Methylome analyses of three glioblastoma cohorts reveal chemotherapy sensitivity markers within DDR genes [EORTC 26101 cohort]
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PROVIDER: PRJNA601485 | ENA |
REPOSITORIES: ENA
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Project description:This SuperSeries is composed of the SubSeries listed below. BACKGROUND: Gliomas evade current therapies through primary and acquired resistance and the effect of temozolomide is mainly restricted to the subgroup of methylguanin-O6-methyltransferase promoter (MGMT) hypermethylated tumors. Further resistance markers and pathways against chemotherapy and radiotherapy are largely unknown and would help for better stratification. METHODS: The diagnostic cohorts involved clinical data and methylation profiles of the NOA-08 (n = 104, elderly glioblastoma) and the EORTC 26101 (n = 297, glioblastoma) studies and 398 patients with glioblastoma from the Heidelberg center. Twenty-eight glioblastoma CpGs from 17 DNA damage response (DDR) genes that negatively correlate with expression derived from a 450 DDR gene list as well as telomerase reverse transcriptase (TERT) promoter mutations were investigated for outcome and interaction with therapy and classifier assignments. RESULTS: CpG methylation in IDH wildtype tumors had the highest association with the mesenchymal (MES) and receptor tyrosine kinase (RTK) I glioblastoma subgroup. MES tumors have lower tumor purity and differ in copy number variations on chromosomes 7 and 10 from the RTK I and II subtypes. CpG hypomethylation of DDR genes (TP73, CCND3, CSNK1E, EXO1, CUL4A and PRPF19) correlated with worse patient survival in particular in MGMT unmethylated tumors. TERT promoter mutation is most frequent in RTK I and II subtypes and associated with worse survival in primary glioblastoma. Primary glioma cells show methylation pattern that resemble RTK I and II glioma and differ from long term established cell lines. Knock-down of selected resistance genes PRPF19 and TERT increase sensitivity to temozolomide treatment in vitro. CONCLUSION: Methylation of DDR genes and TERT promoter mutations are associated with tumor prognosis, dependent on the methylation cluster and MGMT promoter methylation status in high-grade glioma.
2020-11-18 | GSE143843 | GEO
Project description:The data contains Illumina 450k/EPIC array methylation files from 298 glioblastoma patients from the EORTC 26101 study
2020-11-18 | GSE143755 | GEO
Project description:Methylome analyses of three glioblastoma cohorts reveal chemotherapy sensitivity markers within DDR genes
| PRJNA601827 | ENA
Project description:Methylome analyses of three glioblastoma cohorts reveal chemotherapy sensitivity markers within DDR genes [Heidelberg cohort part 2]
| PRJNA601831 | ENA
Project description:BackgroundGliomas evade current therapies through primary and acquired resistance and the effect of temozolomide is mainly restricted to methylguanin-O6-methyltransferase promoter (MGMT) promoter hypermethylated tumors. Further resistance markers are largely unknown and would help for better stratification.MethodsClinical data and methylation profiles from the NOA-08 (104, elderly glioblastoma) and the EORTC 26101 (297, glioblastoma) studies and 398 patients with glioblastoma from the Heidelberg Neuro-Oncology center have been analyzed focused on the predictive effect of DNA damage response (DDR) gene methylation. Candidate genes were validated in vitro.ResultsTwenty-eight glioblastoma 5'-cytosine-phosphat-guanine-3' (CpGs) from 17 DDR genes negatively correlated with expression and were used together with telomerase reverse transcriptase (TERT) promoter mutations in further analysis. CpG methylation of DDR genes shows highest association with the mesenchymal (MES) and receptor tyrosine kinase (RTK) II glioblastoma subgroup. MES tumors have lower tumor purity compared to RTK I and II subgroup tumors. CpG hypomethylation of DDR genes TP73 and PRPF19 correlated with worse patient survival in particular in MGMT promoter unmethylated tumors. TERT promoter mutation is most frequent in RTK I and II subtypes and associated with worse survival. Primary glioma cells show methylation patterns that resemble RTK I and II glioblastoma and long term established glioma cell lines do not match with glioblastoma subtypes. Silencing of selected resistance genes PRPF19 and TERT increase sensitivity to temozolomide in vitro.ConclusionHypomethylation of DDR genes and TERT promoter mutations is associated with worse tumor prognosis, dependent on the methylation cluster and MGMT promoter methylation status in IDH wild-type glioblastoma.
