Classification of clear-cell sarcoma as a subtype of melanoma by genomic profiling

Neil H. Segal, Paul Pavlidis, William Stafford Noble, Cristina R. Antonescu, Agnes Viale, Umadevi V. Wesley, Klaus Busam, Humilidad Gallardo, Dianne DeSantis, Murray F. Brennan, Carlos Cordon-Cardo, Jedd D. Wolchok and Alan N. Houghton

Journal of Clinical Oncology. 21:1775--1781, 2003.


Purpose: The aim of this study was to develop a genome-based classification scheme for clear cell sarcoma (CCS), also known as melanoma of soft parts (MSP), which would have implications for diagnosis and treatment. This tumor displays characteristic features of soft tissue sarcoma, including deep soft tissue primary location and a characteristic translocation, t(12;22)(q13;q12) involving EWS and ATF1 genes. CCS/MSP also has typical melanoma features, including immunoreactivity for S100 and HMB45, pigmentation, MITF-M expression and a propensity for regional lymph node metastases.

Methods: RNA samples from 21 cell lines and 60 pathologically confirmed cases of soft tissue sarcoma, melanoma and CCS/MSP were examined using the Affymetrix. U95A GeneChip. Hierarchical cluster analysis, principal component analysis and support vector machine analysis exploited genomic correlations within the data to classify CCS/MSP.

Results: Unsupervised analyses demonstrated a clear distinction between STS and melanoma, and furthermore showed CCS/MSP to cluster with the melanomas as a distinct group. A supervised support vector machine learning approach further validated this finding and provided a user-independent approach to diagnosis. Genes of interest that discriminate CCS/MSP included those encoding melanocyte differentiation antigens, MITF, SOX10, ERBB3 and FGFR1.

Conclusion: Gene expression profiles support the classification of CCS/MSP as a distinct genomic subtype of melanoma. Gene profiles may be useful using the support vector machine for diagnosis. Genomic analysis identified potential targets for the development of therapeutic strategies in the treatment of this disease.