title: Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing.
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.
authors.affiliation: Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Morin
authors.forename: Karen
authors.initials: K
authors.lastname: Mungall
authors.forename: Erin
authors.initials: E
authors.lastname: Pleasance
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Mungall
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Goya
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Huff
authors.forename: David W
authors.initials: DW
authors.lastname: Scott
authors.forename: Jiarui
authors.initials: J
authors.lastname: Ding
authors.forename: Andrew
authors.initials: A
authors.lastname: Roth
authors.forename: Readman
authors.initials: R
authors.lastname: Chiu
authors.forename: Richard D
authors.initials: RD
authors.lastname: Corbett
authors.forename: Fong Chun
authors.initials: FC
authors.lastname: Chan
authors.forename: Maria
authors.initials: M
authors.lastname: Mendez-Lago
authors.forename: Diane L
authors.initials: DL
authors.lastname: Trinh
authors.forename: Madison
authors.initials: M
authors.lastname: Bolger-Munro
authors.forename: Greg
authors.initials: G
authors.lastname: Taylor
authors.forename: Alireza
authors.initials: A
authors.lastname: Hadj Khodabakhshi
authors.forename: Susana
authors.initials: S
authors.lastname: Ben-Neriah
authors.forename: Julia
authors.initials: J
authors.lastname: Pon
authors.forename: Barbara
authors.initials: B
authors.lastname: Meissner
authors.forename: Bruce
authors.initials: B
authors.lastname: Woolcock
authors.forename: Noushin
authors.initials: N
authors.lastname: Farnoud
authors.forename: Sanja
authors.initials: S
authors.lastname: Rogic
authors.forename: Emilia L
authors.initials: EL
authors.lastname: Lim
authors.forename: Nathalie A
authors.initials: NA
authors.lastname: Johnson
authors.forename: Sohrab
authors.initials: S
authors.lastname: Shah
authors.forename: Steven
authors.initials: S
authors.lastname: Jones
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.forename: Robert
authors.initials: R
authors.lastname: Holt
authors.forename: Inanc
authors.initials: I
authors.lastname: Birol
authors.forename: Richard
authors.initials: R
authors.lastname: Moore
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: Marco A
authors.initials: MA
authors.lastname: Marra
mesh_terms: D014408:Biomarkers, Tumor / Q000737:chemistry* / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000737:chemistry / Q000235:genetics; D020869:Gene Expression Profiling; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D044365:GTP-Binding Protein alpha Subunits, G12-G13