Multigene signature for predicting prognosis of patients with 1p19q co-deletion diffuse glioma

Xin Hu, Emmanuel Martinez-Ledesma, Siyuan Zheng, Hoon Kim, Floris Barthel, Tao Jiang, Kenneth R. Hess, Roel G.W. Verhaak

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background. Co-deletion of 1p and 19q marks a diffuse glioma subtype associated with relatively favorable overall survival; however, heterogeneous clinical outcomes are observed within this category. Methods. We assembled gene expression profles and sample annotation of 374 glioma patients carrying the 1p/19q co-deletion. We predicted 1p/19q status using gene expression when annotation was missing. A frst cohort was randomly split into training (n = 170) and a validation dataset (n = 163). A second validation set consisted of 41 expression profles. An elastic-net penalized Cox proportional hazards model was applied to build a classifer model through cross-validation within the training dataset. Results. The selected 35-gene signature was used to identify high-risk and low-risk groups in the validation set, which showed signifcantly different overall survival (P =.00058, log-rank test). For time-to-death events, the highrisk group predicted by the gene signature yielded a hazard ratio of 1.78 (95% confdence interval, 1.02-3.11). The signature was also signifcantly associated with clinical outcome in the The Cancer Genome Atlas (CGA) IDHmutant 1p/19q wild-type and IDH-wild-type glioma cohorts. Pathway analysis suggested that high risk was associated with increased acetylation activity and inflammatory response. Tumor purity was found to be signifcantly decreased in high-risk IDH-mutant with 1p/19q co-deletion gliomas and IDH-wild-type glioblastomas but not in IDH-wild-type lower grade or IDH-mutant, non-co-deleted gliomas. Conclusion. We identifed a 35-gene signature that identifes high-risk and low-risk categories of 1p/19q positive glioma patients. We have demonstrated heterogeneity amongst a relatively new glioma subtype and provided a stepping stone towards risk stratifcation.

Original languageEnglish (US)
Pages (from-to)786-795
Number of pages10
JournalNeuro-Oncology
Volume19
Issue number6
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

Fingerprint

Glioma
Genes
Gene Expression
Survival
Atlases
Glioblastoma
Acetylation
Proportional Hazards Models
Neoplasms
Genome

Keywords

  • 1p/19q co-deletion
  • elastic net Cox regression model
  • Glioma
  • Prognostic factor

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Hu, X., Martinez-Ledesma, E., Zheng, S., Kim, H., Barthel, F., Jiang, T., ... Verhaak, R. G. W. (2017). Multigene signature for predicting prognosis of patients with 1p19q co-deletion diffuse glioma. Neuro-Oncology, 19(6), 786-795. https://doi.org/10.1093/neuonc/now285

Multigene signature for predicting prognosis of patients with 1p19q co-deletion diffuse glioma. / Hu, Xin; Martinez-Ledesma, Emmanuel; Zheng, Siyuan; Kim, Hoon; Barthel, Floris; Jiang, Tao; Hess, Kenneth R.; Verhaak, Roel G.W.

In: Neuro-Oncology, Vol. 19, No. 6, 01.01.2017, p. 786-795.

Research output: Contribution to journalArticle

Hu, X, Martinez-Ledesma, E, Zheng, S, Kim, H, Barthel, F, Jiang, T, Hess, KR & Verhaak, RGW 2017, 'Multigene signature for predicting prognosis of patients with 1p19q co-deletion diffuse glioma', Neuro-Oncology, vol. 19, no. 6, pp. 786-795. https://doi.org/10.1093/neuonc/now285
Hu, Xin ; Martinez-Ledesma, Emmanuel ; Zheng, Siyuan ; Kim, Hoon ; Barthel, Floris ; Jiang, Tao ; Hess, Kenneth R. ; Verhaak, Roel G.W. / Multigene signature for predicting prognosis of patients with 1p19q co-deletion diffuse glioma. In: Neuro-Oncology. 2017 ; Vol. 19, No. 6. pp. 786-795.
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abstract = "Background. Co-deletion of 1p and 19q marks a diffuse glioma subtype associated with relatively favorable overall survival; however, heterogeneous clinical outcomes are observed within this category. Methods. We assembled gene expression profles and sample annotation of 374 glioma patients carrying the 1p/19q co-deletion. We predicted 1p/19q status using gene expression when annotation was missing. A frst cohort was randomly split into training (n = 170) and a validation dataset (n = 163). A second validation set consisted of 41 expression profles. An elastic-net penalized Cox proportional hazards model was applied to build a classifer model through cross-validation within the training dataset. Results. The selected 35-gene signature was used to identify high-risk and low-risk groups in the validation set, which showed signifcantly different overall survival (P =.00058, log-rank test). For time-to-death events, the highrisk group predicted by the gene signature yielded a hazard ratio of 1.78 (95{\%} confdence interval, 1.02-3.11). The signature was also signifcantly associated with clinical outcome in the The Cancer Genome Atlas (CGA) IDHmutant 1p/19q wild-type and IDH-wild-type glioma cohorts. Pathway analysis suggested that high risk was associated with increased acetylation activity and inflammatory response. Tumor purity was found to be signifcantly decreased in high-risk IDH-mutant with 1p/19q co-deletion gliomas and IDH-wild-type glioblastomas but not in IDH-wild-type lower grade or IDH-mutant, non-co-deleted gliomas. Conclusion. We identifed a 35-gene signature that identifes high-risk and low-risk categories of 1p/19q positive glioma patients. We have demonstrated heterogeneity amongst a relatively new glioma subtype and provided a stepping stone towards risk stratifcation.",
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T1 - Multigene signature for predicting prognosis of patients with 1p19q co-deletion diffuse glioma

