Elucidating Gene Dependencies and Mutations of Chordoma

Background: Chordoma, a rare bone cancer arising from remnants of the notochord, presents unique challenges in surgical management due to its complex biology and variable prognosis. Previous studies have shown that chordoma’s development and treatment are heavily influenced by gene dependencies, such as the reliance on the T-box transcription factor T (TBXT) and the overexpression of the epidermal growth factor receptor (EGFR) gene, contributing to tumor growth, invasiveness, and resistance to therapy. The full landscape of essential genes and mutations in chordomas is poorly defined. Understanding these gene dependencies and mutations is crucial for delivering optimized care to chordoma patients undergoing surgery by enabling surgeons to predict patient outcomes, tailor surgical approaches, and inform prognostication.

Methods: We analyzed cancer cell line data from a 72-year-old female with chordoma (UCH2) as part of the Broad Institute Cancer Dependency Map project to identify critical genes essential for chordoma cell survival and proliferation, focusing on those with significant negative effects on cell viability (gene effect < −0.2, and p < 0.01). Additionally, we performed in-depth mutation analysis on the chordoma samples, utilizing PolyPhen and SIFT programs to predict the functional impact of identified variants. We categorized the genes based on cellular functions and pathways to understand the complex biology underlying chordoma development and progression.

Results: We confirmed the critical dependency on TBXT in chordoma cell viability (gene effect = −0.336, p < 0.001), reinforcing its role as a key driver in chordoma pathogenesis. Despite the absence of TBXT mutations, we identified potentially impactful genomic alterations, including two damaging missense variants in EXTL1 (p.F419I and p.S420G, both with allele fraction = 0.167) that may disrupt heparan sulfate biosynthesis and alter the tumor microenvironment. The proximity of these variants suggests they may have a cooperative effect on EXTL1 function. A high-frequency in-frame deletion in COL9A2 (p.A4del, allele fraction = 0.625) further supports extracellular matrix remodeling in chordoma progression. Notably, the chordoma cells exhibited dependencies on the interleukin-17 receptor A (IL17RA: gene effect = −0.328, p < 0.01) and the HLA class II histocompatibility antigen, DQ beta 2 chain (HLA-DQB2: gene effect = −0.254, p < 0.01), suggesting a role for IL-17 signaling and antigen presentation in chordoma biology. The dependency on HLA-DQB2 raises the possibility that chordoma cells may present specific antigens contributing to their immune evasion. The identification of dependencies on genes involved in the Wnt pathway (FZD3: gene effect = −0.226, p < 0.01) and GABA neurotransmitter signaling (GABBR2: gene effect = −0.296, p < 0.01) suggests that chordoma cells may rely on developmental and neuronal signaling pathways for their growth and survival.

Conclusion: This study comprehensively outlines the gene dependencies and mutations driving chordoma pathogenesis. By identifying critical genes, pathways, and impactful mutations, these findings can guide surgical decision-making by providing insights into tumor biology and behavior, enabling surgeons to tailor their approach based on the specific genetic profile of each patient’s tumor. This personalized approach can lead to more precise and effective surgical interventions, ultimately improving prognostication, outcomes, and quality of life for chordoma patients.

Publikationsverlauf

Artikel online veröffentlicht:
07. Februar 2025