Clonal evolution in myelodysplastic syndromes

Nat Commun. 2017 Apr 21;8:15099. doi: 10.1038/ncomms15099.

Abstract

Cancer development is a dynamic process during which the successive accumulation of mutations results in cells with increasingly malignant characteristics. Here, we show the clonal evolution pattern in myelodysplastic syndrome (MDS) patients receiving supportive care, with or without lenalidomide (follow-up 2.5-11 years). Whole-exome and targeted deep sequencing at multiple time points during the disease course reveals that both linear and branched evolutionary patterns occur with and without disease-modifying treatment. The application of disease-modifying therapy may create an evolutionary bottleneck after which more complex MDS, but also unrelated clones of haematopoietic cells, may emerge. In addition, subclones that acquired an additional mutation associated with treatment resistance (TP53) or disease progression (NRAS, KRAS) may be detected months before clinical changes become apparent. Monitoring the genetic landscape during the disease may help to guide treatment decisions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Angiogenesis Inhibitors / therapeutic use*
  • Biomarkers, Tumor / genetics*
  • Biomarkers, Tumor / metabolism
  • Bone Marrow Cells / drug effects*
  • Bone Marrow Cells / metabolism
  • Bone Marrow Cells / pathology
  • Clonal Evolution / drug effects*
  • Disease Management
  • Disease Progression
  • Drug Resistance, Neoplasm / genetics
  • Female
  • Follow-Up Studies
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lenalidomide
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Middle Aged
  • Monitoring, Physiologic
  • Mutation
  • Myelodysplastic Syndromes / drug therapy
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / metabolism
  • Myelodysplastic Syndromes / pathology
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Thalidomide / analogs & derivatives*
  • Thalidomide / therapeutic use
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Whole Exome Sequencing

Substances

  • Angiogenesis Inhibitors
  • Biomarkers, Tumor
  • KRAS protein, human
  • Membrane Proteins
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Thalidomide
  • GTP Phosphohydrolases
  • NRAS protein, human
  • Proto-Oncogene Proteins p21(ras)
  • Lenalidomide