Diffuse Large B-Cell Lymphoma (Broad, 2012)

Overview

This cohort was generated at the Broad Institute in collaboration with Dana-Farber Cancer Institute, Mayo Clinic, University of Iowa, and Instituto Nacional de Medicina Genomica (Mexico). It comprises 55 primary DLBCL tumor samples with matched germline DNA profiled by whole-exome sequencing at 150-fold mean coverage. Statistical significance testing with MutSig identified 58 significantly mutated genes, including newly implicated drivers such as MEF2B, KMT2D, BTG1, GNA13, ACTB, P2RY8, PCLO, and TNFRSF14.

Composition

  • 55 paired tumor (lymph node biopsy) and germline (peripheral blood) samples; 49 passed QC after excluding 6 with extensive stromal contamination.
  • Cancer type: DLBCLNOS.
  • Multi-institution enrollment across US and Mexico.

Assays / panels (linked)

  • Whole-exome sequencing: 150-fold mean coverage; 97% of bases covered per patient (range 91-98%).
  • MutSig: statistical framework for identifying genes mutated at rates exceeding background.
  • Targeted resequencing for validation: 47 of 47 variants confirmed (97.9% validation rate).

Papers using this cohort

  • PMID:22343534 — Primary WES study identifying 58 significantly mutated genes in DLBCL.

Notable findings derived from this cohort

  • MutSig identified 58 significantly mutated genes (FDR q <= 0.1), confirming known drivers (MYD88, CARD11, EZH2, CREBBP, CD79B, TP53) and uncovering novel ones (MEF2B, KMT2D, BTG1, GNA13, ACTB, P2RY8) PMID:22343534.
  • BCL2 point mutations in patients with BCL2/IgH translocations arise from AID-mediated somatic hypermutation and are subject to purifying selection preserving anti-apoptotic function PMID:22343534.
  • Mean nonsynonymous mutation rate was 3.2 mutations per megabase (range 0.6-8.7), higher than CLL and multiple myeloma PMID:22343534.
  • Histone H1 family proteins were mutated in 69% of patients (59 nonsynonymous mutations across 34 patients) PMID:22343534.

Sources

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