Anti-TSPAN31 monoclonal antibody, clone FQS22336(3)

Purpose: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCGH) on a large set of MPNSTs. Experimental Design: Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens. Results: aCGH revealed highly complex copy number alterations, including both previously reported and completely novel loci. Four regions of copy number gain were associated with poor patient survival. Candidate genes in these regions include SOX5 (12p12.1), NOL1 and MLF2 (12p13.31), FOXM1 and FKBP1 (12p13.33), and CDK4 and TSPAN31 (12q14.1). Alterations of these candidate genes and several others of interest (ERBB2, MYC and TP53) were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence in situ hybridization and immunohistochemistry. Multivariate analysis showed that CDK4 gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (P < 0.05). Conclusions: Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients. Clin Cancer Res; 17(7); 1924-34. (C)2011 AACR.

Background/Aim: Well-differentiated liposarcoma (WDLPS) and de-differentiated liposarcoma (DDLPS) are characterized by amplified sequences derived from the long arm of chromosome 12. The goal of the present study was to identify, besides the well-known candidate genes, novel relevant genes in these large, complex 12q amplicons. Materials and Methods: Using multiplex ligation-dependent probe amplification, genetic alterations in 19 different genes of 12q12-24 were evaluated in 77 lipomatous soft tissue tumors (including lipomas, WDLPS, DDLPS and pleomorphic liposarcomas). Results: We recorded several amplified genes of 12q13-15, including miR-26a-2, a gene not well studied in liposarcoma, and the well-known and previously described genes murine double minute 2 (MDM2), YEATS domain-containing protein 4 (YEATS4), high-mobility AT-hook 2 (HMGA2), cyclin-dependent kinase 4 (CDK4) and tetraspanin 31 (TSPAN31). Interestingly, the amplification profiles of these six genes were found to be significantly different between WDLPS and DDLPS, more frequently having a high-level status in DDLPS than in WDLPS. In addition, DDLPS were found to have significantly higher mean amplification ratios compared to WDLPS. Moreover, we identified additional genes exclusively amplified in DDLPS in 12q13, 12q21 and 12q24, including glioma-associated oncogene homolog 1 (GLI1), mitogen activated protein kinase kinase kinase 12 (MAP3K12), cyclin-dependent kinase 2 (CDK2), ALX homeobox 1 (ALX1) and T-box 5 (TBX5). Conclusion: Differences in amplification profiles among WDLPS and DDLPS may be related to progression/de-differentiation in liposarcomas and show how in the future amplification profiles could provide an adjunctive tool in characterizing progression to DDLPS. In addition, we identified additional genes exclusively amplified in DDLPS, which may play a role in liposarcomagenesis, particularly in the de-differentiation process.