title: Whole exome sequencing of pediatric gastric adenocarcinoma reveals an atypical presentation of Li-Fraumeni syndrome.
abstract: BACKGROUND
  Gastric adenocarcinoma is a rare diagnosis in childhood. A 14-year-old male patient presented with metastatic gastric adenocarcinoma, and a strong family history of colon cancer. Clinical sequencing of CDH1 and APC were negative. Whole exome sequencing was therefore applied to capture the majority of protein-coding regions for the identification of single-nucleotide variants, small insertion/deletions, and copy number abnormalities in the patient's germline as well as primary tumor.
  
  
  METHODS
  DNA was extracted from the patient's blood, primary tumor, and the unaffected mother's blood. DNA libraries were constructed and sequenced on Illumina HiSeq2000. Data were post-processed using Picard and Samtools, then analyzed with the Genome Analysis Toolkit. Variants were annotated using an in-house Ensembl-based program. Copy number was assessed using ExomeCNV.
  
  
  RESULTS
  Each sample was sequenced to a mean depth of coverage of greater than 120×. A rare non-synonymous coding single-nucleotide variant (SNV) in TP53 was identified in the germline. There were 10 somatic cancer protein-damaging variants that were not observed in the unaffected mother genome. ExomeCNV comparing tumor to the patient's germline, identified abnormal copy number, spanning 6,946 genes.
  
  
  CONCLUSIONS
  We present an unusual case of Li-Fraumeni detected by whole exome sequencing. There were also likely driver somatic mutations in the gastric adenocarcinoma. These results highlight the need for more thorough and broad scale germline and cancer analyses to accurately inform patients of inherited risk to cancer and to identify somatic mutations.
authors.affiliation: Department of Pediatrics, Division of Hematology/Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California 90095, USA. vchang@mednet.ucla.edu
authors.forename: Vivian Y
authors.initials: VY
authors.lastname: Chang
authors.forename: Noah
authors.initials: N
authors.lastname: Federman
authors.forename: Julian
authors.initials: J
authors.lastname: Martinez-Agosto
authors.forename: Sergei F
authors.initials: SF
authors.lastname: Tatishchev
authors.forename: Stanley F
authors.initials: SF
authors.lastname: Nelson
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000293:Adolescent; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000150:complications / Q000235:genetics*; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D013274:Stomach Neoplasms / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53