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Downregulated MTAP expression in myxofibrosarcoma: A characterization of inactivating mechanisms, tumor suppressive
Chien-Feng Li1, Fu-Min Fang2, Hsing-Jien Kung3
1Department of Pathology, Chi-Mei Medical Center, Tainan, Taiwan. Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan. National Institute of Cancer Research National Health Research Institutes, Tainan, Taiwan. Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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.
Insights
Methylthioadenosine phosphorylase (MTAP) deficiency, often due to homozygous deletion, drives myxofibrosarcoma aggressiveness and metastasis. Restoring MTAP inhibits tumor growth and sensitizes cells to L-alanosine therapy.
Area of Science:
- Oncology
- Cancer Genetics
- Molecular Pathology
Background:
- Myxofibrosarcomas exhibit genetic complexity, frequently involving chromosome 9p deletions.
- The specific pathogenic targets within deleted regions, particularly 9p21.3, remain incompletely understood.
- Methylthioadenosine phosphorylase (MTAP) is a candidate tumor suppressor gene located in the 9p21.3 region.
Purpose of the Study:
- To characterize the role of chromosome 9p deletions, specifically MTAP inactivation, in myxofibrosarcoma pathogenesis and clinical outcome.
- To investigate the functional consequences of MTAP deficiency on tumor aggressiveness, metastasis, and response to L-alanosine.
- To evaluate MTAP as a prognostic biomarker and therapeutic target in myxofibrosarcoma.
Main Methods:
- Genomic profiling (e.g., copy number analysis) to identify deletions on chromosome 9p.
- Quantitative PCR, methylation-specific PCR, and immunohistochemistry to assess MTAP gene and protein status.
- Functional studies involving MTAP reexpression or knockdown in myxofibrosarcoma cell lines and xenografts, including assessment of cell migration, invasion, proliferation, angiogenesis, and response to L-alanosine.
Main Results:
- Loss of 9p occurred in 12 of 15 myxofibrosarcoma samples, with 9p21.3 being the sole aggressiveness-associated deleted region.
- MTAP inactivation, via homozygous or hemizygous deletion or promoter methylation, was found in 37% of tumors and correlated with unfavorable metastasis-free and disease-specific survival.
- MTAP reexpression suppressed tumor cell migration, invasion, proliferation, and angiogenesis, while conferring sensitivity to L-alanosine; homozygous deletion of MTAP predicted adverse outcomes in deficient cases.
Conclusions:
- MTAP deficiency, primarily driven by homozygous deletion, significantly contributes to the biological aggressiveness and poor prognosis of myxofibrosarcomas.
- Restoration of MTAP function inhibits key oncogenic pathways, including cell motility and angiogenesis.
- MTAP status is a critical determinant of therapeutic response to L-alanosine, highlighting its potential as a predictive biomarker and therapeutic target.
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