title: Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors.
abstract: OBJECTIVE
  Whole-exome sequencing (WES) has the potential to reveal tumor and germline mutations of clinical relevance, but the diagnostic yield for pediatric patients with solid tumors is unknown.
  
  
  OBJECTIVE
  To characterize the diagnostic yield of combined tumor and germline WES for children with solid tumors.
  
  
  METHODS
  Unselected children with newly diagnosed and previously untreated central nervous system (CNS) and non-CNS solid tumors were prospectively enrolled in the BASIC3 study at a large academic children's hospital during a 23-month period from August 2012 through June 2014. Blood and tumor samples underwent WES in a certified clinical laboratory with genetic results categorized on the basis of perceived clinical relevance and entered in the electronic health record.
  
  
  METHODS
  Clinical categorization of somatic mutations; frequencies of deleterious germline mutations related to patient phenotype and incidental medically-actionable mutations.
  
  
  RESULTS
  Of the first 150 participants (80 boys and 70 girls, mean age, 7.4 years), tumor samples adequate for WES were available from 121 patients (81%). Somatic mutations of established clinical utility (category I) were reported in 4 (3%) of 121 patients, with mutations of potential utility (category II) detected in an additional 29 (24%) of 121 patients. CTNNB1 was the gene most frequently mutated, with recurrent mutations in KIT, TSC2, and MAPK pathway genes (BRAF, KRAS, and NRAS) also identified. Mutations in consensus cancer genes (category III) were found in an additional 24 (20%) of 121 tumors. Fewer than half of somatic mutations identified were in genes known to be recurrently mutated in the tumor type tested. Diagnostic germline findings related to patient phenotype were discovered in 15 (10%) of 150 cases: 13 pathogenic or likely pathogenic dominant mutations in adult and pediatric cancer susceptibility genes (including 2 each in TP53, VHL, and BRCA1), 1 recessive liver disorder with hepatocellular carcinoma (TJP2), and 1 renal diagnosis (CLCN5). Incidental findings were reported in 8 (5%) of 150 patients. Most patients harbored germline uncertain variants in cancer genes (98%), pharmacogenetic variants (89%), and recessive carrier mutations (85%).
  
  
  CONCLUSIONS
  Tumor and germline WES revealed mutations in a broad spectrum of genes previously implicated in both adult and pediatric cancers. Combined reporting of tumor and germline WES identified diagnostic and/or potentially actionable findings in nearly 40% of newly diagnosed pediatric patients with solid tumors.
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas3The Human Genome Sequencing Center, Baylor College of Medicine, Houston, T.
authors.forename: D Williams
authors.initials: DW
authors.lastname: Parsons
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston4The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas5Department of Pathology, Texas Children's Hospital, Houston6Department of Pathology a.
authors.forename: Angshumoy
authors.initials: A
authors.lastname: Roy
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston.
authors.forename: Sarah
authors.initials: S
authors.lastname: Scollon
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston.
authors.forename: Katie
authors.initials: K
authors.lastname: Bergstrom
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston.
authors.forename: Robin A
authors.initials: RA
authors.lastname: Kerstein
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Gutierrez
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Petersen
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Bavle
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston4The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Frank Y
authors.initials: FY
authors.lastname: Lin
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston4The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas5Department of Pathology, Texas Children's Hospital, Houston6Department of Pathology a.
authors.forename: Dolores H
authors.initials: DH
authors.lastname: López-Terrada
authors.affiliation: Department of Pathology, Texas Children's Hospital, Houston6Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.
authors.forename: Federico A
authors.initials: FA
authors.lastname: Monzon
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston4The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas5Department of Pathology, Texas Children's Hospital, Houston6Department of Pathology a.
authors.forename: M John
authors.initials: MJ
authors.lastname: Hicks
authors.affiliation: Department of Pathology, Texas Children's Hospital, Houston6Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.
authors.forename: Karen W
authors.initials: KW
authors.lastname: Eldin
authors.affiliation: Department of Pathology, Texas Children's Hospital, Houston6Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.
authors.forename: Norma M
authors.initials: NM
authors.lastname: Quintanilla
authors.affiliation: The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas5Department of Pathology, Texas Children's Hospital, Houston6Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.
authors.forename: Adekunle M
authors.initials: AM
authors.lastname: Adesina
authors.affiliation: Department of Pathology, Texas Children's Hospital, Houston6Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas.
authors.forename: Carrie A
authors.initials: CA
authors.lastname: Mohila
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurosurgery, Baylor College of Medicine, Houston, Texas8Department of Surgery, Texas Children's Hospital, Houston.
authors.forename: William
authors.initials: W
authors.lastname: Whitehead
authors.affiliation: Division of Pediatric Neurosurgery, Department of Neurosurgery, Baylor College of Medicine, Houston, Texas8Department of Surgery, Texas Children's Hospital, Houston.
authors.forename: Andrew
authors.initials: A
authors.lastname: Jea
authors.affiliation: The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas8Department of Surgery, Texas Children's Hospital, Houston9Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
authors.forename: Sanjeev A
authors.initials: SA
authors.lastname: Vasudevan
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston4The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas8Department of Surgery, Texas Children's Hospital, Houston9Michael E. DeBakey Departme.
authors.forename: Jed G
authors.initials: JG
authors.lastname: Nuchtern
authors.affiliation: Dan L. Duncan Institute for Clinical and Translational Research, Baylor College of Medicine, Houston, Texas.
authors.forename: Uma
authors.initials: U
authors.lastname: Ramamurthy
authors.affiliation: The Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas11Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, Texas.
authors.forename: Amy L
authors.initials: AL
authors.lastname: McGuire
authors.affiliation: The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Susan G
authors.initials: SG
authors.lastname: Hilsenbeck
authors.affiliation: The Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Reid
authors.affiliation: The Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Donna M
authors.initials: DM
authors.lastname: Muzny
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas3The Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas4The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: David A
authors.initials: DA
authors.lastname: Wheeler
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston4The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Berg
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston4The Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Murali M
authors.initials: MM
authors.lastname: Chintagumpala
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas3The Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Gibbs
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Baylor College of Medicine, Houston2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas3The Human Genome Sequencing Center, Baylor College of Medicine, Houston, T.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Plon
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