(P 258) THE CRITICALITY OF OXIDATIVE PHOSPHORYLATION IN SYNOVIAL SARCOMA METASTASIS

Objective: Synovial sarcoma (SS) is characterized by the pathognomonic translocation of the SS18 gene on chromosome 18 with the SSX gene on chromosome X. This change results in alteration of the SWItch/Sucrose Non-Fermentable (SWI/SNF) and polycomb complexes, which are ATP-dependent chromatin-remodeling complexes crucial in epigenetic changes and oncogenesis. Evaluating the resultant gene expression patterns from this translocation in SS is critical to determine what leads to increased risk of disease progression and metastasis.

Methods: The primary objective was to evaluate gene expression signatures in SS specimens to determine if there was a particular signal for increased risk of metastasis. Ribonucleic acid (RNA) sequencing was performed on primary tumor specimens from patients who developed metastasis and those who did not. Two analyses were performed, one including tumors that had and had not been exposed to prior treatment and another analysis with only treatment naïve tumors.
Gene set enrichment analysis (GSEA) was employed to evaluate which genes were over-represented, calculating an enrichment score (degree to which a gene set is overrepresented), normalized enrichment score (accounts for differences in gene set size and in correlations between gene sets and the expression dataset), family-wise error rate (FWER) p-value and nominal p-value. Given the relatively small number of patients, a nominal p-value of 0.10 was used for significance.

Results: Multiple pathways were enriched with genes over-expressed in the metastatic cohort in comparison to the non-metastatic cohort (Figure 1 and 2). Primary tumors that were eventually able to metastasize had increased expression of oxidative phosphorylation gene set (NES 1.55; p-val 0.078) and epithelial to mesenchymal transition gene set (NES 1.46; p-val 0.036) (table 1). Treatment naïve tumors showed an even wider array of gene set expression (table 2) and the oxidative phosphorylation gene set continued to be significantly represented (NES 1.6, p-val 0.067). Within the oxidative phosphorylation gene set, translocase of outer mitochondria membrane 22 (TOMM22), mitochondrial ribosomal protein (MRPL11), voltage dependent anion channel (VDAC2), peptidase mitochondrial processing subunit alpha (PMPCA), aconitase 2 (ACO2) were all highly enriched (running ES < 0.05).
Multiple pathways were enriched with genes over-expressed in the metastatic cohort in comparison to the non-metastatic cohort (Figure 1 and 2). Primary tumors that were eventually able to metastasize had increased expression of oxidative phosphorylation gene set (NES 1.55; p-val 0.078) and epithelial to mesenchymal transition gene set (NES 1.46; p-val 0.036) (table 1). Treatment naïve tumors showed an even wider array of gene set expression (table 2) and the oxidative phosphorylation gene set continued to be significantly represented (NES 1.6, p-val 0.067). Within the oxidative phosphorylation gene set, translocase of outer mitochondria membrane 22 (TOMM22), mitochondrial ribosomal protein (MRPL11), voltage dependent anion channel (VDAC2), peptidase mitochondrial processing subunit alpha (PMPCA), aconitase 2 (ACO2) were all highly enriched (running ES < 0.05).

Conclusion: There are two main metabolic pathways for cancer metabolism, glycolysis (generating 2 molecules of ATP) and oxidative phosphorylation (generating 36 molecules of ATP). Even in the presence of sufficient oxygen, most cancers use glycolysis preferentially. While a minority of cancers rely on mitochondrial metabolism, the center of which is oxidative phosphorylation, our findings suggest that SS may be one of those cancer types. Additionally, other tumors with mutant SWI/SNF complexes, including some lung cancers, have demonstrated reliance on oxidative phosphorylation and demonstrated preclinical responses to oxidative phosphorylation blockers. Mitochondrial metabolism can be inhibited by numerous agents, some as commonplace as metformin and statins. There is retrospective data that patients with soft tissue sarcoma that take metformin have improved survival, even after controlling for many confounding factors. Targeting the oxidative pathway is possibly a novel option for treatment of SS and should be investigated.