Genetic aberrations in imatinib-resistant dermatofibrosarcoma protuberans revealed by whole genome sequencing

PLoS One. 2013 Jul 29;8(7):e69752. doi: 10.1371/journal.pone.0069752. Print 2013.


Dermatofibrosarcoma protuberans (DFSP) is a very rare soft tissue sarcoma. DFSP often reveals a specific chromosome translocation, t(17;22)(q22;q13), which results in the fusion of collagen 1 alpha 1 (COL1A1) gene and platelet-derived growth factor-B (PDGFB) gene. The COL1A1-PDGFB fusion protein activates the PDGFB receptor and resultant constitutive activation of PDGFR receptor is essential in the pathogenesis of DFSP. Thus, blocking PDGFR receptor activation with imatinib has shown promising activity in the treatment of advanced and metastatic DFSP. Despite the success with targeted agents in cancers, acquired drug resistance eventually occurs. Here, we tried to identify potential drug resistance mechanisms against imatinib in a 46-year old female with DFSP who initially responded well to imatinib but suffered rapid disease progression. We performed whole-genome sequencing of both pre-treatment and post-treatment tumor tissue to identify the mutational events associated with imatinib resistance. No significant copy number alterations, insertion, and deletions were identified during imatinib treatment. Of note, we identified newly emerged 8 non-synonymous somatic mutations of the genes (ACAP2, CARD10, KIAA0556, PAAQR7, PPP1R39, SAFB2, STARD9, and ZFYVE9) in the imatinib-resistant tumor tissue. This study revealed diverse possible candidate mechanisms by which imatinib resistance to PDGFRB inhibition may arise in DFSP, and highlights the usefulness of whole-genome sequencing in identifying drug resistance mechanisms and in pursuing genome-directed, personalized anti-cancer therapy.

MeSH terms

  • Benzamides / therapeutic use*
  • CARD Signaling Adaptor Proteins / genetics
  • Carrier Proteins / genetics
  • Dermatofibrosarcoma / drug therapy
  • Dermatofibrosarcoma / genetics*
  • Drug Resistance, Neoplasm / genetics
  • Female
  • GTPase-Activating Proteins / genetics
  • Humans
  • Imatinib Mesylate
  • In Vitro Techniques
  • Matrix Attachment Region Binding Proteins / genetics
  • Middle Aged
  • Nuclear Matrix-Associated Proteins / genetics
  • Piperazines / therapeutic use*
  • Pyrimidines / therapeutic use*
  • Receptors, Estrogen / genetics


  • Benzamides
  • CARD Signaling Adaptor Proteins
  • CARD10 protein, human
  • Carrier Proteins
  • GTPase-Activating Proteins
  • Matrix Attachment Region Binding Proteins
  • Nuclear Matrix-Associated Proteins
  • Piperazines
  • Pyrimidines
  • Receptors, Estrogen
  • SAFB2 protein, human
  • STARD9 protein, human
  • Imatinib Mesylate

Grant support

The authors have no support or funding to report.