Abstract
Myxofibrosarcomas are genetically complex and involve recurrently deleted chromosome 9p, for which we characterized the pathogenically relevant target(s) using genomic profiling. In 12 of the 15 samples, we detected complete or partial losses of 9p. The only aggressiveness-associated, differentially lost region was 9p21.3, spanning the potential inactivated methylthioadenosine phosphorylase (MTAP) that exhibited homozygous (4/15) or hemizygous (3/15) deletions. In independent samples, MTAP gene status was assessed using quantitative- and methylation-specific PCR assays, and immunoexpression was evaluated. We applied MTAP reexpression or knockdown to elucidate the functional roles of MTAP and the therapeutic potential of L-alanosine in MTAP-preserved and MTAP-deficient myxofibrosarcoma cell lines and xenografts. MTAP protein deficiency (37%) was associated with MTAP gene inactivation (P < 0.001) by homozygous deletion or promoter methylation, and independently portended unfavorable metastasis-free survival (P = 0.0318) and disease-specific survival (P = 0.014). Among the MTAP-deficient cases, the homozygous deletion of MTAP predicted adverse outcome. In MTAP-deficient cells, MTAP reexpression inhibited cell migration and invasion, proliferation, and anchorage-independent colony formation and downregulated cyclin D1. This approach also attenuated the tube-forming abilities of human umbilical venous endothelial cells, attributable to the transcriptional repression of MMP-9, and abrogated the susceptibility to L-alanosine. The inhibiting effects of MTAP expression on tumor growth, angiogenesis, and the induction of apoptosis by L-alanosine were validated using MTAP-reexpressing xenografts and reverted using RNA interference in MTAP-preserved cells. In conclusion, homozygous deletion primarily accounts for the adverse prognostic impact of MTAP deficiency and confers the biological aggressiveness and susceptibility to L-alanosine in myxofibrosarcomas.
Highlights
Myxofibrosarcoma is characterized by the multinodular growth of spindle to polygonal sarcoma cells within variably myxoid stroma containing long curvilinear vessels [1, 2]
We identified the clinical, biological, and therapeutic relevance of methylthioadenosine phosphorylase (MTAP) deficiency, which was observed in 37% of primary myxofibrosarcomas, strongly linked to homozygous deletion or promoter methylation, and independently predictive of adverse survival
No inactivating mechanism was detected in the 3 MTAPdeficient cases, suggesting that MTAP downregulation was caused by alternative molecular defects such as small deletions of 5’ regions [20, 21]
Summary
Myxofibrosarcoma is characterized by the multinodular growth of spindle to polygonal sarcoma cells within variably myxoid stroma containing long curvilinear vessels [1, 2]. Increased tumor grades and stages are frequently observed in myxofibrosarcomas after local recurrence, and may cause metastatic diseases [1,2,3,4]. By using ultrahigh-resolution array comparative genomic hybridization (aCGH), we previously profiled the global copy-number alterations (CNAs) in myxofibrosarcoma specimens and cell lines and characterized SKP2 on 5p and CDK6 and MET on 7q as amplified oncogenes of pathogenic relevance [6,7,8]. Regarding DNA losses, chromosome 9p was the most frequently lost chromosomal arm in myxofibrosarcomas [5], prompting the search for potential tumor suppressor gene(s) underlying this selection pressure for the loss of 9p. We characterized methylthioadenosine phosphorylase (MTAP) on 9p21.3 because whether the tumor-suppressive role of this polyamine metabolism-regulating enzyme is independent from the frequently co-deleted CDKN2A and CDKN2B genes still remains debated [9,10,11,12]
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