Evolution of dermatofibrosarcoma protuberans to DFSP-derived fibrosarcoma: An event marked by epithelial-mesenchymal transition-like process and 22q loss

Silvia Stacchiotti, Annalisa Astolfi, Alessandro Gronchi, Andrea Fontana, Maria A. Pantaleo, Tiziana Negri, Monica Brenca, Marcella Tazzari, Milena Urbini, Valentina Indio, Chiara Colombo, Stefano Radaelli, Silvia Brich, Angelo P Dei Tos, Paolo G. Casali, Chiara Castelli, Gian Paolo Dagrada, Silvana Pilotti, Roberta Maestro

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Abstract

Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma. At times, a fibrosarcomatous transformation marked by a more aggressive clinical behavior may be present. We investigated the natural history and the molecular bases of progression from classic DFSP to the fibrosarcomatous form (FS-DFSP), looking, retrospectively, at the outcome of all patients affected by primary DFSP treated at our institution from 1993 to 2012 and analyzing the molecular profile of 5 DFSPs and 5 FS-DFSPs by an integrated genomics approach (whole transcriptome sequencing, copy number analysis, FISH, qRT-PCR, IHC). The presence of fibrosarcomatous features was identified in 20 (7.6%) patients out of 263 DFSP. All cases were treated with macroscopic complete surgery. A local relapse occurred in 4 of 23 patients who received a microscopic marginal surgery (2 classic DFSP, 2 FS-DFSP), while metastasis affected 2 patients, both FS-DFSP (10% of FS-DFSP), being the first event. DFSP evolution to FS-DFSP was paralleled by a transcriptional reprogramming. The recurrent loss of chromosome 22q appeared to contribute to this phenomenon by promoting the expression of epigenetic regulators, such as EZH2. Loss of the p16/CDKN2A/INK4A locus at 9p was also observed in two FS-DFSP metastatic cases. Implications: FS-DFSP is a rare subgroup among DFSP, with a 10% metastatic risk, that was independent from local recurrence and that was not observed in DFSP, that were all cured by wide surgery. Chromosome 22q deletion might play a role in FS-DFSP, and p16 loss may convey a poor outcome. EZH2 dysregulation was also found and represents a druggable target.

Original languageEnglish
Pages (from-to)820-829
Number of pages10
JournalMolecular Cancer Research
Volume14
Issue number9
DOIs
Publication statusPublished - Sep 1 2016

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Dermatofibrosarcoma
Epithelial-Mesenchymal Transition
Fibrosarcoma
Cyclin-Dependent Kinase Inhibitor p16
Recurrence
Chromosome Deletion

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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Evolution of dermatofibrosarcoma protuberans to DFSP-derived fibrosarcoma : An event marked by epithelial-mesenchymal transition-like process and 22q loss. / Stacchiotti, Silvia; Astolfi, Annalisa; Gronchi, Alessandro; Fontana, Andrea; Pantaleo, Maria A.; Negri, Tiziana; Brenca, Monica; Tazzari, Marcella; Urbini, Milena; Indio, Valentina; Colombo, Chiara; Radaelli, Stefano; Brich, Silvia; Tos, Angelo P Dei; Casali, Paolo G.; Castelli, Chiara; Dagrada, Gian Paolo; Pilotti, Silvana; Maestro, Roberta.

In: Molecular Cancer Research, Vol. 14, No. 9, 01.09.2016, p. 820-829.