AU - Hu, Xin

AU - Martinez-Ledesma, Emmanuel

AU - Zheng, Siyuan

AU - Kim, Hoon

AU - Barthel, Floris

AU - Jiang, Tao

AU - Hess, Kenneth R.

AU - Verhaak, Roel G.W.

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N2 - Background. Co-deletion of 1p and 19q marks a diffuse glioma subtype associated with relatively favorable overall survival; however, heterogeneous clinical outcomes are observed within this category. Methods. We assembled gene expression profles and sample annotation of 374 glioma patients carrying the 1p/19q co-deletion. We predicted 1p/19q status using gene expression when annotation was missing. A frst cohort was randomly split into training (n = 170) and a validation dataset (n = 163). A second validation set consisted of 41 expression profles. An elastic-net penalized Cox proportional hazards model was applied to build a classifer model through cross-validation within the training dataset. Results. The selected 35-gene signature was used to identify high-risk and low-risk groups in the validation set, which showed signifcantly different overall survival (P =.00058, log-rank test). For time-to-death events, the highrisk group predicted by the gene signature yielded a hazard ratio of 1.78 (95% confdence interval, 1.02-3.11). The signature was also signifcantly associated with clinical outcome in the The Cancer Genome Atlas (CGA) IDHmutant 1p/19q wild-type and IDH-wild-type glioma cohorts. Pathway analysis suggested that high risk was associated with increased acetylation activity and inflammatory response. Tumor purity was found to be signifcantly decreased in high-risk IDH-mutant with 1p/19q co-deletion gliomas and IDH-wild-type glioblastomas but not in IDH-wild-type lower grade or IDH-mutant, non-co-deleted gliomas. Conclusion. We identifed a 35-gene signature that identifes high-risk and low-risk categories of 1p/19q positive glioma patients. We have demonstrated heterogeneity amongst a relatively new glioma subtype and provided a stepping stone towards risk stratifcation.

AB - Background. Co-deletion of 1p and 19q marks a diffuse glioma subtype associated with relatively favorable overall survival; however, heterogeneous clinical outcomes are observed within this category. Methods. We assembled gene expression profles and sample annotation of 374 glioma patients carrying the 1p/19q co-deletion. We predicted 1p/19q status using gene expression when annotation was missing. A frst cohort was randomly split into training (n = 170) and a validation dataset (n = 163). A second validation set consisted of 41 expression profles. An elastic-net penalized Cox proportional hazards model was applied to build a classifer model through cross-validation within the training dataset. Results. The selected 35-gene signature was used to identify high-risk and low-risk groups in the validation set, which showed signifcantly different overall survival (P =.00058, log-rank test). For time-to-death events, the highrisk group predicted by the gene signature yielded a hazard ratio of 1.78 (95% confdence interval, 1.02-3.11). The signature was also signifcantly associated with clinical outcome in the The Cancer Genome Atlas (CGA) IDHmutant 1p/19q wild-type and IDH-wild-type glioma cohorts. Pathway analysis suggested that high risk was associated with increased acetylation activity and inflammatory response. Tumor purity was found to be signifcantly decreased in high-risk IDH-mutant with 1p/19q co-deletion gliomas and IDH-wild-type glioblastomas but not in IDH-wild-type lower grade or IDH-mutant, non-co-deleted gliomas. Conclusion. We identifed a 35-gene signature that identifes high-risk and low-risk categories of 1p/19q positive glioma patients. We have demonstrated heterogeneity amongst a relatively new glioma subtype and provided a stepping stone towards risk stratifcation.

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KW - Prognostic factor

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