Abstract
BackgroundStructural chromosomal rearrangements that lead to expressed fusion genes are a hallmark of acute lymphoblastic leukemia (ALL). In this study, we performed transcriptome sequencing of 134 primary ALL patient samples to comprehensively detect fusion transcripts.MethodsWe combined fusion gene detection with genome-wide DNA methylation analysis, gene expression profiling, and targeted sequencing to determine molecular signatures of emerging ALL subtypes.ResultsWe identified 64 unique fusion events distributed among 80 individual patients, of which over 50% have not previously been reported in ALL. Although the majority of the fusion genes were found only in a single patient, we identified several recurrent fusion gene families defined by promiscuous fusion gene partners, such as ETV6, RUNX1, PAX5, and ZNF384, or recurrent fusion genes, such as DUX4-IGH. Our data show that patients harboring these fusion genes displayed characteristic genome-wide DNA methylation and gene expression signatures in addition to distinct patterns in single nucleotide variants and recurrent copy number alterations.ConclusionOur study delineates the fusion gene landscape in pediatric ALL, including both known and novel fusion genes, and highlights fusion gene families with shared molecular etiologies, which may provide additional information for prognosis and therapeutic options in the future.
Highlights
Structural chromosomal rearrangements that lead to expressed fusion genes are a hallmark of acute lymphoblastic leukemia (ALL)
Transcriptome sequencing and detection of fusion genes To identify fusion genes in pediatric ALL, we sequenced the transcriptomes of 134 ALL samples, including 116 B cell precursor acute lymphoblastic leukemia (BCP-ALL) and 18 T cell acute lymphoblastic leukemia (T-ALL) patients (Table 1; Additional file 1: Table S1)
To reduce the number of potential false-positive fusion transcripts, we performed stringent filtering of the candidate fusion transcripts, including filtering of fusion genes called in the normal B and T cell to enrich for cancer-specific fusion genes in the ALL samples
Summary
Structural chromosomal rearrangements that lead to expressed fusion genes are a hallmark of acute lymphoblastic leukemia (ALL). We performed transcriptome sequencing of 134 primary ALL patient samples to comprehensively detect fusion transcripts. Chromosomal rearrangements giving rise to fusion genes play a central role in the malignant transformation of many cancers, including acute lymphoblastic leukemia (ALL) [1]. Recurrent large-scale structural rearrangements that result in expressed fusion transcripts are a hallmark of ALL and are included in the predictors of clinical outcome of individual patients that form the basis for treatment stratification [2]. In addition to recurrent rearrangements, ALL cells typically harbor other chromosomal aberrations that are detectable by routine cytogenetic screening and are nonrecurrent or have not yet been associated with expressed fusion genes. There is large heterogeneity regarding the cytogenetic subtypes screened and type of fusion genes that have been reported in these studies
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