Research output: Contribution to journalArticle

Stacchiotti, Silvia ; Astolfi, Annalisa ; Gronchi, Alessandro ; Fontana, Andrea ; Pantaleo, Maria A. ; Negri, Tiziana ; Brenca, Monica ; Tazzari, Marcella ; Urbini, Milena ; Indio, Valentina ; Colombo, Chiara ; Radaelli, Stefano ; Brich, Silvia ; Tos, Angelo P Dei ; Casali, Paolo G. ; Castelli, Chiara ; Dagrada, Gian Paolo ; Pilotti, Silvana ; Maestro, Roberta. / Evolution of dermatofibrosarcoma protuberans to DFSP-derived fibrosarcoma : An event marked by epithelial-mesenchymal transition-like process and 22q loss. In: Molecular Cancer Research. 2016 ; Vol. 14, No. 9. pp. 820-829.
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abstract = "Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma. At times, a fibrosarcomatous transformation marked by a more aggressive clinical behavior may be present. We investigated the natural history and the molecular bases of progression from classic DFSP to the fibrosarcomatous form (FS-DFSP), looking, retrospectively, at the outcome of all patients affected by primary DFSP treated at our institution from 1993 to 2012 and analyzing the molecular profile of 5 DFSPs and 5 FS-DFSPs by an integrated genomics approach (whole transcriptome sequencing, copy number analysis, FISH, qRT-PCR, IHC). The presence of fibrosarcomatous features was identified in 20 (7.6{\%}) patients out of 263 DFSP. All cases were treated with macroscopic complete surgery. A local relapse occurred in 4 of 23 patients who received a microscopic marginal surgery (2 classic DFSP, 2 FS-DFSP), while metastasis affected 2 patients, both FS-DFSP (10{\%} of FS-DFSP), being the first event. DFSP evolution to FS-DFSP was paralleled by a transcriptional reprogramming. The recurrent loss of chromosome 22q appeared to contribute to this phenomenon by promoting the expression of epigenetic regulators, such as EZH2. Loss of the p16/CDKN2A/INK4A locus at 9p was also observed in two FS-DFSP metastatic cases. Implications: FS-DFSP is a rare subgroup among DFSP, with a 10{\%} metastatic risk, that was independent from local recurrence and that was not observed in DFSP, that were all cured by wide surgery. Chromosome 22q deletion might play a role in FS-DFSP, and p16 loss may convey a poor outcome. EZH2 dysregulation was also found and represents a druggable target.",
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T1 - Evolution of dermatofibrosarcoma protuberans to DFSP-derived fibrosarcoma

T2 - An event marked by epithelial-mesenchymal transition-like process and 22q loss

AU - Stacchiotti, Silvia

AU - Astolfi, Annalisa

AU - Gronchi, Alessandro

AU - Fontana, Andrea

AU - Pantaleo, Maria A.

AU - Negri, Tiziana

AU - Brenca, Monica

AU - Tazzari, Marcella

AU - Urbini, Milena

AU - Indio, Valentina

AU - Colombo, Chiara

AU - Radaelli, Stefano

AU - Brich, Silvia

AU - Tos, Angelo P Dei

AU - Casali, Paolo G.

AU - Castelli, Chiara

AU - Dagrada, Gian Paolo

AU - Pilotti, Silvana

AU - Maestro, Roberta

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N2 - Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma. At times, a fibrosarcomatous transformation marked by a more aggressive clinical behavior may be present. We investigated the natural history and the molecular bases of progression from classic DFSP to the fibrosarcomatous form (FS-DFSP), looking, retrospectively, at the outcome of all patients affected by primary DFSP treated at our institution from 1993 to 2012 and analyzing the molecular profile of 5 DFSPs and 5 FS-DFSPs by an integrated genomics approach (whole transcriptome sequencing, copy number analysis, FISH, qRT-PCR, IHC). The presence of fibrosarcomatous features was identified in 20 (7.6%) patients out of 263 DFSP. All cases were treated with macroscopic complete surgery. A local relapse occurred in 4 of 23 patients who received a microscopic marginal surgery (2 classic DFSP, 2 FS-DFSP), while metastasis affected 2 patients, both FS-DFSP (10% of FS-DFSP), being the first event. DFSP evolution to FS-DFSP was paralleled by a transcriptional reprogramming. The recurrent loss of chromosome 22q appeared to contribute to this phenomenon by promoting the expression of epigenetic regulators, such as EZH2. Loss of the p16/CDKN2A/INK4A locus at 9p was also observed in two FS-DFSP metastatic cases. Implications: FS-DFSP is a rare subgroup among DFSP, with a 10% metastatic risk, that was independent from local recurrence and that was not observed in DFSP, that were all cured by wide surgery. Chromosome 22q deletion might play a role in FS-DFSP, and p16 loss may convey a poor outcome. EZH2 dysregulation was also found and represents a druggable target.

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