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Nat Genet. 2015 Apr;47(4):330-7. doi: 10.1038/ng.3230. Epub 2015 Mar 2.

The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.

Author information

1
1] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Clinical Genetics, Lund University, Lund, Sweden.
2
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
3
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
4
Pediatric Cancer Genome Project Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
5
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
6
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
7
Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia.
8
Tumor Bank, Children's Cancer Research Unit, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
9
Department of Pediatrics, Skåne University Hospital, Lund, Sweden.
10
Department of Clinical Genetics, Lund University, Lund, Sweden.
11
1] Department of Genetics, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA. [2] Genome Institute, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
12
1] Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. [2] Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Abstract

Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole-genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R cases) and 20 older children (MLL-R cases) with leukemia. Our data show that infant MLL-R ALL has one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite this paucity of mutations, we detected activating mutations in kinase-PI3K-RAS signaling pathway components in 47% of cases. Surprisingly, these mutations were often subclonal and were frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (mean of 6.5 mutations/case versus 1.3 mutations/case, P = 7.15 × 10(-5)) and had frequent mutations (45%) in epigenetic regulators, a category of genes that, with the exception of MLL, was rarely mutated in infant MLL-R ALL.

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PMID:
25730765
PMCID:
PMC4553269
DOI:
10.1038/ng.3230
[Indexed for MEDLINE]
Free PMC Article
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