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Leukemia. 2014 Jun;28(6):1235-41. doi: 10.1038/leu.2013.367. Epub 2013 Dec 4.

Excess congenital non-synonymous variation in leukemia-associated genes in MLL- infant leukemia: a Children's Oncology Group report.

Author information

1
1] Department of Genetics, Washington University School of Medicine, St Louis, MO, USA [2] Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
2
Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
3
Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.
4
Department of Pathology, Ohio State University, Columbus, OH, USA.
5
Department of Oncology/Hematology, Peyton Manning Children's Hospital at St Vincent, Indianapolis, IN, USA.
6
1] Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA [2] Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.

Abstract

Infant leukemia (IL) is a rare sporadic cancer with a grim prognosis. Although most cases are accompanied by MLL rearrangements and harbor very few somatic mutations, less is known about the genetics of the cases without MLL translocations. We performed the largest exome-sequencing study to date on matched non-cancer DNA from pairs of mothers and IL patients to characterize congenital variation that may contribute to early leukemogenesis. Using the COSMIC database to define acute leukemia-associated candidate genes, we find a significant enrichment of rare, potentially functional congenital variation in IL patients compared with randomly selected genes within the same patients and unaffected pediatric controls. IL acute myeloid leukemia (AML) patients had more overall variation than IL acute lymphocytic leukemia (ALL) patients, but less of that variation was inherited from mothers. Of our candidate genes, we found that MLL3 was a compound heterozygote in every infant who developed AML and 50% of infants who developed ALL. These data suggest a model by which known genetic mechanisms for leukemogenesis could be disrupted without an abundance of somatic mutation or chromosomal rearrangements. This model would be consistent with existing models for the establishment of leukemia clones in utero and the high rate of IL concordance in monozygotic twins.

PMID:
24301523
PMCID:
PMC4045651
DOI:
10.1038/leu.2013.367
[Indexed for MEDLINE]
Free PMC Article

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