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Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing
- Publication Year :
- 2013
- Publisher :
- American Society of Hematology, 2013.
-
Abstract
- Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous cancer composed of at least 2 molecular subtypes that differ in gene expression and distribution of mutations. Recently, application of genome/exome sequencing and RNA-seq to DLBCL has revealed numerous genes that are recurrent targets of somatic point mutation in this disease. Here we provide a whole-genome-sequencing-based perspective of DLBCL mutational complexity by characterizing 40 de novo DLBCL cases and 13 DLBCL cell lines and combining these data with DNA copy number analysis and RNA-seq from an extended cohort of 96 cases. Our analysis identified widespread genomic rearrangements including evidence for chromothripsis as well as the presence of known and novel fusion transcripts. We uncovered new gene targets of recurrent somatic point mutations and genes that are targeted by focal somatic deletions in this disease. We highlight the recurrence of germinal center B-cell-restricted mutations affecting genes that encode the S1P receptor and 2 small GTPases (GNA13 and GNAI2) that together converge on regulation of B-cell homing. We further analyzed our data to approximate the relative temporal order in which some recurrent mutations were acquired and demonstrate that ongoing acquisition of mutations and intratumoral clonal heterogeneity are common features of DLBCL. This study further improves our understanding of the processes and pathways involved in lymphomagenesis, and some of the pathways mutated here may indicate new avenues for therapeutic intervention.
- Subjects :
- Genetics
Chromothripsis
Lymphoid Neoplasia
DNA Copy Number Variations
Genome, Human
Point mutation
Immunology
Copy number analysis
Cell Biology
Hematology
Biology
medicine.disease
Biochemistry
Genome
Gene expression profiling
hemic and lymphatic diseases
Mutation
medicine
Biomarkers, Tumor
Humans
Human genome
Lymphoma, Large B-Cell, Diffuse
Diffuse large B-cell lymphoma
Exome sequencing
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....dcec22125ef50997afef9860b2c58663