Abstract
BackgroundAcute 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.MethodsExome 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.ResultsThere 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.ConclusionThis 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.
Highlights
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
* Correspondence: vchang@mednet.ucla.edu 1Department of Pediatrics, Division of Hematology-Oncology, University of California, Los Angeles, 10833 Le Conte Ave., MDCC A2-410, Los Angeles, CA 90095, USA Full list of author information is available at the end of the article sufficient for leukemogenesis [4,5] and does not entirely explain the aggressiveness of ALL in this population of patients [6,7,8]. These data demonstrate that congenital ALL is a biologically different disease, and may be caused by a distinct set of mutations in ALL blast cells that differ from blasts from older patients
We report whole-exome sequencing on four paired tumor-normal samples from patients with congenital ALL and fully characterize the germline and somatic mutations
Summary
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 may be caused by a distinct set of mutations. A recent study of 30 patients with congenital ALL treated on the Interfant-99 protocol reported a 2-year event-free survival of 20% despite intensive chemotherapy [1] This is significantly worse than the 5-year event-free survival of older children with ALL, which approaches 80% [2]. Our results demonstrate that there are very few somatic mutations in cALL and that there are potential druggable targets that may provide new therapeutic options to improve outcomes
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