Beyond COL1A1::PDGFB: Rare fusions and their clinical implications in dermatofibrosarcoma protuberans

Abstract

Dermatofibrosarcoma protuberans (DFSP) is a rare cutaneous intermediate-grade soft tissue tumor characterized by COL1A1::PDGFB fusion in most cases. This fusion drives tumorigenesis and forms the basis for imatinib treatment, which acts by blocking platelet-derived growth factor receptor-beta kinase activity. Apart from this canonical fusion, there is an expanding spectrum of rare fusions, including COL6A3::PDGFD, EMILIN::PDGFD, TNC::PDGFD, etc., through molecular profiling. These atypical rearrangements may be encountered in morphologically classic DFSP, unusual anatomic sites, or diagnostically challenging variants such as fibrosarcomatous DFSP. Their recognition is clinically relevant, as they may influence tumor biology, response to targeted therapy, and eligibility for clinical trials. This newly documented DFSP involving the lacrimal sac was initially misdiagnosed as a solitary fibrous tumor, emphasizing the diagnostic pitfalls in anatomically constrained regions and the importance of integrated diagnosis combining histology, immunohistochemistry, and molecular testing. In this editorial commentary, we briefly highlight the ever-growing genomic landscape of DFSP, report rare fusions and their biological implications, and examine the role of expanded molecular diagnostics in refining diagnosis, guiding therapy, and informing prognosis. Incorporating comprehensive fusion analysis into routine workup may be critical for accurate classification, especially in unusual presentations where reliance on morphology alone risks misdiagnosis.

Key Words: Dermatofibrosarcoma protuberans; COL1A1::PDGFB; EMILIN; TNC; Molecular diagnostics

Core Tip: Apart from canonical COL1A1::PDGFB fusion, dermtofibrosarcoma harbors an expanding spectrum of gene fusions, which include COL1A2::PDGFB, COL6A3::PDGFD, EMILIN2::PDGFD, TNC::PDGFD, FBN1::CSAD, MAP3K7CL::ERG, SLC2A5::BTBD7, and LARGE1::PRKCA, which influence tumor biology, therapeutic response to treatment, and disease prognosis. Since molecular techniques like fluorescence in situ hybridization and polymerase chain reaction can miss these variants, a comprehensive genomic profiling, like next-generation sequencing or ribonucleic acid sequencing, is necessary for correct diagnosis, risk stratification, and eligibility for personalized medicine, particularly in morphologically challenging fibrosarcomatous variants.

TO THE EDITOR

We have come across an interesting case report by Panda et al[1]. The case highlights the importance of diagnosing this entity in an anatomically challenging area for appropriate management and preventing recurrence. A molecular study was not performed in this case; however, most cases of dermatofibrosarcoma protuberans (DFSP) show COL1A1::PDGFB fusion. In this editorial, we highlight the importance of molecular studies in looking for fusion, particularly when targeted therapy is planned for such cases. DFSP is an intermediate-grade soft tissue tumor that arises from skin and shows characteristic COL1A1::PDGFB fusion in most cases[2]. The genetic translocation t (17;22) (q22;q13) lies in the tumorigenesis and the characteristic fusion in 90%-96% of cases[3,4]. This fusion is clinically crucial and relevant because of the available targeted therapy, imatinib, which blocks the constitutive PDGFB signaling pathway and produces a remarkable response[5]. However, the genetic landscape of DFSP is growing, with a larger number of next-generation sequencing (NGS) being performed during day-to-day activities. A proportion of DFSP cases do not show the canonical COL1A1::PDGFB fusion, and they show diverse and novel fusions, which account for approximately 4%-10% of cases[4]. The clinical implications of such novel fusions are critical as they may show distinct clinicopathological findings and may have completely different therapeutic implications for the oncology community.

Rare fusions: New frontier

The genetic study of DFSP and fibrosarcomatous DFSP has revealed numerous novel gene fusions. Including the following parts.

