title: A pathogenic mosaic TP53 mutation in two germ layers detected by next generation sequencing.
abstract: BACKGROUND
  Li-Fraumeni syndrome is caused by germline TP53 mutations and is clinically characterized by a predisposition to a range of cancers, most commonly sarcoma, brain tumours and leukemia. Pathogenic mosaic TP53 mutations have only rarely been described.
  
  
  RESULTS
  We describe a 2 years old child presenting with three separate cancers over a 6 month period; two soft tissue mesenchymal tumors and an aggressive metastatic neuroblastoma. As conventional testing of blood DNA by Sanger sequencing for mutations in TP53, ALK, and SDH was negative, whole exome sequencing of the blood DNA of the patient and both parents was performed to screen more widely for cancer predisposing mutations. In the patient's but not the parents' DNA we found a c.743 G>A, p.Arg248Gln (CCDS11118.1) TP53 mutation in 3-20% of sequencing reads, a level that would not generally be detectable by Sanger sequencing. Homozygosity for this mutation was detected in all tumor samples analyzed, and germline mosaicism was demonstrated by analysis of the child's newborn blood spot DNA. The occurrence of separate tumors derived from different germ layers suggests that this de novo mutation occurred early in embryogenesis, prior to gastrulation.
  
  
  CONCLUSIONS
  The case demonstrates pathogenic mosaicim, detected by next generation deep sequencing, that arose in the early stages of embryogenesis.
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom; Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Sam
authors.initials: S
authors.lastname: Behjati
authors.affiliation: Unit of Molecular Haematology and Cancer Biology, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Mariana
authors.initials: M
authors.lastname: Maschietto
authors.affiliation: Unit of Molecular Haematology and Cancer Biology, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Williams
authors.affiliation: Departments of Clinical Genetics, Great Ormond Street Hospital, London, United Kingdom.
authors.forename: Lucy
authors.initials: L
authors.lastname: Side
authors.affiliation: Unit of Molecular Haematology and Cancer Biology, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Mike
authors.initials: M
authors.lastname: Hubank
authors.affiliation: Unit of Molecular Haematology and Cancer Biology, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Rebecca
authors.initials: R
authors.lastname: West
authors.affiliation: Unit of Molecular Haematology and Cancer Biology, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Katie
authors.initials: K
authors.lastname: Pearson
authors.affiliation: Departments of Histopathology, Great Ormond Street Hospital, London, United Kingdom.
authors.forename: Neil
authors.initials: N
authors.lastname: Sebire
authors.affiliation: Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tarpey
authors.affiliation: Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Futreal
authors.affiliation: Unit of Molecular Haematology and Cancer Biology, UCL Institute of Child Health, London, United Kingdom.
authors.forename: Tony
authors.initials: T
authors.lastname: Brooks
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: Unit of Molecular Haematology and Cancer Biology, UCL Institute of Child Health, London, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Anderson
mesh_terms: D002675:Child, Preschool; D004252:DNA Mutational Analysis; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D008297:Male; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53