Yang, L;
Forker, L;
Irlam, JJ;
Pillay, N;
Choudhury, A;
West, CML;
(2018)
Validation of a hypoxia related gene signature in multiple soft tissue sarcoma cohorts.
Oncotarget
, 9
(3)
pp. 3946-3955.
10.18632/oncotarget.23280.
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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.
| Type: | Article |
|---|---|
| Title: | Validation of a hypoxia related gene signature in multiple soft tissue sarcoma cohorts |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.18632/oncotarget.23280 |
| Publisher version: | https://doi.org/10.18632/oncotarget.23280 |
| Language: | English |
| Additional information: | 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). |
| Keywords: | soft tissue sarcoma; tumor hypoxia; gene expression signature; prognostic biomarker |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10053986 |
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