COL1A2::PDGFD: COL1A2 gene encodes for the pro-alpha two chain of type I collagen, which is crucial for the strength of tissues like skin, bone, cartilage, etc. COL1A1 (two pro-alpha one chains) and COL1A2 (one pro-alpha two chain) are two integral parts of type I collagen, which form the triple helix and give structural integrity to tissues[6]. Like COL1A1::PDGFB fusion, the COL1A2::PDGFB fusion juxtaposes the collagen gene promoter with PDGFB, causing constitutive overexpression of PDGFB. This novel fusion is seen in classic DFSP on histology in the superficial skin[7].

COL6A3::PDGFD: COL6A3 gene encodes for the alpha chain of type VI collagen, which is involved in the organization of the extracellular matrix[8]. PDGFD is a platelet-derived growth factor that helps cell growth, proliferation, survival, migration, and disease progression[9]. The fusion of these genes, COL6A3 and PDGFD, drives the overexpression of the PDGFRB receptor signaling pathway by mimicking the oncogenic function of COL1A1::PDGFB fusion. This results in tumor proliferation and survival[10]. This fusion has a predilection for DFSP in the breast in females[10,11]. PDGFD is secreted in a latent form and needs extracellular proteolytic activity to activate. After activation, it binds to PDGFRB and causes its dimerization. This dimerization results in autophosphorylation of tyrosine residues and triggers downstream signaling pathways, causing activation of phosphoinositol-3 kinase/protein kinase B and rat sarcoma viral oncogene homolog/mitogen-activated protein kinase/extracellular signal-regulated kinase pathways, and cell proliferation and angiogenesis[12]. Extensive clinicopathological and multi-omics analysis of DFSP has shown that PDGFD fusion confers better survival when compared to PDGFB fusion[11].

EMILIN2::PDGFD and EMILIN1::PDGFD: EMILIN2 is an extracellular matrix glycoprotein involved in numerous physiological processes like cell-matrix interaction, vascular homeostasis, thrombosis regulation, etc[13]. The N-terminal domain of EMILIN2 fuses with PDGFD in DFSP and causes aberrant expression and activation of PDGFRB[14]. EMILIN1 (Elastin microfibril interface located protein 1) is another glycoprotein of the extracellular matrix that plays a crucial role in elastogenesis, vascular integrity, and lymphatic vessel homeostasis[15]. Fusion of EMILIN1 with PDGFD causes similar constitutive activation of PDGFRB. Among these fusions, EMILIN2::PDGFD is more common and seen in the superficial skin of extremities, whereas EMILIN1::PDGFD is very recently described[16]. EMILIN2/EMILIN1 causes ectopic PDGFD, and the rest of the mechanism of the same.

TNC::PDGFD: TNC is another extracellular matrix glycoprotein that plays a vital role in tissue remodeling, development, wound repair, etc. TNC regulates cell proliferation, migration, adhesion, etc[17]. Fusion of TNC with PDGFD causes similar constitutive activation of PDGFRB, promoting oncogenic proliferation in tumor cells. It is a recently discovered fusion is seen in the fibrosarcomatous variant of DFSP[18]. However, Legrand M et al[19] have shown in a case report that this fusion is associated with a distinct superficial spindle cell tumor different from DFSP[19]. Nevertheless, the true nature of this tumor needs to be explored in many cases.

FBN1::CSAD: FBN1 encodes fibrillin-1, an extracellular matrix glycoprotein that is a structural component of microfibrils. Fibrillin 1 regulates extracellular matrix assembly and cell-matrix interaction[20]. At the same time, CSAD (cysteine sulfinic acid decarboxylase) is a key enzyme in the taurine biosynthesis pathway. It converts cysteine sulfinic acid to hypotaurine, which later gets converted to taurine. Taurine helps in antioxidation, neuromodulation, osmoregulation, etc[21]. The fusion of FBN1::CSAD is a novel oncogenic mechanism in DFSP. In this fusion, the FBN1 domain likely alters extracellular matrix components and growth factor milieu, while CSAD sequences influence the dysregulated mechanism. This fusion has been described very recently and hints towards alternate molecular pathogenesis, particularly in fibrosarcomatous DFSP, and the biological consequences remain obscured[22].

