title: Deep sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas.
abstract: BACKGROUND
  Molecular mechanisms associated with frequent relapse of diffuse large B-cell lymphoma (DLBCL) are poorly defined. It is especially unclear how primary tumor clonal heterogeneity contributes to relapse. Here, we explore unique features of B-cell lymphomas - VDJ recombination and somatic hypermutation - to address this question.
  
  
  RESULTS
  We performed high-throughput sequencing of rearranged VDJ junctions in 14 pairs of matched diagnosis-relapse tumors, among which 7 pairs were further characterized by exome sequencing. We identify two distinctive modes of clonal evolution of DLBCL relapse: an early-divergent mode in which clonally related diagnosis and relapse tumors diverged early and developed in parallel; and a late-divergent mode in which relapse tumors developed directly from diagnosis tumors with minor divergence. By examining mutation patterns in the context of phylogenetic information provided by VDJ junctions, we identified mutations in epigenetic modifiers such as KMT2D as potential early driving events in lymphomagenesis and immune escape alterations as relapse-associated events.
  
  
  CONCLUSIONS
  Altogether, our study for the first time provides important evidence that DLBCL relapse may result from multiple, distinct tumor evolutionary mechanisms, providing rationale for therapies for each mechanism. Moreover, this study highlights the urgent need to understand the driving roles of epigenetic modifier mutations in lymphomagenesis, and immune surveillance factor genetic lesions in relapse.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Jiang
authors.forename: David
authors.initials: D
authors.lastname: Redmond
authors.forename: Kui
authors.initials: K
authors.lastname: Nie
authors.forename: Ken W
authors.initials: KW
authors.lastname: Eng
authors.forename: Thomas
authors.initials: T
authors.lastname: Clozel
authors.forename: Peter
authors.initials: P
authors.lastname: Martin
authors.forename: Leonard Hc
authors.initials: LH
authors.lastname: Tan
authors.forename: Ari M
authors.initials: AM
authors.lastname: Melnick
authors.forename: Wayne
authors.initials: W
authors.lastname: Tam
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
mesh_terms: D060965:Clonal Evolution; D004268:DNA-Binding Proteins / Q000235:genetics*; D044127:Epigenesis, Genetic; D059472:Exome; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D010802:Phylogeny; D017422:Sequence Analysis, DNA / Q000379:methods; D060152:V(D)J Recombination
chemical_list: D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins