High-Resolution Array CGH and Gene Expression Profiling of Alveolar Soft Part Sarcoma

• Published in: Clinical cancer research Vol. 20; no. 6; pp. 1521 - 1530
• Main Authors: SELVARAJAH, Shamini, PYNE, Saumyadipta, CHEN, Eleanor, SOMPALLAE, Ramakrishna, LIGON, Azra H, NIELSEN, Gunnlaugur P, DRANOFF, Glenn, STACK, Edward, LODA, Massimo, FLAVIN, Richard
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.03.2014
• Subjects: Adult; Antineoplastic agents; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Biological and medical sciences; Comparative Genomic Hybridization; Eye Proteins - genetics; Female; Gene Expression Profiling - methods; High-Throughput Screening Assays; Homeodomain Proteins - genetics; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Kaplan-Meier Estimate; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncogene Proteins, Fusion - genetics; Paired Box Transcription Factors - genetics; PAX6 Transcription Factor; Pharmacology. Drug treatments; Repressor Proteins - genetics; Sarcoma, Alveolar Soft Part - genetics; Sarcoma, Alveolar Soft Part - mortality; Tumors; Young Adult; High resolution; Comparative genomic hybridization; DNA chip; Malignant tumor; Gene expression; Cancer; Alveolar sarcoma; Gene expression profile
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-13-2090

Alveolar soft part sarcoma (ASPS) is a soft tissue sarcoma with poor prognosis, and little molecular evidence exists for its origin, initiation, and progression. The aim of this study was to elucidate candidate molecular pathways involved in tumor pathogenesis. We employed high-throughput array comparative genomic hybridization (aCGH) and cDNA-Mediated Annealing, Selection, Ligation, and Extension Assay to profile the genomic and expression signatures of primary and metastatic ASPS from 17 tumors derived from 11 patients. We used an integrative bioinformatics approach to elucidate the molecular pathways associated with ASPS progression. FISH was performed to validate the presence of the t(X;17)(p11.2;q25) ASPL-TFE3 fusion and, hence, confirm the aCGH observations. FISH analysis identified the ASPL-TFE3 fusion in all cases. aCGH revealed a higher number of numerical aberrations in metastatic tumors relative to primaries, but failed to identify consistent alterations in either group. Gene expression analysis highlighted 1,063 genes that were differentially expressed between the two groups. Gene set enrichment analysis identified 16 enriched gene sets (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 upregulated 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 tentative neural line of differentiation for ASPS, these results implicate transcriptional deregulation from fusion genes in the pathogenesis of ASPS.