MAP3K7CL::ERG: MAP3K7 is involved in MAPK pathway signaling. It engages in hypoxia adaptation, inflammation, immune response regulation, cancer pathways, etc[23]. Meanwhile, ERG, an ETS family member, modulates gene expression that causes cell proliferation, differentiation, angiogenesis, etc[24]. This fusion causes dysregulation of signaling pathways, which contributes to tumor progression. This fusion was identified in fibrosarcomatous DFSP on RNA-sequencing, and its clinicopathological characteristics are under investigation[4,25].

SLC2A5::BTBD7: SLC2A5 encodes GLUT5, a fructose transporter, which causes fructose uptake in the small intestine and other tissues[26]. SLC2A5 overexpression in cancer is associated with raised fructose uptake, thus causing cell proliferation, migration, invasion, etc[27]. Meanwhile, BTBD7 helps in epithelial branching morphogenesis during the organogenesis of specific organs. It promotes cell motility, regulates cell-cell adhesion dynamics by modulating E-cadherin ubiquitination and degradation, and facilitates epithelial-mesenchymal transition[28]. This fusion results in enhanced metabolic capacity by fructose uptake and increased cellular migration and epithelial plasticity. It was identified in one of the studies with t(1;14). However, the characteristics of this fusion with clinicopathological findings remain elusive[29].

LARGE1::PRKCA: Another very recently discovered fusion in DFSP, the clinicopathological features must be established for therapeutic purposes[30].

Clinical and therapeutic implications

The identification of non-COL1A1::PDGFB fusions has significant implications. (1) Diagnosis: Diagnostic modalities like FISH, PCR, etc., are commonly used for COL1A1::PFGFB fusion[3]. However, these modalities will miss non-COL1A1::PDGFB fusions. This may cause prolonged diagnostic ambiguity. NGS is preferred in case fusion detection is necessary, and broader panel testing is advised[31]; (2) Targeted therapy: The therapeutic advantage of tyrosine kinase inhibitors like imatinib is promising in DFSP with PDGFB or PDGFD fusion. Imatinib acts by inhibiting the PDGFB signaling pathway. In cases of COL6A3::PDGFD fusion, it upregulates PDGFB activity, and because of this, analogous PDGF receptor activation, sensitivity to imatinib is excellent[32]. However, the therapeutic implications of truly novel fusions like FBN1::CSAD, MAP3K7CL::ERG, and SLC2A5::BTBD7 are mainly unknown. These fusions must be studied further to identify their signaling pathways and therapeutic vulnerabilities; (3) Prognosis and risk stratification: Apart from COL1A1:PDGFB, which has an association with fibrosarcomatous transformation in DFSP in adults as well as children, most of the new fusions identified have shown fibrosarcomatous transformation and may confer aggressive behavior[4,33-36]; and (4) Personalized Medicine: A personalized approach to therapy is required in DFSP cases, especially for these rare and diverse fusions. Individualized molecular testing will optimize diagnosis, prognosis, and therapy selection as more fusions are recognized. Table 1 highlighting the fusions in DFSP and its correlation with clinicopathological findings and therapeutic sensitivity.

Table 1 Clinicopathological and therapeutic correlation of gene fusions reported in dermatofibrosarcoma protuberans.

Fusion	Key clinicopathological profile	Sensitivity to targeted therapy
COL1A1::PDGFB	Classic DFSP morphology (m/c location extremities), fibrosarcomatous DFSP	Excellent sensitivity to imatinib
COL1A2::PDGFB	Classic DFSP morphology (m/c location extremities), fibrosarcomatous DFSP	Excellent sensitivity to imatinib
COL6A3::PDGFD	Classic DFSP in female (m/c location breast), less aggressive course and better survival	Strong sensitivity to imatinib
EMILIN2::PDGFD and EMILIN1::PDGFD	Seen in superficial skin of extremities (EMILIN2 fusion), EMILIN1 fusion very recently described	Presumed to be similar to other PDGFD fusion
TNC::PDGFD	Fibrosarcomatous DFSP	Therapeutic sensitivity is under investigation, likely imatinib sensitive via PDGFB pathway
FBN1::CSAD	Fibrosarcomatous DFSP, clinicopathological features are unexplored and require more research	Involvement of alternate molecular pathogenesis, imtaninib sensitivity yet to be explored
MAP3K7CL::ERG	Fibrosarcomatous DFSP, clinicopathological features are unexplored and require more research	Involvement of alternate molecular pathogenesis, imtaninib sensitivity yet to be explored
SLC2A5::BTBD7	Recently described fusion, clinicopathological features are unexplored and require more research	Involvement of alternate molecular pathogenesis, imtaninib sensitivity yet to be explored
LARGE1::PRKCA	Recently described fusion, clinicopathological data yet to be explored	Very recently described fusion, therapeutic sensitivity yet to be explored

