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Identification of somatic and germline mutations using whole exome sequencing of congenital acute lymphoblastic leukemia

Vivian Y Chang1*, Giuseppe Basso2, Kathleen M Sakamoto3 and Stanley F Nelson4

Author Affiliations

1 Department of Pediatrics, Division of Hematology-Oncology, University of California, Los Angeles, 10833 Le Conte Ave., MDCC A2-410, Los Angeles, CA, 90095, USA

2 Woman and Child Health Department, University of Padova, Via Giustiniani, 335128, PADOVA, Italy

3 Department of Pediatrics, Division of Hematology/Oncology, Stanford University School of Medicine, CCSR-1215C, 269 Campus Drive, Stanford, CA, 94305-5162, USA

4 Department of Human Genetics, Pathology and Laboratory Medicine, and Psychiatry, University of California, Los Angeles, 695 Charles E. Young Drive South, Los Angeles, CA, 90095, USA

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BMC Cancer 2013, 13:55  doi:10.1186/1471-2407-13-55

Published: 4 February 2013



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.


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.


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.


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.

Pediatric leukemia; Congenital acute lymphoblastic leukemia; Exome sequencing