Federico A. , Yang Yaping , López-Terrada Dolores H. , Chintagumpala Murali M. , Berg Stacey L. , Hilsenbeck Susan G. , Wang Tao , Kerstein Robin A. , Scollon Sarah , Bergstrom Katie , Street Richard L. , McCullough Laurence B. , McGuire Amy L. , Ramamurthy Uma , Reid Jeff G. , Muzny Donna M. , Wheeler David A. , Eng Christine M. , Gibbs Richard A. , Plon Sharon E. 
Published: May 2015

Abstract
Background: Advances in sequencing technologies allow for provision of genome-scale data to physicians caring for pediatric cancer patients but current experience with the clinical application of genomic sequencing is limited and the diagnostic yield of these methods is unclear.
Methods: The goal of the BASIC3 (Baylor Advancing Sequencing into Childhood Cancer Care) study is to determine the clinical impact of incorporating tumor and constitutional whole exome sequencing (WES) into the care of children with newly diagnosed solid tumors at Texas Children's Cancer Center (target enrollment n=280). WES of patient blood and frozen tumor samples is being conducted in the CLIA-certified Whole Genome Laboratory at Baylor College of Medicine using the VCRome 2.1 capture reagent and Illumina paired-end sequencing with reports incorporated in the medical record.
Results: 120 patients have enrolled to date, including 39 (33%) and 81 (67%) with CNS and non-CNS tumors, respectively. Despite limited diagnostic biopsies in many patients, tumor samples adequate for WES have been obtained from 97 subjects (81%). WES results have been reported for 89 patients. Tumor WES (n=73) revealed 20 of 73 tumors (27%) to contain mutations classified as having proven or potential clinical utility, including recurrent alterations of CTNNB1, BRAF, KIT, and NRAS/KRAS. Notably, less than 50% of somatic mutations would have been detected on an adult-focused cancer panel, BCM Cancer Gene Mutation Panel v.2. Germline WES (n=89) identified diagnostic findings in 11 cases (12%) including 8 patients with pathogenic mutations in dominant cancer susceptibility genes (singletons except for 2 patients with TP53 mutations). Four of these 8 patients had genetic testing recommended clinically. There were 2 patients with mutations providing the genetic cause of non-cancer medical problems and 1 patient with a mutation which explained both liver disease and hepatocellular carcinoma. Downstream testing of at-risk relatives has occurred rapidly in several families and cancer screening recommendations implemented. Seven (8%) medically actionable incidental findings unrelated to phenotype were reported, predominantly in cardiovascular genes and mitochondrial DNA.
Conclusions: These data demonstrate the feasibility of routine WES in the pediatric oncology setting. Early results demonstrate that clinically relevant findings are identified by tumor and germline WES in 38% of pediatric solid tumor patients. The yield of clinically relevant somatic and germline alterations would likely increase further by incorporation of complementary genomic methods (e.g. RNA-seq or copy number analysis). Assessment of the clinical utility of the tumor and germline exomes and preferences for reporting of these results to physicians and parents are under study. Supported by NHGRI/NCI 1U01HG006485.
Citation Format: Donald W. Parsons, Angshumoy Roy, Federico A. Monzon, Yaping Yang, Dolores H. López-Terrada, Murali M. Chintagumpala, Stacey L. Berg, Susan G. Hilsenbeck, Tao Wang, Robin A. Kerstein, Sarah Scollon, Katie Bergstrom, Richard L. Street, Laurence B. McCullough, Amy L. McGuire, Uma Ramamurthy, Jeff G. Reid, Donna M. Muzny, David A. Wheeler, Christine M. Eng, Richard A. Gibbs, Sharon E. Plon. Diagnostic yield of clinical tumor and germline exome sequencing for newly diagnosed children with solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5169. doi:10.1158/1538-7445.AM2014-5169