Universität zu Köln

Roever, Lea Kristin, Gevensleben, Heidrun, Dietrich, Joern, Bootz, Friedrich, Landsberg, Jennifer ORCID: 0000-0001-8029-3883, Goltz, Diane and Dietrich, Dimo (2018). PD-1 (PDCD1) Promoter Methylation Is a Prognostic Factor in Patients With Diffuse Lower-Grade Gliomas Harboring Isocitrate Dehydrogenase (IDH) Mutations. EBioMedicine, 28. S. 97 - 105. AMSTERDAM: ELSEVIER SCIENCE BV. ISSN 2352-3964

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Abstract

Immune checkpoints are important targets for immunotherapies. However, knowledge on the epigenetic modification of immune checkpoint genes is sparse. In the present study, we investigated promoter methylation of CTLA4, PD-L1, PD-L2, and PD-1 in diffuse lower-grade gliomas (LGG) harboring isocitrate dehydrogenase (IDH) mutations with regard to mRNA expression levels, clinicopathological parameters, previously established methylation subtypes, immune cell infiltrates, and survival in a cohort of 419 patients with IDH-mutated LGG provided by The Cancer Genome Atlas. PD-L1, PD-L2, and CTLA-4 mRNA expression levels showed a significant inverse correlation with promoter methylation (PD-L1: p=0.005; PD-L2: p < 0.001; CTLA-4: p b 0.001). Furthermore, immune checkpoint methylation was significantly associated with age (PD-L2: p = 0.003; PD-1: p = 0.015), molecular alterations, i.e. MGMT methylation (PD-L1: p < 0.001; PD-L2: p < 0.001), ATRX mutations (PD-L2: p < 0.001, PD-1: p = 0.001), and TERT mutations (PD-L1: p= 0.035, PD-L2: p < 0.001, PD-1: p b 0.001, CTLA4: p < 0.001) as well a smethylation subgroups and immune cell infiltrates. In multivariate Cox proportional hazard analysis, PD-1 methylation qualified as strong prognostic factor (HR = 0.51 [ 0.34-0.76], p=0.001). Our findings suggest an epigenetic regulation of immune checkpoint genes via DNA methylation in LGG. PD-1 methylation may assist the identification of patients that might benefit from an alternative treatment, particularly in the context of emerging immunotherapies. (c) 2018 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Roever, Lea Kristin UNSPECIFIED UNSPECIFIED UNSPECIFIED Gevensleben, Heidrun UNSPECIFIED UNSPECIFIED UNSPECIFIED Dietrich, Joern UNSPECIFIED UNSPECIFIED UNSPECIFIED Bootz, Friedrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Landsberg, Jennifer UNSPECIFIED orcid.org/0000-0001-8029-3883 UNSPECIFIED Goltz, Diane UNSPECIFIED UNSPECIFIED UNSPECIFIED Dietrich, Dimo UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-196401
DOI:	10.1016/j.ebiom.2018.01.016
Journal or Publication Title:	EBioMedicine
Volume:	28
Page Range:	S. 97 - 105
Date:	2018
Publisher:	ELSEVIER SCIENCE BV
Place of Publication:	AMSTERDAM
ISSN:	2352-3964
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language RECURRENCE-FREE SURVIVAL; SAFETY; PEMBROLIZUMAB; IPILIMUMAB; NIVOLUMAB; ANTIBODY; MONOTHERAPY; BIOMARKER; ANTI-PD-1; CTLA-4 Multiple languages Medicine, General & Internal; Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19640