| S-EPMC7666733 | biostudies-literature
Project description:The data contains Illumina 450k/EPIC array methylation files from 18 patients with diffuse IDH wild-type glioma from the Heidelberg Neuro-Oncology center
2020-11-18 | GSE143842 | GEO
Project description:Treatment modalities for patients with low grade glioma (LGG) WHO grade II are controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk adjusted treatments are required to preserve cognitive function and quality of life. We aim at identifying mechanisms and associated molecular markers predicting benefit from radiotherapy (RT) or temozolomide (TMZ) on progression free survival in 120 isocitrate dehydrogenase 1 or 2 (IDHmt) mutant LGG treated in the randomized phase III trial EORTC 22033. IDH mutations, the characteristic hallmark of LGG, are associated with a CpG island methylator phenotype (CIMP). Given the genotoxic treatments in this study we determined the DNA methylome of DNA damage response (DDR) genes and assessed the association with progression free survival (PFS). We identified 62 functional CpGs corresponding to 24 of 410 DDR genes in the multidimensional LGG dataset from The Cancer Genome Atlas. Despite the low-powered study, the simulations suggested that seven CpGs, associated with 4 genes could be predictive for PFS in EORTC 22033. Most interestingly, two of the CpGs correspond to MGMT and consisted of the 2 probes used in the MGMT-STP27 classifier. The extent of methylation was predictive for PFS in the TMZ, but not the RT arm. LGG IDHmt and 1p and 19q codeleted that overlap largely with oligodendroglioma displayed a higher extent of MGMT methylation than the IDHmt non-codeleted tumors based on several independent LGG datasets. This is consistent with a better PFS of codeleted patients in the TMZ arm as compared to the non-codeleted patients, while no difference was observed in the RT-arm.
2018-01-31 | GSE104293 | GEO
Project description:The DNA damage response (DDR) is a cellular process that protects the genetic information against DNA damage and inhibits malignant transformation. Tumor cells are characterized by an aberrant DDR, which is exploited by genotoxic chemotherapy. However, cancer cells are able to develop drug resistance, for example by modulation of the DDR. Although the regulation of the DDR has been extensively studied, not much is known about the role of microRNAs (miRNAs). Here, we describe an approach to specifically identify DDR miRNAs in human primary epithelial cells that also play a role in tumorigenesis and response to cancer therapy in corresponding cancer cells. The miRNA expression profile was determined of 18 non-small cell lung tumors and 16 normal lung samples.
2013-05-31 | E-GEOD-47525 | biostudies-arrayexpress
Project description:The DNA damage response (DDR) is a cellular process that protects the genetic information against DNA damage and inhibits malignant transformation. Tumor cells are characterized by an aberrant DDR, which is exploited by genotoxic chemotherapy. However, cancer cells are able to develop drug resistance, for example by modulation of the DDR. Although the regulation of the DDR has been extensively studied, not much is known about the role of microRNAs (miRNAs). We used an approach to specifically identify DDR miRNAs in human primary epithelial cells that also play a role in tumorigenesis and response to cancer therapy in corresponding cancer cells. The miRNA expression profile was determined in 132 samples: 2 primary epithelial cell types, 1 untreated sample, 4 genotoxic treated samples, 3 timepoints, 4 replicates each and 6 zero timepoints for each cell type
2013-05-31 | E-GEOD-47523 | biostudies-arrayexpress
Project description:The DNA damage response (DDR) is a cellular process that protects the genetic information against DNA damage and inhibits malignant transformation. Tumor cells are characterized by an aberrant DDR, which is exploited by genotoxic chemotherapy. However, cancer cells are able to develop drug resistance, for example by modulation of the DDR. Although the regulation of the DDR has been extensively studied, not much is known about the role of microRNAs (miRNAs). Here, we describe an approach to specifically identify DDR miRNAs in human primary epithelial cells that also play a role in tumorigenesis and response to cancer therapy in corresponding cancer cells. The miRNA expression profile was determined of 12 lung cancer cell lines.
2013-05-31 | E-GEOD-47524 | biostudies-arrayexpress