Gains of COL1A1-PDGFB genomic copies occur in fibrosarcomatous transformation of dermatofibrosarcoma protuberans

Abstract

Dermatofibrosarcoma protuberans is a superficial low-grade sarcoma that rarely evolves into a high-grade fibrosarcoma. Dermatofibrosarcoma protuberans is genetically characterized by the unbalanced chromosomal t(17;22)(q21;q13), usually in the form of a supernumerary ring chromosome. The product of this chromosomal translocation is the chimeric gene COL1A1-PDGFB (collagen type I alpha I-platelet-derived growth factor beta), which is amplified at low levels in the ring chromosome. The aims of this study were to evaluate (1) whether genomic gains of this fusion gene occur during the clonal evolution of dermatofibrosarcoma protuberans into fibrosarcomatous dermatofibrosarcoma protuberans and (2) whether there is a difference between the number of genomic copies of COL1A1-PDGFB between classic dermatofibrosarcoma protuberans and dermatofibrosarcoma protuberans areas associated with fibrosarcomatous dermatofibrosarcoma protuberans. Eleven cases of fibrosarcomatous dermatofibrosarcoma protuberans with both dermatofibrosarcoma protuberans and fibrosarcomatous areas and 10 cases of classic dermatofibrosarcoma protuberans were studied. Genomic copies of COL1A1-PDGFB were evaluated by fluorescence in situ hybridization using a custom designed probe for the PDGFB locus on 4 lm thick paraffin-embedded tissue sections. Genomic gains of the COL1A1-PDGFB gene were observed in six (of 10) fibrosarcomatous dermatofibrosarcoma protuberans in the fibrosarcomatous areas when compared to the dermatofibrosarcoma protuberans areas of the same tumor (2-7 gene copies (median PDGFB copy gain, 2.8) versus 1-3 gene copies (median PDGFB copy gain, 1.7), respectively, P ¼ 0.004). Four fibrosarcomatous dermatofibrosarcoma protuberans did not show genomic gains of COL1A1-PDGFB fusion gene between the two areas. Essentially no difference in the copy number of COL1A1-PDGFB fusion gene was observed between dermatofibrosarcoma protuberans areas of classic dermatofibrosarcoma protuberans and dermatofibrosarcoma protuberans areas of fibrosarcomatous dermatofibrosarcoma protuberans (median PDGFB copy gain of 1.8 versus 1.7, respectively, P ¼ 0.36). Genomic gains of COL1A1-PDGFB fusion gene is possibly an oncogenic mechanism that is identified in the clonal evolution of a subset of dermatofibrosarcoma protuberans that evolves into fibrosarcomatous dermatofibrosarcoma protuberans. Since this finding was not observed in all cases of fibrosarcomatous dermatofibrosarcoma protuberans, other oncogenic mechanisms may be operating in this form of tumor progression. Copy number of COL1A1-PDGFB fusion gene in the classic dermatofibrosarcoma protuberans areas does not seem to be a major predisposing mechanism for fibrosarcomatous transformation.

Molecular diagnosis of dermatofibrosarcoma protuberans: A comparison between reverse transcriptase‐polymerase chain reaction and fluorescence in situ hybridization methodologies

“…We thus analyzed if the presence of COL1A1/PDGFB extra fusion signals was frequently observed in DFSP-FS. In agreement with Stacchiotti et al (2011), no significant relationship was observed in contrast to previously reported series, including earlier results from our group (Abbott et al, 2006;Macarenco et al, 2008;Segura et al, 2011). The limited number of such cases included in these studies may explain these negative results.…”

“…A positive result using DCDF probes requires two fusion signals, an event that is very unlikely to occur by chance. A limited number of studies on DFSP using FISH techniques has been reported and most of them were small series using both PDGFB break-apart (Abbott et al, 2006;Macarenco et al, 2008;Patel et al, 2008) and DCDF COL1A1/PDGFB probes (Craver et al, 2006;Maire et al, 2007;Segura et al, 2011). Regarding PDGFB break-apart probes, the largest series reported included 27 patients and the presence of the translocation was observed in 96% of cases (Patel et al, 2008).…”

“…Instead, we observed a variant FISH pattern in the vast majority of our cases showing from three to more than six fusion signals. Several authors have associated the presence of multiple fusion signals with the DFSP-FS subtype and have suggested that this phenomenon corresponds to tumor progression, (Abbott et al, 2006). We thus analyzed if the presence of COL1A1/PDGFB extra fusion signals was frequently observed in DFSP-FS.…”

“…In our previous experience (Llombart et al, accepted for publication), we observed that 76% is detected using RT-PCR in paraffin embedded tissue samples. FISH has been performed using both PDGFB break-apart and COL1A1/PDGFB dual color dual fusion (DCDF) non-commercial probe strategies (Abbott et al, 2006;Craver et al, 2006;Maire et al, 2007;Macarenco et al, 2008;Patel et al, 2008;Segura et al, 2011). It has been postulated that dual fusion probes are better than break-apart regarding sensitivity because their false positive rate in normal tissues is very low (Ventura et al, 2006).…”

Genomic gains of COL1A1‐PDFGB occur in the histologic evolution of giant cell fibroblastoma into dermatofibrosarcoma protuberans

“…The product of this chromosomal translocation is the fusion gene COL1A1-PDGFB, which has been detected in both GCF and DFSP (Simon et al, 1997). Interestingly, one to three genomic copies of this fusion gene are commonly observed in DFSP (Abbott et al, 2006 In this study, we aimed to determine the frequency and genomic copy number of COL1A1-PDGFB fusion in cases of pure GCF and in distinct areas of hybrid cases of GCF/DFSP to better understand the biology of this histologic evolution. In addition, we aimed to determine the molecular cytogenetic signature of the individual mononuclear and giant cell components of GCF.…”