Validation of a hypoxia related gene signature in multiple soft tissue sarcoma cohortsCitation formats

TY - JOUR

T1 - Validation of a hypoxia related gene signature in multiple soft tissue sarcoma cohorts

AU - Yang, Lingjian

AU - Forker, Laura

AU - Irlam, Joely

AU - Pillay, Nischalan

AU - Choudhury, Ananya

AU - West, Catharine

PY - 2017/12/22

Y1 - 2017/12/22

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.PATIENTS 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 hypoxia signature and a genome instability signature significantly improved prognostication. Transcriptomic analyses showed high-hypoxia tumors had more genome instability and lower immune scores. CONCLUSION: A 24-gene STS-specific hypoxia signature may be useful for prognostication and identifying patients for hypoxia-targeted therapy in clinical trials.

AB - 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.PATIENTS 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 hypoxia signature and a genome instability signature significantly improved prognostication. Transcriptomic analyses showed high-hypoxia tumors had more genome instability and lower immune scores. CONCLUSION: A 24-gene STS-specific hypoxia signature may be useful for prognostication and identifying patients for hypoxia-targeted therapy in clinical trials.

KW - Soft tissue sarcoma

KW - Tumor hypoxia

KW - gene expression signature

KW - Prognostic biomarker

U2 - 10.18632/oncotarget.23280

DO - 10.18632/oncotarget.23280

M3 - Article

VL - 9

SP - 3946

EP - 3955

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

ER -