No correlation between the molecular subtype of COL1A1-PDGFB fusion gene and the clinico-histopathological features of dermatofibrosarcoma protuberans.

collagen type I-α 1 dermatofibrosarcoma protuberans platelet-derived growth factor-B chain TO THE EDITOR Dermatofibrosarcoma protuberans (DFSP) is a dermal tumor of intermediate malignancy. Propensity for metastases is low but local recurrence risk is high unless a wide surgical excision is performed. In addition to the classical presentation of DFSP, several clinical and histological variants have been described, such as DFSP-containing fibrosarcomatous areas or malignant fibrous histiocytoma areas, Bednar tumor, giant cell fibroblastoma, and superficial adult fibrosarcoma (Simon et al., 1997Simon M.P. Pedeutour F. Sirvent N. Grosgeorge J. Minoletti F. Coindre J.M. et al.Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma.Nat Genet. 1997; 15: 95-98Crossref PubMed Scopus (430) Google Scholar; Sheng et al., 2001Sheng W.Q. Hashimoto H. Okamoto S. Ishida T. Meis-Kindblom J.M. Kindblom L.G. et al.Expression of COL1A1-PDGFB fusion transcripts in superficial adult fibrosarcoma suggests a close relationship to dermatofibrosarcoma protuberans.J Pathol. 2001; 194: 88-94Crossref PubMed Scopus (43) Google Scholar; Maire et al., 2002aMaire G. Martin L. Michalak-Provost S. Gattas G.J. Turc-Carel C. Lorette G. et al.Fusion of COL1A1 exon 29 with PDGFB exon 2 in a der(22)t(17;22) in a pediatric giant cell fibroblastoma with a pigmented Bednar tumor component. Evidence for age-related chromosomal pattern in dermatofibrosarcoma protuberans and related tumors.Cancer Genet Cytogenet. 2002; 134: 156-161Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar; Sirvent et al., 2003Sirvent N. Maire G. Pedeutour F. Genetics of dermatofibrosarcoma protuberans family of tumors: from ring chromosomes to tyrosine kinase inhibitor treatment.Genes Chromosomes Cancer. 2003; 37: 1-19Crossref PubMed Scopus (217) Google Scholar; Bianchini et al., 2007Bianchini L. Maire G. Pedeutour F. From cytogenetics to cytogenomics of dermatofibrosarcoma protuberans family of tumors.Bull Cancer. 2007; 94: 179-189PubMed Google Scholar; Szollosi et al., 2007Szollosi Z. Scholtz B. Egervari K. Nemes Z. Transformed dermatofibrosarcoma protuberans: real time polymerase chain reaction detection of COL1A1-PDGFB fusion transcripts in sarcomatous areas.J Clin Pathol. 2007; 60: 190-194Crossref PubMed Scopus (22) Google Scholar). DFSP and related tumors are molecularly characterized by the presence of an abnormal chimeric gene that fuses COL1A1 (17q21.3) with platelet-derived growth factor-B chain (PDGFB) (22q13.1) (Simon et al., 1997Simon M.P. Pedeutour F. Sirvent N. Grosgeorge J. Minoletti F. Coindre J.M. et al.Deregulation of the platelet-derived growth factor B-chain gene via fusion with collagen gene COL1A1 in dermatofibrosarcoma protuberans and giant-cell fibroblastoma.Nat Genet. 1997; 15: 95-98Crossref PubMed Scopus (430) Google Scholar). The detection of COL1A1–PDGFB is mandatory in case of unusual clinical or histological presentation, as well as in pediatric cases (Sirvent et al., 2003Sirvent N. Maire G. Pedeutour F. Genetics of dermatofibrosarcoma protuberans family of tumors: from ring chromosomes to tyrosine kinase inhibitor treatment.Genes Chromosomes Cancer. 2003; 37: 1-19Crossref PubMed Scopus (217) Google Scholar; Bianchini et al., 2007Bianchini L. Maire G. Pedeutour F. From cytogenetics to cytogenomics of dermatofibrosarcoma protuberans family of tumors.Bull Cancer. 2007; 94: 179-189PubMed Google Scholar; Maire et al., 2007Maire G. Fraitag S. Galmiche L. Keslair F. Ebran N. Terrier-Lacombe M.J. et al.A clinical, histologic, and molecular study of 9 cases of congenital dermatofibrosarcoma protuberans.Arch Dermatol. 