Abstract
PurposeThere is a need for adjuvant/neo-adjuvant treatment strategies to prevent metastatic relapse in soft tissue sarcoma (STS). Tumor hypoxia is associated with a high-risk of metastasis and is potentially targetable. This study aimed to derive and validate a hypoxia mRNA signature for STS for future biomarker-driven trials of hypoxia targeted therapy.Materials and MethodsRNA sequencing was used to identify seed genes induced by hypoxia in seven STS cell lines. Primary tumors in a training cohort (French training) were clustered into two phenotypes by seed gene expression and a de novo hypoxia signature derived. Prognostic significance of the de novo signature was evaluated in the training and two independent validation (French validation and The Cancer Genome Atlas) cohorts.Results37 genes were up-regulated by hypoxia in all seven cell lines, and a 24-gene signature was derived. The high-hypoxia phenotype defined by the signature was enriched for well-established hypoxia genes reported in the literature. The signature was prognostic in univariable analysis, and in multivariable analysis in the training (n = 183, HR 2.16, P = 0.0054) and two independent validation (n = 127, HR 3.06, P = 0.0019; n = 258, HR 2.05, P = 0.0098) cohorts. Combining information from the de novo hypoxia signature and a genome instability signature significantly improved prognostication. Transcriptomic analyses showed high-hypoxia tumors had more genome instability and lower immune scores.ConclusionsA 24-gene STS-specific hypoxia signature may be useful for prognostication and identifying patients for hypoxia-targeted therapy in clinical trials.
Highlights
Soft tissue sarcomas (STS) are a group of rare cancers arising from mesenchymal cells that account for less than 1% of solid tumors in adults
A 24-gene soft tissue sarcoma (STS)-specific hypoxia signature may be useful for prognostication and identifying patients for hypoxia-targeted therapy in clinical trials
RNA sequencing data were generated in triplicate for seven cell lines, representing the most common histologic STS subtypes reported in adults
Summary
Soft tissue sarcomas (STS) are a group of rare cancers arising from mesenchymal cells that account for less than 1% of solid tumors in adults. They are extremely heterogeneous with over 50 malignant histologic subtypes and can occur in any anatomical position [1]. Most patients present with localized disease, for which surgery (+/– radiotherapy) is the cornerstone of treatment. Despite high local control rates, the five-year overall survival is only around 50% in patients with high-risk disease (high grade, deep, large tumors) [2, 3], where most deaths are attributable to distant metastasis. Novel strategies to target and prevent metastatic spread are urgently needed
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