Identification of a novel MTAP-RAF1 fusion in a soft tissue sarcoma
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RAF family activating fusions have been described as a potentially targetable molecular finding in a subset of soft tissue sarcomas. To further expand upon the landscape of this genetic feature, we describe a novel MTAP-RAF1 activating fusion identified in a S100 positive soft tissue sarcoma.
A 51 year old man underwent excision of a soft tissue mass in his foot. Pathology revealed a spindle cell neoplasm with S100 positivity, ultimately classified as a soft tissue sarcoma, not otherwise specified. Comprehensive molecular profiling was performed to help establish the diagnosis and revealed a novel MTAP-RAF1 fusion that includes the tyrosine kinase domain of RAF1.
Our report adds to the spectrum of fusion-driven RAF activation observed in soft tissue sarcomas and lends additional evidence that RAF activation plays an important role in some soft tissue sarcomas. Identification of novel fusions involving the MAPK/ERK pathway in sarcomas may provide new avenues for precision medicine strategies involving targeted kinase inhibitors.
KeywordsSoft tissue sarcoma RAF1 MTAP Fusion Next generation sequencing Molecular diagnostics
Next generation sequencing
Recently, recurrent BRAF gene fusions have been identified in several subgroups of soft tissue sarcomas [1, 2]. To further expand upon the landscape of activating RAF family fusions identified in sarcomas, we report a case of soft tissue sarcoma harboring a novel MTAP-RAF1 fusion. The case was diagnostically challenging as attempts to classify towards a sarcoma subtype were unsuccessful. In addition to sarcoma subtypes, the diagnoses of a spindle cell melanoma variant or clear cell sarcoma were considered given S100 positivity and the biphasic nature of the tumor. In an attempt to aid in the pathological classification of the tumor, comprehensive molecular profiling was performed and interestingly harbored a novel MTAP-RAF1 fusion. To our knowledge, this fusion partnering has not previously been described in the literature to date. Given the potentially high-impact nature and novelty of this finding, we report the clinicopathological details of this case to add to the spectrum of RAF family driven soft tissue sarcomas.
S100 positive, SOX10 negative spindle cell malignancy is a broad pathologic differential. This pattern is observed commonly in a number sarcoma subtypes including synovial sarcoma, Ewing sarcoma, rhabdomyosarcoma, and extraskeletal myxoid chondrosarcoma . S100 positivity is also common in ossifying fibromyxoid tumors, though is typically negative in the malignant cases . SOX10 negative melanoma, clear cell sarcoma, and malignant peripheral nerve sheath tumor (MPNST) are also diagnostic possibilities. We therefore performed additional molecular profiling studies. There was retained nuclear staining of INI-1 and H3K27m3 by immunohistochemistry. Molecular testing performed and interpreted at University of Nebraska, Omaha NE reported the tumor as negative for fusion of the EWSR1 (22q12) and ATF1 (12q13) loci, negative for rearrangement of the TFE3 (Xp11) locus, and negative for fusion of the EWSR1 (22q12) and CREB1 (2q33.3) loci. Additionally, no SS18/SSX1 or SS18/SSX2 fusion transcript was detected by RT-DNA amplification. Given the lack of a more specific molecular finding, the malignant S100-positive tumor was therefore favored to be a soft tissue sarcoma that could not be further subtyped, though could not rule out either a spindle cell melanoma or a fusion-negative clear cell sarcoma.
Discussion and conclusions
To our knowledge, we report the first observation of an oncogenic MTAP-RAF1 fusion. RAF1 is part of the MAPK/ERK pathway, with the fusion product predicted to upregulate signaling. MTAP has rarely been reported as a partner gene in cancers, typically in relation to intrachromosomal deletion events of the nearby CDKN2A locus . As a known tumor suppressor, loss of MTAP activity due to a fusion event may also contribute to oncogenesis . Recurrent activating BRAF fusions have been reported in several soft tissue sarcoma subtypes [1, 2]. Additionally, BRAF activating mutations have been identified in clear cell sarcomas with observed response to vemurafenib [10, 11]. Our report therefore adds to the spectrum of fusion-driven RAF activation observed in soft tissue sarcomas and lends additional evidence that RAF activation plays an important role in some sarcomas. Though systemic therapy was not indicated in the described case, identification of novel fusions involving the MAPK/ERK pathway in soft tissue sarcomas may provide new avenues for precision medicine strategies involving targeted kinase inhibitors.
We thank Andrej Savol and Joel Greenbowe for assistance with bioinformatics support for the creation of Fig. 2b.
Availability of data and materials
The datasets generated and analyzed during the current study are not publicly available due patient confidentiality concerns but are available from the corresponding author on reasonable request.
JKH and ASB conceived and designed the study and were the primary writers of the manuscript. EHJ performed pathological review of the case. JD performed bioinformatics analysis of genomics results. DMJ provided care of the patient and clinical input for the case report. All authors read and approved the final manuscript.
Ethics approval and consent to participate
This retrospective case review was approved by our local institutional review board. The protocol is MCC19161 entitled “Clinical outcomes of the implementation of a personalized medicine clinical service at a major academic cancer center.”
Consent for publication
Written informed consent for publication of their clinical details was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.
Julia Duggan is an employee of Foundation Medicine, Inc. The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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