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

  • External authors:
  • Lingjian Yang
  • Joely Irlam
  • Nischalan Pillay

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Validation of a hypoxia related gene signature in multiple soft tissue sarcoma cohorts. / Yang, Lingjian; Forker, Laura; Irlam, Joely; Pillay, Nischalan; Choudhury, Ananya; West, Catharine.

In: Oncotarget, Vol. 9, 22.12.2017, p. 3946-3955.

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Yang, Lingjian ; Forker, Laura ; Irlam, Joely ; Pillay, Nischalan ; Choudhury, Ananya ; West, Catharine. / Validation of a hypoxia related gene signature in multiple soft tissue sarcoma cohorts. In: Oncotarget. 2017 ; Vol. 9. pp. 3946-3955.

Bibtex

@article{e6d1e84e0c39466f8efe112c92e724e8,
title = "Validation of a hypoxia related gene signature in multiple soft tissue sarcoma cohorts",
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.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.",
keywords = "Soft tissue sarcoma, Tumor hypoxia, gene expression signature, Prognostic biomarker",
author = "Lingjian Yang and Laura Forker and Joely Irlam and Nischalan Pillay and Ananya Choudhury and Catharine West",
year = "2017",
month = dec,
day = "22",
doi = "10.18632/oncotarget.23280",
language = "English",
volume = "9",
pages = "3946--3955",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals LLC",

}

RIS

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 -