BCGSC Non-Hodgkin Lymphoma Genome and Exome Sequencing

Overview

Whole-genome, whole-exome, and transcriptome sequencing study of 127 B-cell non-Hodgkin lymphoma (NHL) tumor samples plus 10 DLBCL cell lines from the BC Cancer Agency Genome Sciences Centre. The study used a multi-platform design: 14 cases with matched tumor/normal whole-genome or whole-exome sequencing for discovery, and 113 additional cases with RNA-seq. Extensive Sanger and Illumina amplicon validation cohorts were used to confirm mutations in KMT2D (89 cases) and MEF2B (572 total samples across multiple NHL subtypes). Data are deposited at SRA (SRP001599) and dbGaP (phs000235.v2.p1).

Composition

  • Cancer types: DLBCLNOS, FL
  • 127 B-cell NHL tumors + 10 DLBCL cell lines
  • 14 cases: matched tumor/normal whole-genome-seq or whole-exome-seq
  • 113 additional cases: rna-seq
  • KMT2D validation cohort: 89 cases (35 FL, 37 DLBCL, 17 DLBCL cell lines) via Illumina amplicon resequencing
  • MEF2B validation cohort: 261 FL, 259 DLBCL, 17 cell lines, 35 other NHL, 8 centroblasts via sanger-sequencing
  • Key clinical fields: COO subtype (GCB vs. ABC), histology (DLBCL vs. FL), survival

Assays / panels (linked)

Papers using this cohort

  • PMID:21796119 — Morin et al. 2011, genome/exome sequencing revealing histone-modifier mutations in NHL

Notable findings derived from this cohort

  • KMT2D (MLL2) mutated in 89% (31/35) of FL and 32% (12/37) of DLBCL; 91% of mutations were inactivating (frameshift, nonsense, splice-site); bi-allelic inactivation in 8 FL cases PMID:21796119
  • MEF2B recurrent non-synonymous mutations in 12.7% of DLBCL and 15.3% of FL; 59.4% of variants clustered at four residues (K4, Y69, N81, D83); restricted to GCB subtype PMID:21796119
  • GNA13 mutated in 17% of DLBCL, restricted to GCB subtype (P = 2.28e-4); multiple nonsense mutations indicate tumor suppressor role PMID:21796119
  • EZH2 Y641 hotspot mutations with allelic imbalance; novel sites A682G and A692V identified PMID:21796119
  • 109 genes confirmed somatically mutated in ≥2 NHL cases; 26 genes with significant evidence of positive selection (FDR 0.03) PMID:21796119
  • Mutual exclusion between ABC-enriched mutations (MYD88, CD79B) and GCB-enriched mutations (EZH2, GNA13) supports distinct molecular pathogenesis of COO subtypes PMID:21796119

Sources

  • PMID:21796119 — Morin et al., “Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma,” Nature 2011
  • SRA: SRP001599
  • dbGaP: phs000235.v2.p1

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