Mutations Driving CLL and Their Evolution in Progression and Relapse

Nature. 2015 Oct 22;526(7574):525-30. doi: 10.1038/nature15395. Epub 2015 Oct 14.

Abstract

Which genetic alterations drive tumorigenesis and how they evolve over the course of disease and therapy are central questions in cancer biology. Here we identify 44 recurrently mutated genes and 11 recurrent somatic copy number variations through whole-exome sequencing of 538 chronic lymphocytic leukaemia (CLL) and matched germline DNA samples, 278 of which were collected in a prospective clinical trial. These include previously unrecognized putative cancer drivers (RPS15, IKZF3), and collectively identify RNA processing and export, MYC activity, and MAPK signalling as central pathways involved in CLL. Clonality analysis of this large data set further enabled reconstruction of temporal relationships between driver events. Direct comparison between matched pre-treatment and relapse samples from 59 patients demonstrated highly frequent clonal evolution. Thus, large sequencing data sets of clinically informative samples enable the discovery of novel genes associated with cancer, the network of relationships between the driver events, and their impact on disease relapse and clinical outcome.

Publication types

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

MeSH terms

  • Cell Transformation, Neoplastic / genetics
  • Clone Cells / metabolism
  • Clone Cells / pathology
  • DNA Copy Number Variations / genetics
  • Disease Progression*
  • Evolution, Molecular*
  • Exome / genetics
  • Genes, myc / genetics
  • Humans
  • Ikaros Transcription Factor / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / diagnosis
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology
  • Leukemia, Lymphocytic, Chronic, B-Cell / therapy
  • MAP Kinase Signaling System / genetics
  • Mutation / genetics*
  • Neoplasm Recurrence, Local / genetics*
  • Prognosis
  • RNA Processing, Post-Transcriptional / genetics
  • RNA Transport / genetics
  • Ribosomal Proteins / genetics
  • Treatment Outcome

Substances

  • IKZF3 protein, human
  • Ribosomal Proteins
  • ribosomal protein S21
  • Ikaros Transcription Factor

Associated data

  • dbGaP/PHS000922.V1.P1