Abstract
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.
Highlights
Dermatofibrosarcoma protuberans (DFSP) is a very rare tumor, with an incidence of only 0.8 to 4.5 cases per million persons per year in the United States [1,2,3]
The disease recurred in a paraspinal space at the level of L5–S1, and she had received further surgery followed by postoperative radiotherapy to the surgical bed
We investigated the changes in the mutational spectrum before and after imatinib treatment by whole-genome sequencing and tried to identify the mutational events associated with imatinib resistance in DFSP
Summary
Dermatofibrosarcoma protuberans (DFSP) is a very rare tumor, with an incidence of only 0.8 to 4.5 cases per million persons per year in the United States [1,2,3]. The resulting COL1A1-PDGFB fusion protein eventually activates the PDGFB receptor (PDGFRB), which acts as a protein tyrosine kinase and a potent growth factor [11,12] This discovery prompted further studies on the use of PDGFRB tyrosine kinase inhibitors, such as imatinib, for the treatment of advanced and metastatic DFSP. A recent pooled analysis of two phase II trials reported promising clinical activity of imatinib with an objective response rate approaching 50% and a 1-year overall survival (OS) rate of 87.5% [18] Beyond this there is no established salvage treatment after failure of imatinib for DFSP, and the acquisition of imatinib resistance has never been investigated by systematic approaches. We were able to identify a number of genetic changes associated with imatinib resistance
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