2007; 143: 203-210Crossref PubMed Scopus (79) Google Scholar). A striking feature of COL1A1–PDGFB fusion consists of the high variability of the break point location between the exons 6 and 49 of COL1A1 (Sirvent et al., 2003Sirvent N. Maire G. Pedeutour F. Genetics of dermatofibrosarcoma protuberans family of tumors: from ring chromosomes to tyrosine kinase inhibitor treatment.Genes Chromosomes Cancer. 2003; 37: 1-19Crossref PubMed Scopus (217) Google Scholar; Bianchini et al., 2007Bianchini L. Maire G. Pedeutour F. From cytogenetics to cytogenomics of dermatofibrosarcoma protuberans family of tumors.Bull Cancer. 2007; 94: 179-189PubMed Google Scholar). In contrast, the break point in PDGFB is consistently located in the first intron. We have investigated whether the COL1A1 break point location is associated with clinical or histological features. In such a case, the precise detection of the COL1A1 break point detection by using multiplex reverse transcriptase–PCR and sequencing could be useful for diagnosis or evaluation of prognosis. For this purpose we compiled a series of 172 DFSP cases with both molecular and clinico-histological data (Supplementary Table S1), including (i) 35 cases of DFSP or related tumors addressed for molecular diagnosis referral to the laboratory of Solid Tumors Genetics (Nice, France) from nine different French Hospitals and previously unreported; (ii) 22 DFSP cases previously published by our group (Pedeutour et al., 1994Pedeutour F. Coindre J.M. Sozzi G. Nicolo G. Leroux A. Toma S. et al.Supernumerary ring chromosomes containing chromosome 17 sequences. A specific feature of dermatofibrosarcoma protuberans?.Cancer Genet Cytogenet. 1994; 76: 1-9Abstract Full Text PDF PubMed Scopus (68) Google Scholar, Pedeutour et al., 1995Pedeutour F. Simon M.P. Minoletti F. Sozzi G. 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Lazar A.J. et al.Dermatofibrosarcoma protuberans COL1A1-PDGFB fusion is identified in virtually all dermatofibrosarcoma protuberans cases when investigated by newly developed multiplex reverse transcription polymerase chain reaction and fluorescence in situ hybridization assays.Hum Pathol. 2008; 39: 184-193Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). The description of the clinical and histological features of the 172 cases is compiled in Supplementary Table S1. Download .pdf (.02 MB) Help with pdf files Supplementary Data Continuous data (age, tumor size) were described with mean, SD, and range (minimum–maximum); nominal scale data (gender, anatomic location, histological variant) were described by frequencies and relative frequencies (expressed as percentage). A Fisher exact test showed no significant differences in terms of gender, clinical presentation, and histological variant between our series and tumors studied by other groups (Table 1). Similarly, an unpaired Student's t-test showed no significant differences in the two series in terms of tumor size. In contrast, a slight difference between the two series was observed for the anatomic location and the mean age. The first could be explained by reports of exceptional anatomical locations in the literature, and the later by a more frequent recruitment of pediatric patients in our laboratory.Table 1Comparison between our cases and the literature for main clinico-pathological features% From the literature (n)% From our series (n)Total %P-valueSex0.84 Female48 (54)52 (29)49 Male52 (59)48 (28)51100 (113)100 (57)Anatomical location0.038 Trunk57 (64)49 (28)54 Lower limb25 (28)19 (11)23 Upper limb8 (9)19 (11)12 