Abstract 5061: Genomic and functional analysis of Myxofibrosarcoma identifies novel prognostic markers and promising therapeutic targets

Abstract

Abstract Introduction: Myxofibrosarcoma (MXF), which primarily affects the limbs of older patients, has few effective systemic therapies. Little is known about the MXF genome or the genes that drive tumorigenesis. We sought to identify subgroups and to identify genes that associate with outcome and could serve as therapeutic targets. Methods: Copy number alterations (CNAs) and gene expression profiles were measured in 73 MXF, 11 normal muscle, and 22 normal fat samples using Agilent 1M CGH and Affymetrix U133A arrays. Profiles were analyzed by unsupervised clustering and correlated with disease-specific survival (DSS) and distant recurrence-free survival (DRFS). Associations with disease-specific survival (DSS) and distant recurrence-free survival (DRFS) were analyzed for the 68 patients with primary disease; this cohort included 21 patients who had distant recurrence and 15 who died of disease during follow-up (mean, 2.7 years). [ss1] Genes of interest were assayed using shRNA knockdown (for ITGA10) or serum ELISA levels (for HGF). Results: MXF samples had highly complex CNAs, some spanning entire chromosome arms. Unsupervised clustering based on CGH divided samples into 4 main groups driven by a loss at 1q and a gain at 5p. Unsupervised clustering based on U133A profiles divided samples into 3 main groups, 2 of which had a 3-year DSS of 85% while the third had a DSS of 31% (p<0.02). This third group was defined in part by high expression of integrin alpha-10 (ITGA10) and hepatocyte growth factor (HGF). Expression of ITGA10 was associated with worse DRFS (HR=2.7, p=0.03), and particularly strongly associated with worse DSS (HR=8.2, p=0.006). HGF expression was also associated with worse outcomes for both DRFS (HR=3.2, p=0.01) and DSS (HR=3.5, p=0.01). Knockdown of ITGA10 inhibited proliferation and induced apoptosis in an MXF cell line, but not in a normal fat cell line. Patients with high expression of both HGF and its receptor MET had a 3-year DRFS of 25%, vs approximately 60% for those with low expression of one of these genes and 85% for those with low expression of both genes (p=0.0016). Serum HGF was elevated in preoperative patients with MXF (n=38) compared to healthy volunteers (n=8): mean ± SD 1626 pg/mL ± 725 vs. 771 ± 110 (p=0.002). Patients with low serum HGF (≤mean +3 SD of normal [1101 pg/mL], n=10) tended to have better DSS (100% vs. 64%, p=0.14) and better DRFS (83% vs. 55%, p=0.08). Conclusions: MXF is genomically complex and diverse, but gene expression profiles cluster patients into groups associated with outcome. Levels of ITGA10, HGF and MET associate with outcome, and ITGA10 overexpression in a MXF cell line contributes to cell proliferation and survival. All three of these genes may be useful as therapeutic targets. Preoperative serum HGF levels may be a useful prognostic indicator in patients with MXF. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5061. doi:1538-7445.AM2012-5061