Structural and functional analysis of a chimeric protein COL1A1-PDGFB generated by the translocation t(17;22)(q22;q13.1) in Dermatofibrosarcoma Protuberans (DP)

Abstract

Dermato®brosarcoma protuberans (DP), an in®ltrative skin tumour of intermediate malignancy, presents speci®c cytogenetic features such as reciprocal translocations t(17;22)(q22;q13.1) or supernumerary ring chromosomes derived from t(17;22). We have previously shown that both rings and translocated chromosomes derived from t(17;22) presented the same molecular rearrangement with fusion of the COL1A1 gene on chromosome 17 to the PDGFB gene on chromosome 22. To study the structure and function of the COL1A1 ± PDGFB chimeric protein, we used a tumour-derived chimeric COL1A1 ± PDGFB cDNA to perform stable and transient transfections in the Chinese hamster lung ®broblastic cell line PS200 and the human epithelial cell line HEK293. We demonstrated that the stably transfected clones that expressed the COL1A1 ± PDGFB chimeric protein became growth factors independent and tumorigenic in nude mice. In addition, COL1A1 ± PDGFB transfected cell supernatants signi®cantly stimulated ®broblastic cell growth, through the activation of the PDGFB receptor pathway. By using anti-PDGFB and speci®c anti-COL1A1 ± PDGFB antibodies, we showed that, similar to PDGFB, the COL1A1 ± PDGFB chimeric proteins are processed in transfected cells into mature PDGFB dimers. These results strongly suggest that the COL1A1 ± PDGFB chimeric gene expression associated with DP, induces tumours formation through production of mature PDGFB, in an autocrine or paracrine way. Strikingly, mutagenesis experiments indicated that uncleaved COL1A1 ± PDGFB forms are mitogenic and therefore could contribute, as well as mature PDGFB, to the establishment of a transformed phenotype. Oncogene (2001) 20, 2965 ± 2975.

Detection of COL1A1-PDGFB fusion transcripts and PDGFB/PDGFRB mRNA expression in dermatofibrosarcoma protuberans

“…The COL1A1-PDGFB fusion transcript is translated to form a precursor fusion protein that is processed into a mature and fully functional PDGFB proteina ligand for PDGFRB. 25,26 Consequently, the abnormal fusion transcripts probably cause autocrine stimulation and cell proliferation, which are responsible for the development of dermatofibrosarcoma protuberans. To evaluate the importance of the autocrine signaling of PDGFB in dermatofibrosarcoma protuberans, in the present study, we quantified the PDGFB copy numbers and mRNA expression by using a real-time PCR system.…”

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

“…The fusion product COL1A1-PDGFB is amplified at low levels on the ring chromosome (1-3 copies) and its protein product creates an autocrine loop with increased PDGFRB activity. [9][10][11] Early case reports examining the cytogenetic alterations within fibrosarcomatous dermatofibrosarcoma protuberans indicate that the COL1A1-PDGFB fusion product is present in both fibrosarcomatous and dermatofibrosarcoma protuberans areas, indicating a common genetic origin for the two tumor components. 12 However, a single previous study was not able to find a difference in copy numbers between fibrosarcomatous and dermatofibrosarcoma protuberans areas using comparative genomic hybridization.…”

Dermatofibrosarcoma Protuberans: A Case Report and Review of Surgical Management

“…This chromosomal rearrangement causes the fusion of the collagen type 1-alpha 1 (COL1A1) and platelet-derived growth factor beta (PDGFB) genes. The resulting COL1A1-PDGFB fusion gene promotes fibroblastic cell growth by upregulating the PDGFB receptor pathway [5]. Histopathology of our patient's right posterior shoulder mass from her first excision procedure revealed spindle cells in a storiform pattern characteristic of DFSP (Fig.…”