TY  - JOUR
IS  - 3
KW  - soft tissue sarcoma; tumor hypoxia; gene expression signature; prognostic biomarker
A1  - Yang, L
A1  - Forker, L
A1  - Irlam, JJ
A1  - Pillay, N
A1  - Choudhury, A
A1  - West, CML
EP  - 3955
VL  - 9
Y1  - 2018/01/09/
TI  - Validation of a hypoxia related gene signature in multiple soft tissue sarcoma cohorts
AV  - public
N2  - 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.
SN  - 1949-2553
SP  - 3946
JF  - Oncotarget
PB  - IMPACT JOURNALS LLC
UR  - https://doi.org/10.18632/oncotarget.23280
ID  - discovery10053986
N1  - 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).
ER  -