Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia

Nat Commun. 2015 Mar 19;6:6604. doi: 10.1038/ncomms7604.

Abstract

There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.

Publication types

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

MeSH terms

  • 5'-Nucleotidase / genetics
  • CREB-Binding Protein / genetics
  • Child
  • Clonal Evolution / genetics*
  • Clone Cells
  • DNA Copy Number Variations
  • Disease Progression
  • Exome
  • Extracellular Matrix Proteins / genetics
  • Female
  • GTP Phosphohydrolases / genetics
  • Histone-Lysine N-Methyltransferase / genetics
  • Humans
  • Ikaros Transcription Factor / genetics
  • Male
  • Membrane Proteins / genetics
  • Mutation
  • Neoplasm Recurrence, Local / genetics*
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Repressor Proteins / genetics
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Extracellular Matrix Proteins
  • IKZF1 protein, human
  • Membrane Proteins
  • Repressor Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • USH2A protein, human
  • Ikaros Transcription Factor
  • Histone-Lysine N-Methyltransferase
  • NSD2 protein, human
  • CREB-Binding Protein
  • CREBBP protein, human
  • 5'-Nucleotidase
  • NT5C2 protein, human
  • GTP Phosphohydrolases
  • NRAS protein, human

Associated data

  • dbGaP/PHS000218