Recurrent somatic mutations affecting B-cell receptor signaling pathway genes in follicular lymphoma

Blood. 2017 Jan 26;129(4):473-483. doi: 10.1182/blood-2016-07-729954. Epub 2016 Nov 14.

Abstract

Follicular lymphoma (FL) is the most common form of indolent non-Hodgkin lymphoma, yet it remains only partially characterized at the genomic level. To improve our understanding of the genetic underpinnings of this incurable and clinically heterogeneous disease, whole-exome sequencing was performed on tumor/normal pairs from a discovery cohort of 24 patients with FL. Using these data and mutations identified in other B-cell malignancies, 1716 genes were sequenced in 113 FL tumor samples from 105 primarily treatment-naive individuals. We identified 39 genes that were mutated significantly above background mutation rates. CREBBP mutations were associated with inferior PFS. In contrast, mutations in previously unreported HVCN1, a voltage-gated proton channel-encoding gene and B-cell receptor signaling modulator, were associated with improved PFS. In total, 47 (44.8%) patients harbor mutations in the interconnected B-cell receptor (BCR) and CXCR4 signaling pathways. Histone gene mutations were more frequent than previously reported (identified in 43.8% of patients) and often co-occurred (17.1% of patients). A novel, recurrent hotspot was identified at a posttranslationally modified residue in the histone H2B family. This study expands the number of mutated genes described in several known signaling pathways and complexes involved in lymphoma pathogenesis (BCR, Notch, SWitch/sucrose nonfermentable (SWI/SNF), vacuolar ATPases) and identified novel recurrent mutations (EGR1/2, POU2AF1, BTK, ZNF608, HVCN1) that require further investigation in the context of FL biology, prognosis, and treatment.

MeSH terms

  • Adult
  • Agammaglobulinaemia Tyrosine Kinase
  • Aged
  • Aged, 80 and over
  • CREB-Binding Protein / genetics*
  • CREB-Binding Protein / metabolism
  • Disease-Free Survival
  • Early Growth Response Protein 1 / genetics
  • Early Growth Response Protein 1 / metabolism
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Ion Channels / genetics*
  • Ion Channels / metabolism
  • Lymphoma, Follicular / diagnosis
  • Lymphoma, Follicular / genetics*
  • Lymphoma, Follicular / mortality
  • Lymphoma, Follicular / pathology
  • Male
  • Middle Aged
  • Mutation
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism
  • Receptors, Antigen, B-Cell / genetics*
  • Receptors, Antigen, B-Cell / metabolism
  • Receptors, CXCR4 / genetics
  • Receptors, CXCR4 / metabolism
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction / genetics*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Vacuolar Proton-Translocating ATPases / genetics
  • Vacuolar Proton-Translocating ATPases / metabolism

Substances

  • BCL6B protein, human
  • CXCR4 protein, human
  • EGR1 protein, human
  • Early Growth Response Protein 1
  • Histones
  • Hv1 channel, human
  • Ion Channels
  • POU2AF1 protein, human
  • Receptors, Antigen, B-Cell
  • Receptors, CXCR4
  • Receptors, Notch
  • Repressor Proteins
  • Trans-Activators
  • CREB-Binding Protein
  • CREBBP protein, human
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Vacuolar Proton-Translocating ATPases