Complete response to CSF1R inhibitor in a translocation variant of teno-synovial giant cell tumor without genomic alteration of the CSF1 gene

Teno-synovial giant cell tumour (TGCT), also known as pigmented villonodular synovitis (PVNS), is a rare neoplasm affecting the synovium and tendon sheaths in young adults, with recurrent translocations involving COL6A3 and CSF1 genes [1.West R.B. Rubin B.P. Miller M.A. et al.A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells.Proc Natl Acad Sci USA. 2006; 103: 690-695Crossref PubMed Scopus (291) Google Scholar]. The fusion protein is cleaved, resulting in the overproduction of CSF1, which attracts CSF1R-expressing non-neoplastic cells (macrophages and monocytes) through a paracrine effect [1.West R.B. Rubin B.P. Miller M.A. et al.A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells.Proc Natl Acad Sci USA. 2006; 103: 690-695Crossref PubMed Scopus (291) Google Scholar]. Complete surgical resection is not always feasible and/or may lead to functional impairment or amputation. Tyrosine kinase inhibitors or antibodies, such as imatinib, pexidartinib or emactuzumab showed encouraging clinical activity in clinical studies [2.Blay J.-Y. El Sayadi H. Thiesse P. et al.Complete response to imatinib in relapsing pigmented villonodular synovitis/tenosynovial giant cell tumor (PVNS/TGCT).Ann Oncol. 2007; 19: 821-822Abstract Full Text Full Text PDF Scopus (115) Google Scholar, 3.Cassier P.A. Italiano A. Gomez-Roca C.A. et al.CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study.Lancet Oncol. 2015; 16: 949-956Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 4.Tap W.D. Wainberg Z.A. Anthony S.P. et al.Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor.N Engl J Med. 2015; 373: 428-437Crossref PubMed Scopus (242) Google Scholar]. CSF1 gene alteration is therefore considered as the actionable driver oncogene in PVNS. We report the case of a 61-year-old female with a rapidly growing TGCT of the dominant hand (Figure 1). Because complete surgery could not be conservative, this patient was proposed for inclusion in a phase III study testing pexidartinib [4.Tap W.D. Wainberg Z.A. Anthony S.P. et al.Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor.N Engl J Med. 2015; 373: 428-437Crossref PubMed Scopus (242) Google Scholar]. She achieved complete response still ongoing at 17 months. A PCR analysis failed to identify the classical fusion gene COL6A3-CSF1. The tumour was submitted to RNAseq analysis from FFPE tissues using TruSeq RNA Access Library Prep Kit (Illumina®) and NextSeq sequencing system. Two in-frame fusion transcripts, HMGA2-NCOR2 and NCOR2-SUPT3H, were identified. High level of CSF1 gene expression was also detected, similar to 15 other PVNS, and relatively higher IL-34 gene expression was observed in this patient. Other target receptors of pexidartinib (KIT, FLT3, and ligands) were expressed at similar levels as in other PVNS (not shown). Fluorescence in situ hybridization was carried out, showing rearrangement of HMGA2, followed by confirmation of the fusion by RT-PCR. The antitumor activity of CSF1R TKI in PVNS is thought to result from the over production of the CSF1 ligand resulting from the genomic alteration of CSF1 gene. Response to a CSF1R TKI in a PVNS without genomic alterations of the CSF1 gene has not been previously described. Similarly, the response to a CSF1R TKI in a tumour overexpressing both CSF1 and IL-34, another ligand of CSF1R [5.Guillonneau C. Bézie S. Anegon I. Immunoregulatory properties of the cytokine IL-34.Cell Mol Life Sci. 2017; 74: 2569-2586Crossref PubMed Scopus (49) Google Scholar], has not been previously reported. The overexpression of the CSF1 and IL-34 genes is probably the consequence of the expression of HMGA2/NCOR2 and/or NCOR2/SUPT3H. One or both of these fusion transcripts are the likely drivers of the upregulation of the expression of the CSF1 gene as in “classical” PVNS, and also of IL-34 [1.West R.B. Rubin B.P. Miller M.A. et al.A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells.Proc Natl Acad Sci USA. 2006; 103: 690-695Crossref PubMed Scopus (291) Google Scholar]. The HMGA2-NCOR2 fusion protein may be a more likely candidate, given the role of HMGA2 in connective tissue tumours and the protein domains remaining in the fusion gene. This observation points to the molecular heterogeneity of PVNS, which exhibit translocations encoding for fusion proteins not involving the CSF1 gene, but inducing the expression of the CSF1 and IL-34 genes. This molecular heterogeneity converges therefore to the activation of CSF1R with a major clinical response to a CSF1R inhibitor in this patient. It also shows that overexpression of CSF1 and/or IL-34 may be biomarkers of interest for CSF1 TKI in PVNS and possibly other tumours. This is the first report of translocation variant of a TGCT without genomic alteration of the CSF1 or IL-34 gene responding to CSF1 inhibition. NetSARC (INCA) and RREPS (INCA), Association DAM’s, Ensemble contre Le GIST, Eurosarc (FP7-278742), la Fondation ARC, Infosarcome, InterSARC (INCA), LabEx DEvweCAN (ANR-10-LABX-0061), Ligue de L’Ain contre le Cancer, LYric (DGOS-INCa-4664), and EURACAN (EU project 739521).