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PLoS One. 2014 May 8;9(5):e96531. doi: 10.1371/journal.pone.0096531. eCollection 2014.

A pathogenic mosaic TP53 mutation in two germ layers detected by next generation sequencing.

Author information

  • 1Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom; Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom.
  • 2Unit of Molecular Haematology and Cancer Biology, UCL Institute of Child Health, London, United Kingdom.
  • 3Departments of Clinical Genetics, Great Ormond Street Hospital, London, United Kingdom.
  • 4Departments of Histopathology, Great Ormond Street Hospital, London, United Kingdom.
  • 5Department of Paediatrics, University of Cambridge, Cambridge, United Kingdom.
  • 6Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, United Kingdom.

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.

METHODS AND FINDINGS:

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.

CONCLUSION:

The case demonstrates pathogenic mosaicim, detected by next generation deep sequencing, that arose in the early stages of embryogenesis.

PMID:
24810334
[PubMed - in process]
PMCID:
PMC4014518
Free PMC Article
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