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DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome - including in elderly patients

ABSTRACT: GBM samples (FFPE tissue) obtained from patients treated in clinical trials according to pre-specified clinical criteria (EORTC 26981/NCIC CE.3 pooled with the Lausanne Pilot trial, n=156).

ORGANISM(S): Homo sapiens

PROVIDER: GSE195640 | GEO | 2022/03/31

REPOSITORIES: GEO

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DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome - including in elderly patients [GBMnordic]

Project description:GBM samples (FFPE tissue) obtained from patients treated in clinical trials according to pre-specified clinical criteria (Nordic, n=116).

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DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome - including in elderly patients

Project description:DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome - including in elderly patients

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DNA methylation-based age acceleration observed in IDH wild-type glioblastoma is associated with better outcome - including in elderly patients [GBMnordic]

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Observed Physical Function Is Associated With Better Cognition Among Elderly Adults: The Adventist Health Study-2.

Project description:Lifestyle factors may individually protect against the development of mild cognitive impairment. We investigate the relationships between both self-reported physical activity and measured physical function with cognition in a population of elderly adults, more than half of whom follow vegetarian dietary patterns. Otherwise healthy adults (n = 127, mean age 74.9 ± 7.9 years, 61.3% current vegetarians) were assessed using a comprehensive neuropsychological battery. A principal components analysis derived processing speed, executive function, and memory/language factors. Participants reported current levels of vigorous physical activity on questionnaires, and physical function and mobility were measured with the Physical Performance Test (PPT) and Timed Up and Go (TUG) Test. Generalized linear models estimated β coefficients for cross-sectional associations between cognitive factors and indicators of physical abilities and self-reported physical activity. Better physical function indicated by PPT was associated with higher scores on the processing speed factor (β = 0.21 SDs for each 4.4-point increase in PPT score; p = 0.02). Faster TUG times were also associated with higher processing speed factor scores (β = 0.21 SDs increase for each 2.8 second less TUG time; p = 0.02). Self-reported levels of vigorous physical activity were not associated with any area of cognitive function; the association between PPT, TUG and processing speed was independent of physical activity. Associations between PPT and TUG and processing speed were stronger among participants who followed vegetarian dietary patterns. Better physical function may have an effect on cognition in a context of healthy lifestyles.

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Evolving Treatment Strategies for Elderly Leukemia Patients with IDH Mutations.

Project description:Acute myeloid leukemia (AML) is a debilitating and life-threatening condition, especially for elderly patients who account for over 50% of diagnoses. For over four decades, standard induction therapy with intensive cytotoxic chemotherapy for AML had remained unchanged. However, for most patients, standard therapy continues to have its shortcomings, especially for elderly patients who may not be able to tolerate the complications from intensive cytotoxic chemotherapy. New research into the development of targeted and alternative therapies has led to a new era in AML therapy. For the nearly 20% of diagnoses harboring a mutation in isocitrate dehydrogenase 1 or 2 (IDH1/2), potential treatment options have undergone a paradigm shift away from intensive cytotoxic chemotherapy and towards targeted therapy alone or in combination with lower intensity chemotherapy. The first FDA approved IDH2 inhibitor was enasidenib in 2017. In addition, IDH1 inhibitors are in ongoing clinical studies, and the oral BCL-2 inhibitor venetoclax shows preliminary efficacy in this subset of patients. These new tools aim to improve outcomes and change the treatment paradigm for elderly patients with IDH mutant AML. However, the challenge of how to best incorporate these agents into standard practice remains.

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The methylome of DDR genes and benefit from RT or TMZ in IDH mutant low grade glioma treated in EORTC 22033

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

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IDH-mutated astrocytomas with 19q-loss constitute a subgroup that confers better prognosis.

Project description:IDH-mutant gliomas are classified into astrocytic or oligodendroglial tumors by 1p/19q status in the WHO 2016 classification, with the latter presenting with characteristic morphology and better prognosis in general. However, the morphological and genetic features within each category are varied, and there might be distinguishable subtypes. We analyzed 170 WHO grade II-IV gliomas resected in our institution. 1p/19q status was analyzed by microsatellite analysis, and genetic mutations were analyzed by next-generation sequencing and Sanger sequencing. For validation, the Brain Lower Grade Glioma dataset of The Cancer Genome Atlas was analyzed. Of the 42 grade III IDH-mutated gliomas, 12 were 1p-intact/19q-intact (anaplastic astrocytomas [AA]), 7 were 1p-intact/19q-loss (AA), and 23 showed 1p/19q-codeletion (anaplastic oligodendrogliomas). Of the 88 IDH-wild type glioblastomas (GBMs), 14 showed 1p-intact/19q-loss status. All of the seven 1p-intact/19q-loss AAs harbored TP53 mutation, but no TERT promotor mutation. All 19q-loss AAs had regions presenting oligodendroglioma-like morphology, and were associated with significantly longer overall survival compared to 19q-intact AAs (P = .001). This tendency was observed in The Cancer Genome Atlas Lower Grade Glioma dataset. In contrast, there was no difference in overall survival between the 19q-loss GBM and 19q-intact GBM (P = .4). In a case of 19q-loss AA, both oligodendroglial morphology and 19q-loss disappeared after recurrence, possibly indicating correlation between 19q-loss and oligodendroglial morphology. We showed that there was a subgroup, although small, of IDH-mutated astrocytomas harboring 19q-loss that present oligodendroglial morphology, and also were associated with significantly better prognosis compared to other 19q-intact astrocytomas.

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Project description:The goal of the study was to identify a gene expression signature capable of predicting a pathological complete response following neoadjuvant anthracycline-based chemotherapy of breast cancer. The samples were taken from the FEC arm (5-fluorouracil, epirubicin, cyclophosphamide) of the EORTC 10994 trial. EORTC 10994 is a phase III clinical trial comparing FEC with ET (epirubicin, docetaxel) in patients with large operable, locally advanced or inflammatory breast cancer (www.eortc.be). Frozen biopsies were taken at randomisation. RNA was extracted from 100um thickness of 14G core needle biopsies. Adjacent sections were tested by H&E to confirm >20% tumour cell content. 200 ng total RNA per chip was amplified using the Affymetrix small sample protocol (IVT then Enzo). 102 tumours were tested on Affymetrix X3P chips. Single biopsies were tested per tumour. The CEL files were quantile normalised using rma. The clinical response measure was pathological complete response (pCR, disappearance of the tumour after chemotherapy with at most scattered invasive cells detected by histology). 102 tumors

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