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

Nature Genetics
Anna K AnderssonSt. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project

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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Methods Mentioned

BETA
RNAseq
exome
Illumina sequencing
reverse-transcription PCR
exome sequencing
PCR
RNA-seq
Illumina
Illumina-based sequencing
PCRs

Software Mentioned

R
BWA
sffinfo
targetScanS
mclust
STAR
Pymol
CREST
VarScan
AceView

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