DLBCL Duke 2017 (Reddy et al.)

Overview

Reddy et al. performed integrative whole-exome and transcriptome sequencing of 1001 newly-diagnosed DLBCL patients (502 with paired germline DNA) treated uniformly with rituximab-containing regimens. The study defined a comprehensive landscape of 150 recurrently mutated driver genes, characterized functional dependencies via a genome-wide CRISPR screen across six lymphoma cell lines, and built a multivariate prognostic model combining genetic alterations with cell-of-origin and MYC/BCL2 expression. Published in Cell (2017).

Composition

  • 1001 de novo DLBCL tumors with whole-exome sequencing; 400 paired tumor-normal pairs from this study plus 102 previously published pairs for a total 502-pair primary discovery set.
  • All cases treated with a rituximab-containing standard regimen (de facto R-CHOP); complete clinical annotation including IPI, response, overall survival, gender, age, stage, performance status, and extranodal sites.
  • RNA-seq performed on 775 cases; 625 used in core integrative analysis.
  • Cell-of-origin assignment via RNA-seq classifier: 313 ABC, 331 GCB, remainder unclassified.
  • Cancer type: DLBCL NOS.
  • CRISPR screen: GeCKO v2 genome-wide library (~120,000 sgRNAs, 19,050 protein-coding genes) across six cell lines — three ABC DLBCL (LY3, TMD8, HBL1), two GCB DLBCL (SUDHL4, Pfeiffer), one Burkitt-like (BJAB).

Assays / panels (linked)

  • whole-exome sequencing — Agilent All Exon V5, ~75X coverage on Illumina HiSeq 2500
  • RNA-seq — transcriptome profiling for cell-of-origin and expression analysis
  • MuTect v1.1.4 — somatic variant calling
  • BWA mem — alignment to hg19
  • EXCAVATOR — copy-number variant calling
  • ANNOVAR — variant annotation
  • FISH — MYC/BCL2 translocation detection
  • IHC — IRF4, BCL6, CD10 (Hans algorithm cell-of-origin)
  • Sanger sequencing — variant validation (1130 events, 61 genes, 90% concordance)

Papers using this cohort

  • PMID:28985567 — Reddy et al., Cell (2017): Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma.

Notable findings derived from this cohort

  • 150 recurrent driver genes identified in DLBCL (mean 7.75 mutations per case); 27 newly implicated in DLBCL including SPEN, KLHL14, and MGA. PMID:28985567
  • 20 driver genes differentially mutated between ABC and GCB subtypes: EZH2, SGK1, GNA13, SOCS1, STAT6, TNFRSF14 enriched in GCB; ETV6, MYD88, PIM1, TBL1XR1 enriched in ABC. PMID:28985567
  • CRISPR screen identified 1956 essential genes across at least one cell line; ABC-selective dependencies include CARD11, MYD88, IKBKB, IRF4; GCB-selective include XPO1, ZBTB7A, TGFBR2, PTPN6. PMID:28985567
  • 36% of DLBCL patients harbor genetic alterations in 9 CRISPR-validated essential driver genes that are direct drug targets. PMID:28985567
  • A 3-tier genomic risk classifier integrating 150 driver genes with cell-of-origin, MYC, and BCL2 expression outperforms IPI, cell-of-origin, and MYC/BCL2 dual-expressor models; validated on an independent 20% test set (p=8×10⁻⁵) and 5-fold cross-validation. PMID:28985567
  • Mutations associated with poorer OS across all DLBCL: MYC, CD79B, ZFAT. Favorable: NF1, SGK1. PMID:28985567
  • Within GCB DLBCL: EZH2 mutations associated with better survival; within ABC DLBCL: KLHL14, BTG1, PAX5, CDKN2A alterations associated with poorer survival. PMID:28985567

Sources

  • cBioPortal study ID: dlbcl_duke_2017
  • Interactive web tool: dlbcl.davelab.org

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