Identification of an Actionable Mutation of KIT in a Case of Extraskeletal Myxoid Chondrosarcoma

Abstract

Extraskeletal myxoid chondrosarcoma (EMC) is an extremely rare soft tissue sarcoma, marked by a translocation involving the NR4A3 gene. EMC is usually indolent and moderately sensitive to anthracycline-based chemotherapy. Recently, we reported on the therapeutic activity of sunitinib in a series of EMC cases, however the molecular target of sunitinib in EMC is unknown. Moreover, there is still the need to identify alternative therapeutic strategies. To better characterize this disease, we performed whole transcriptome sequencing in five EMC cases. Peculiarly, in one sample, an in-frame deletion (c.1735_1737delGAT p.D579del) was identified in exon 11 of KIT. The deletion was somatic and heterozygous and was validated both at DNA and mRNA level. This sample showed a marked high expression of KIT at the mRNA level and a mild phosphorylation of the receptor. Sanger sequencing of KIT in additional 15 Formalin Fixed Paraffin Embedded (FFPE) EMC did not show any other mutated cases. In conclusion, exon 11 KIT mutation was detected only in one out of 20 EMC cases analyzed, indicating that KIT alteration is not a recurrent event in these tumors and cannot explain the EMC sensitivity to sunitinib, although it is an actionable mutation in the individual case in which it has been identified.

Mutation of KIT In Cellular Extraskeletal Myxoid Chondrosarcoma: A Case of And Literature Review

“…The IHC staining results in the study by Stacchiotti et al [20] suggested the presence of CD117 expression in 6 of 9 EMC cases, including four cases of weak focal expression of CD117, while the western blot test results in the same study indicated the KIT expression without phosphorylation; yet, no KIT gene analysis was conducted. Subsequently, Urbini et al [21] reported the case of an EMC patient (1/20) with KIT exon 11 mutations, which, apart from this paper, is the only reported EMC case with KIT gene mutations; however, no IHC staining results were provided in the study. In this case, the presence of KIT exon 13 mutations was established based on the NGS and morphological ndings, i.e.…”

“…KIT exon 13 mutations are relatively rare, accounting for 0.8-4.1% of all KIT mutations, and patients with KIT exon 13 mutations bene t from sunitinib therapy [23] . A patient with EMC who had KIT exon 11 mutations and had never received sunitinib was reported to bene t from sunitinib therapy [21] . In this case, the patient experienced KIT exon 13 mutations but was not administered sunitinib; therefore, the therapeutic activity of sunitinib as part of the treatment for this patient remains unclear.…”

Primary extraskeletal myxoid chondrosarcoma of ovary with novel KIT mutation: A case report and literature review

“…However, beside the diagnosis hall-marker of NR4A3 gene translocation, few gene variation of EMC has been noticed. As previously reported, there are only three cases EMC have KIT gene mutation [10][11][12] . Here we report the rst primary EMC of ovary and the fourth case with KIT mutation.…”

Rationale for Early Detection of EWSR1 Translocation-Associated Sarcoma Biomarkers in Liquid Biopsy

“… Translocation partners in EWSR1-associated sarcomas. Extraskeletal mxyoid chondrosarcoma (EMC) [ 64 , 65 , 66 ], clear cell sarcoma (CCS) [ 67 ], desmoplastic small round cell tumour (DSRCT) [ 68 ], Ewing’s sarcoma (ES) [ 69 ], and myxoid liposarcoma (ML) [ 70 , 71 ] have common variants, which are driven by genes EWSR1 , FUS , TAF15 fused to NR4A3 , ATF1 , WT1 , FLI1 , ERG, or DDIT3 ; numbers refer to exons adjacent to the mRNA splicing. …”

“…Expression of vimentin, S100, class III β-tubulin, and micro-tubule-associated protein-2 have been noted, which are suggestive of a mesenchymal cell lineage with neuro-endocrine differentiation [ 112 ]. The transformation of the cell is driven by the translocation of the TAF15 - NR4A3 or EWSR1 - NR4A3 fusion proteins [ 64 , 65 , 66 ]; however, these findings are yet to be translated to a liquid biopsy. Survival at five years was estimated at >80%, but by 15 years had decreased to ~60%, indicating that long term surveillance, especially after five years post treatment, is necessary [ 110 ].…”