Identification of neural stem cell gene expression signatures associated with disease progression in alveolar soft part sarcoma by integrated molecular profiling [aCGH]

Alveolar soft part sarcoma (ASPS) is a soft tissue sarcoma with poor prognosis. Apart from the recurrent, non-reciprocal t(X,17)(p11.2;q25) translocation, there is little molecular evidence for the origin, initiation and progression of this cancer. We analysed 16 primary and metastatic ASPS samples to elucidate candidate molecular pathways involved in tumor pathogenesis. FISH analysis identified the ASPL-TFE3 fusion in all cases. High-resolution aCGH revealed a higher number of numerical aberrations in metastatic tumors relative to primaries, but failed to identify any consistent alterations in either group. Gene expression analysis highlighted 1,063 genes which were differentially expressed between primary and metastatic tumors. Gene set enrichment analysis identified 16 enriched genesets (p < 0.1) associated with differentially expressed genes. Notable among these were several stem cell gene expression signatures and pathways related to differentiation. In particular, the paired box transcription factor PAX6 was up-regulated in the primary tumors, along with several genes whose mouse orthologs have previously been implicated in Pax6-DNA binding during neural stem cell differentiation. In addition to suggesting a neural origin for ASPS, these results implicate transcriptional deregulation from fusion genes in the pathogenesis of ASPS, rather than extensive chromosomal instability. 15 different tumor and normal paired samples were analysed