DFSP: Dermatofibrosarcoma protuberans; m/c: Most common; EMILIN1: Elastin microfibrillar interface protein 1; EMILIN2: Elastin microfibrillar interface protein 2; PDGFD: Platelet-derived growth factor-D; PDGFB: Platelet-derived growth factor-B.

Editorial perspective

With rapid advancement in molecular diagnostics with cost-effective NGS and RNA-sequencing, the “molecularly unclassified” group of DFSP is vanishing. These newly discovered fusions have emphasized the importance of performing extended molecular testing in every DFSP case, particularly those lacking COL1A1::PDGFB fusion. As the number of newly formed fusion partners is increasing, research should quickly focus on whether these tumors are equally sensitive to traditional targeted therapy like imatinib or require a novel treatment approach. Multicenter registries and collaborative trials are needed to pool knowledge of these rare DFSP subtypes, guiding development of tailored and effective treatments.

Discovery of potential biomarkers is another need of the hour. The prognostic role of tousled-like kinase 2 (TLK2) has been described in hepatocellular carcinoma, colorectal carcinoma, and breast carcinoma[37-39]. Recently, the role of TLK2 has been explored in DFSP, and it was found that it can act as a potential biomarker. Along with TLK2, the promising role of FAM118B as a biomarker has also been explored[22]. Notwithstanding, comprehensive molecular profiling like NGS or RNA-sequencing is crucial for identifying fusions with therapeutic implications; several practical obstacles limit its universal adoption in day-to-day diagnostics. The cost of these tests remains high, varying from $1250 to $5000 (depending on the platform and gene panel size), which is substantial in low- and middle-income countries where a good healthcare system is a luxury[40]. There is a stark difference in insurance and reimbursement policies globally[41,42]. Coverage and reimbursement vary according to country, payer, and clinical indication. In the United States, programs like Medicare use Local Coverage Determinations through MACs to define reimbursement policies, which are often adopted more broadly[43,44]. Nevertheless, limited and inconsistent reimbursement remains a challenge to broader adoption.

NGS for molecular testing, in reference to soft tissue sarcomas, can take several weeks (2-3 weeks)[45,46]. There can be delays considering factors like sample transportation, sample preparation, lengthy sequencing, etc. In a resource-limited setup, the turnaround time may go up to 6-8 weeks[45]. The interpretation of NGS requires high-performance computing or cloud infrastructure with network-attached storage for large data volumes at multiple stages and complex data analysis[47]. Expert bioinformaticians are needed for complex data information, which is challenging in smaller labs and resource-constrained areas[48]. These barriers highlight the gap between the auspicious role of comprehensive genomic profiling and its routine practical implementation in the global clinical practice.

Most DFSP cases show COL1A1::PDGFB fusion, where imatinib sensitivity is excellent. Some non-canonical fusions also indirectly drive oncogenesis by activating PDGFRB; imatinib is presumed to be sensitive against those fusions. In a classical location with classic morphology and CD34 positivity, where DFSP can be diagnosed, implementing the costly tests may not be feasible and rational. In cases of diagnostic ambiguity, like an uncommon site or fibrosarcomatous changes, the necessity of NGS or RNA-sequencing becomes crucial. The discovery of new oncogenic fusions that do not involve PDGFRB activation, where imatinib is presumed ineffective, makes molecular testing vital. To conclude and bring things into perspective, the story of DFSP is one of molecular genetic diversity and clinical opportunity. There is a clinical necessity to embrace complexity and not just pursue it as a scholarly pursuit. The goal is that every patient must get personalized treatment based on the latest molecular data.

ACKNOWLEDGEMENTS

We extend our sincere gratitude to Swati Singh, PhD Scholar in Neuropathology at All India Institute of Medical Sciences, New Delhi, for her invaluable support in enhancing the quality of this manuscript.