期刊
NATURE GENETICS
卷 47, 期 4, 页码 330-U192出版社
NATURE PORTFOLIO
DOI: 10.1038/ng.3230
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资金
- St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project
- American Lebanese and Syrian Associated Charities of St. Jude Children's Research Hospital
- US National Institutes of Health [P30 CA021765]
- Swedish Childhood Cancer Society
- Swedish Research Council
- Swedish Cancer Society
- BioCARE
- Gunnar Nilsson Cancer Foundation
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 x 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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