The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias
Date
2015
Authors
Andersson, A.
Ma, J.
Wang, J.
Chen, X.
Gedman, A.
Dang, J.
Nakitandwe, J.
Holmfeldt, L.
Parker, M.
Easton, J.
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Journal article
Citation
Nature Genetics, 2015; 47(4):330-337
Statement of Responsibility
Anna K Andersson ... Charles G Mullighan ... et al. for The St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project
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DOI
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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Includes 3 unnumbered pages at the end of the article.
Published online 2 March 2015
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© 2015 Nature America, Inc. All rights reserved.