Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial-Mesenchymal Transition-like Process and 22q Loss.

Abstract

UNLABELLED:

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. Mol Cancer Res; 14(9); 820-9. ©2016 AACR.

• Authors: 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
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 14 Issue 9 Pg. 820-9 (09 2016) ISSN: 1557-3125 [Electronic] United States
• PMID: 27256159 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Chromosomes, Human, Pair 22
• Dermatofibrosarcoma (genetics, pathology)
• Disease Progression
• Epithelial-Mesenchymal Transition
• Female
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Skin Neoplasms (genetics, pathology)
• Young Adult