Head and neck5 (6)7 (4)6 Genitalia4 (5)2 (1)3 Lung1 (1)4 (2)2100 (113)100 (57)Clinical presentation0.69 Nodular74 (16)72 (26)71 Atrophic13 (3)20 (8)19 Atrophic and nodular13 (3)7 (3)10100 (22)100 (37)Histological variant0.93 DFSP55 (63)70 (37)60 DFSP-FS22 (25)13 (7)19 GCF5 (6)7 (8)8 Myxoid DFSP7 (8)0 (0)5 BT5 (6)2 (1)4 SAF3 (4)0 (0)2 DFSP-MFH3 (3)0 (0)2100 (115)100 (53)BT, Bednar tumor; DFSP, dermatofibrosarcoma protuberans; DFSP-FS, dermatofibrosarcoma protuberans with fibrosarcoma component; DFSP-MFH, dermatofibrosarcoma protuberans with malignant fibrous histiocytoma areas; GCF, giant cell fibroblastoma; SAF, superficial adult fibrosarcoma. Open table in a new tab BT, Bednar tumor; DFSP, dermatofibrosarcoma protuberans; DFSP-FS, dermatofibrosarcoma protuberans with fibrosarcoma component; DFSP-MFH, dermatofibrosarcoma protuberans with malignant fibrous histiocytoma areas; GCF, giant cell fibroblastoma; SAF, superficial adult fibrosarcoma. The very high variability of the COL1A1 break point position was confirmed, as 38 different COL1A1 exons have been identified. The most frequently rearranged COL1A1 exons were exon 25 (n=19), 32 (n=18), and 47 (n=15) (Figure 1). A standard analysis of variance of the COL1A1 break point position with respect to the clinico-histological parameters was performed by grouping the break points into four distinct groups of 11 exons each (group A: exons 6–16; group B: exons 17–27; group C: exons 28–38; and group D: exons 39–49). The following parameters were tested for the COL1A1 break point position: age, histological variant, anatomic location, and gender. None of the parameters tested showed a significant association with the either group. Only the anatomic location showed a slight trend, P=0.01843 (Supplementary Table S2). Also, no significant correlation between the most represented COL1A1 break points (n>5) (exons 7, 25, 29, 32, 33–34, 40, 42, 46, and 47) and clinical or histological features was observed. This result is consistent with the role of the COL1A1 side of the fusion gene as a simple cis element for PDGFB overexpression (Greco et al., 1998Greco A. Fusetti L. Villa R. Sozzi G. Minoletti F. Mauri P. et al.Transforming activity of the chimeric sequence formed by the fusion of collagen gene COL1A1 and the platelet derived growth factor b-chain gene in dermatofibrosarcoma protuberans.Oncogene. 1998; 17: 1313-1319Crossref PubMed Scopus (94) Google Scholar; Simon et al., 2001Simon M.P. Navarro M. Roux D. Pouyssegur J. 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In conclusion, we have demonstrated that although the COL1A1-PDGFB fusion detection is necessary for assessing the diagnosis of DFSP, the determination of the COL1A1 break point position within the fusion gene does not provide any medically valuable information. Therefore, interphase fluorescence in situ hybridization analysis (which is simpler to handle but does not indicate the location of the break point within COL1A1) seems to be a more appropriate method than multiplex reverse transcriptase–PCR for routine detection of COL1A1–PDGFB. The reverse transcriptase–PCR and sequencing analysis should be reserved for validation of unexpected negative fluorescence in situ hybridization results and for research prospective purposes. The authors state no conflict of interest. We thank L. Bianchini (Laboratory of Solid Tumors Genetics, Nice) for advice and support, and F. Maitre (Orleans Regional Hospital), E. Mahe, and U. Zimmerman (Ambroise Paré University Hospital, Boulogne) for providing some clinical and histological data. Supplementary material is linked to the online version of the paper at http://www.nature.com/jid