Integrated Genomic Analysis Identifies Recurrent Mutations and Evolution Patterns Driving the Initiation and Progression of Follicular Lymphoma

Nat Genet. 2014 Feb;46(2):176-181. doi: 10.1038/ng.2856. Epub 2013 Dec 22.

Abstract

Follicular lymphoma is an incurable malignancy, with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma-transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • CREB-Binding Protein / genetics
  • Cell Transformation, Neoplastic / genetics*
  • Cluster Analysis
  • Cohort Studies
  • DNA-Binding Proteins / genetics
  • Disease Progression*
  • Enhancer of Zeste Homolog 2 Protein
  • Exome / genetics
  • Genomics / methods*
  • High-Throughput Nucleotide Sequencing
  • Histones / genetics
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Lymphoma, Follicular / genetics*
  • Lymphoma, Follicular / physiopathology*
  • Molecular Sequence Annotation
  • Molecular Sequence Data
  • Mutagenesis
  • Mutation / genetics
  • Myeloid Differentiation Factor 88 / genetics
  • Neoplasm Proteins / genetics
  • Nuclear Proteins / genetics
  • Phylogeny
  • Polycomb Repressive Complex 2 / genetics
  • Polymorphism, Single Nucleotide / genetics
  • Sequence Analysis, DNA
  • Trans-Activators / genetics
  • Tumor Necrosis Factor alpha-Induced Protein 3

Substances

  • DNA-Binding Proteins
  • EBF1 protein, human
  • Histones
  • Intracellular Signaling Peptides and Proteins
  • KMT2D protein, human
  • MYD88 protein, human
  • Myeloid Differentiation Factor 88
  • Neoplasm Proteins
  • Nuclear Proteins
  • Trans-Activators
  • EZH2 protein, human
  • Enhancer of Zeste Homolog 2 Protein
  • Polycomb Repressive Complex 2
  • CREB-Binding Protein
  • CREBBP protein, human
  • TNFAIP3 protein, human
  • Tumor Necrosis Factor alpha-Induced Protein 3

Associated data

  • GEO/GSE42525