Mutational and structural analysis of diffuse large B-cell lymphoma using whole genome sequencing
Menée sur 13 lignées cellulaires et 136 cas de lymphome diffus à grandes cellules B, cette étude de séquençage du génome entier met en évidence un ensemble de réarrangements génomiques et de mutations somatiques, puis estime l'ordre d'acquisition de ces mutations
Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous cancer comprising at least two 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 mutation and genes that are targeted by focal somatic deletions in this disease. We highlight the recurrence of GCB-restricted mutations affecting genes that encode the S1P receptor and two 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 intra-tumoral 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.