Genomic and transcriptomic features of dermatofibrosarcoma protuberans: Unusual chromosomal origin of the COL1A1-PDGFB fusion gene and synergistic effects of amplified regions in tumor development

Abstract

The dermatofibrosarcoma protuberans family of tumors (DPFT) comprises cutaneous soft tissue neoplasms associated with aberrant PDGFBR signaling, typically through a COL1A1-PDGFB fusion. The aim of the present study was to obtain a better understanding of the chromosomal origin of this fusion and to assess the spectrum of secondary mutations at the chromosome and nucleotide levels. We thus investigated 42 tumor samples from 35 patients using chromosome banding, fluorescence in situ hybridization, single nucleotide polymorphism arrays, and/or massively parallel sequencing (gene panel, whole exome and transcriptome sequencing) methods. We confirmed the age-associated differences in the origin of the COL1A1-PDGFB fusion and could show that it in most cases must arise after DNA synthesis, i.e., in the S or G2 phase of the cell cycle. Whereas there was a non-random pattern of secondary chromosomal rearrangements, single nucleotide variants seem to have little impact on tumor progression. No clear genomic differences between low-grade and high-grade DPFT were found, but the number of chromosomes and chromosomal imbalances as well as the frequency of 9p deletions all tended to be greater among the latter. Gene expression profiling of tumors with COL1A1-PDGFB fusions associated with unbalanced translocations or ring chromosomes identified several transcriptionally up-regulated genes in the amplified regions of chromosomes 17 and 22, including TBX2, PRKCA, MSI2, SOX9, SOX10 , and PRAME .

PRAME expression in cellular neurothekeoma: A study of 11 cases

“…A recent study has observed high expression in solitary fibrous tumors, particularly in those arising in the thorax of elderly people, possibly escaping immune response 19 . Upregulation of the PRAME gene has been found also in dermatofibrosarcoma protuberans 20 …”

“…19 Upregulation of the PRAME gene has been found also in dermatofibrosarcoma protuberans. 20 In the skin, PRAME expression has been widely investigated in melanocytic neoplasms. [3][4][5][6] The expression in benign pigmented lesions, however, seems to hamper its diagnostic value in differentiating benign from malignant melanocytic lesions.…”

Molecular Characterization of Dermatofibrosarcoma Protuberans

“…However, negative PDGFB -FISH findings of primary tumors might result in misdiagnosis as benign entities, possibly leading to biased recurrent rates in cryptic PDGFB -rearranged or alternative PDGFD -rearranged DFSPs if complete re-excision is not performed. Notably, a recent comprehensive genomic and transcriptomic study21 reported no clear genomic differences between classic and FS variants of COL1A1-PDGFB -positive DFSPs, except for more frequent, but not exclusively, 9p21 deletion in the FS-DFSPs. In contrast, several amplified genes residing in the unbalanced translocation or ring chromosomes of DFSPs (eg, PRKCA and SOX9 on chromosome 17, PRAME and SOX10 on chromosome 22) were differentially upregulated but had no apparent impact on FS progression 21.…”

Genomic and transcriptomic characterization of desmoplastic small round cell tumors

“…Several fusion gene-associated sarcomas show copy number shifts in or near the genes involved in the fusions, thus serving as proxy markers for the fusion. For instance, dermatofibrosarcoma protuberans in adults consistently display amplification of the parts of COL1A1 and PDGFB that are present in the chimeric gene, 20 and a substantial proportion of low-grade fibromyxoid sarcomas and sclerosing epithelioid fibrosarcomas shows loss of the parts of the fusionforming genes that are not included in the hybrid chimera. 18,35 However, genomic arrays are not useful for identifying the EWSR1-WT1 fusion in DSRCT; copy number shifts affecting the EWSR1 or WT1 loci were seen in only one and two samples, respectively.…”

“…Extracted DNA from 8 fresh frozen tumor samples from 5 patients was analyzed using high-resolution SNP arrays (Cytoscan HD, Affymetrix, Santa Clara, CA), as described. 20 DNA from 17 FFPE samples from 15 patients was analyzed using the Affymetrix Oncoscan CNV platform, as described 19 ; in total, 25 loci. The position of the probes was aligned according to the GRCh37/hg19 genome build.…”