Identification of biomarkers to distinguish clear cell sarcoma from malignant melanoma

Abstract

Clear cell sarcoma is a rare and malignant soft tissue tumor that shows phenotypic and immunohistochemical overlap with cutaneous malignant melanoma; identification of biomarkers that differentiate clear cell sarcoma from malignant melanoma is therefore needed. In this study, we performed mutation analysis of BRAF and NRAS, investigated the EWSR1 gene rearrangement and evaluated the protein expression of insulin-like growth factor 2 and insulin-like growth factor 1R in 31 cases of malignant melanoma and 16 cases of clear cell sarcoma. By direct sequencing and high-resolution melting analysis, we identified BRAF and NRAS mutations in 51.6% and 12.9% of malignant melanoma cases, respectively, while none of clear cell sarcoma harbored BRAF or NRAS mutations. Fluorescence in situ hybridization showed that 78.6% of clear cell sarcoma exhibited the t(12;22)(q13;q12) translocation. The presence of type 1, 2, and 3 EWSR1/ATF1 fusion gene transcripts was confirmed by reverse transcriptase polymerase chain reaction analysis, but type 4 and EWSR1/CREB1 fusion gene transcripts were not found. No fusion transcript could be detected in any of the malignant melanoma cases. Additionally, immunohistochemistry showed that the majority of clear cell sarcoma and malignant melanoma had insulin-like growth factor 2 and insulin-like growth factor receptor 1 expression; however the expression of insulin-like growth factor 1R was significantly higher in clear cell sarcoma compared to melanoma (p = .006). Our results suggest that the combination of BRAF and NRAS mutation analysis with fusion gene detection contributes to diagnosis of malignant melanoma and clear cell sarcoma, and that insulin-like growth factor 1R might be a novel target for the treatment of these two malignancies.