@article{discovery10053986,
          volume = {9},
            year = {2018},
           title = {Validation of a hypoxia related gene signature in multiple soft tissue sarcoma cohorts},
          number = {3},
           month = {January},
           pages = {3946--3955},
         journal = {Oncotarget},
            note = {Copyright: Yang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY
3.0) (https://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. - Correction issued March 08, 2019 (https://doi.org/10.18632/oncotarget.26783).},
       publisher = {IMPACT JOURNALS LLC},
        abstract = {Purpose: There 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 Methods: RNA 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. //

Results: 37 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. //

Conclusions: A 24-gene STS-specific hypoxia signature may be useful for prognostication and identifying patients for hypoxia-targeted therapy in clinical trials.},
             url = {https://doi.org/10.18632/oncotarget.23280},
          author = {Yang, L and Forker, L and Irlam, JJ and Pillay, N and Choudhury, A and West, CML},
        keywords = {soft tissue sarcoma; tumor hypoxia; gene expression signature; prognostic biomarker},
            issn = {1949-2553}
}