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Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils
distinct mutational patterns between genetic subtypes and novel
relapse-associated genes
#MMPMID27590521
Lindqvist CM
; Lundmark A
; Nordlund J
; Freyhult E
; Ekman D
; Carlsson Almlöf J
; Raine A
; Övernäs E
; Abrahamsson J
; Frost BM
; Grandér D
; Heyman M
; Palle J
; Forestier E
; Lönnerholm G
; Berglund EC
; Syvänen AC
Oncotarget
2016[Sep]; 7
(39
): 64071-64088
PMID27590521
show ga
To characterize the mutational patterns of acute lymphoblastic leukemia (ALL) we
performed deep next generation sequencing of 872 cancer genes in 172 diagnostic
and 24 relapse samples from 172 pediatric ALL patients. We found an overall
greater mutational burden and more driver mutations in T-cell ALL (T-ALL)
patients compared to B-cell precursor ALL (BCP-ALL) patients. In addition, the
majority of the mutations in T-ALL had occurred in the original leukemic clone,
while most of the mutations in BCP-ALL were subclonal. BCP-ALL patients carrying
any of the recurrent translocations ETV6-RUNX1, BCR-ABL or TCF3-PBX1 harbored few
mutations in driver genes compared to other BCP-ALL patients. Specifically in
BCP-ALL, we identified ATRX as a novel putative driver gene and uncovered an
association between somatic mutations in the Notch signaling pathway at ALL
diagnosis and increased risk of relapse. Furthermore, we identified EP300, ARID1A
and SH2B3 as relapse-associated genes. The genes highlighted in our study were
frequently involved in epigenetic regulation, associated with germline
susceptibility to ALL, and present in minor subclones at diagnosis that became
dominant at relapse. We observed a high degree of clonal heterogeneity and
evolution between diagnosis and relapse in both BCP-ALL and T-ALL, which could
have implications for the treatment efficiency.
|*High-Throughput Nucleotide Sequencing
[MESH]
|*Mutation
[MESH]
|Adaptor Proteins, Signal Transducing
[MESH]
|Child
[MESH]
|Child, Preschool
[MESH]
|Cohort Studies
[MESH]
|DNA Mutational Analysis
[MESH]
|DNA-Binding Proteins
[MESH]
|E1A-Associated p300 Protein/genetics
[MESH]
|Epigenesis, Genetic
[MESH]
|Humans
[MESH]
|Immunophenotyping
[MESH]
|Infant
[MESH]
|Intracellular Signaling Peptides and Proteins
[MESH]
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