title: Identification of somatic and germline mutations using whole exome sequencing of congenital acute lymphoblastic leukemia.
abstract: BACKGROUND
  Acute lymphoblastic leukemia (ALL) diagnosed within the first month of life is classified as congenital ALL and has a significantly worse outcome than ALL diagnosed in older children. This suggests that congenital ALL is a biologically different disease, and thus may be caused by a distinct set of mutations. To understand the somatic and germline mutations contributing to congenital ALL, the protein-coding regions in the genome were captured and whole-exome sequencing was employed for the identification of single-nucleotide variants and small insertion and deletions in the germlines as well as the primary tumors of four patients with congenital ALL.
  
  
  METHODS
  Exome sequencing was performed on Illumina GAIIx or HiSeq 2000 (Illumina, San Diego, California). Reads were aligned to the human reference genome and the Genome Analysis Toolkit was used for variant calling. An in-house developed Ensembl-based variant annotator was used to richly annotate each variant.
  
  
  RESULTS
  There were 1-3 somatic, protein-damaging mutations per ALL, including a novel mutation in Sonic Hedgehog. Additionally, there were many germline mutations in genes known to be associated with cancer predisposition, as well as genes involved in DNA repair.
  
  
  CONCLUSIONS
  This study is the first to comprehensively characterize the germline and somatic mutational profile of all protein-coding genes patients with congenital ALL. These findings identify potentially important therapeutic targets, as well as insight into possible cancer predisposition genes.
authors: Department of Pediatrics, Division of Hematology-Oncology, University of California, Los Angeles, MDCC A2-410, Los Angeles, CA 90095, USA. vchang@mednet.ucla.edu
authors: Vivian Y
authors: VY
authors: Chang
authors: Giuseppe
authors: G
authors: Basso
authors: Kathleen M
authors: KM
authors: Sakamoto
authors: Stanley F
authors: SF
authors: Nelson
mesh_terms: D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D059472:Exome; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016254:Mutagenesis, Insertional; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000151:congenital / Q000235:genetics*; D017384:Sequence Deletion
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