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PD-1 (PDCD1) Promoter Methylation Is a Prognostic Factor in Patients With Diffuse Lower-Grade Gliomas Harboring Isocitrate Dehydrogenase (IDH) Mutations
| Content Provider | Directory of Open Access Journals (DOAJ) |
|---|---|
| Author | Jörn Dietrich Friedrich Bootz Jennifer Landsberg Lea Kristin Röver Diane Goltz Dimo Dietrich Heidrun Gevensleben |
| 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 < 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 < 0.001, CTLA4: p < 0.001) as well as methylation 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. |
| Related Links | http://www.sciencedirect.com/science/article/pii/S2352396418300203 |
| ISSN | 23523964 |
| DOI | 10.1016/j.ebiom.2018.01.016 |
| Journal | EBioMedicine |
| Issue Number | C |
| Volume Number | 28 |
| Language | English |
| Publisher | Elsevier |
| Publisher Date | 2018-01-01 |
| Publisher Place | Netherlands |
| Access Restriction | Open |
| Subject Keyword | Medicine Medicine (general) Pd-1 Pd-l1 Ctla-4 Dna Methylation Lower-grade Glioma Prognosis |
| Content Type | Text |
| Resource Type | Article |
| Subject | Medicine Biochemistry, Genetics and Molecular Biology |
