Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

DNA methylation adds prognostic value to minimal residual disease status in pediatric T-cell acute lymphoblastic leukemia

ABSTRACT: Background: Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis, and used for post-induction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL. Procedure: Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the NOPHO-ALL2008 protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype. Results: Two distinct CpG Island Methylator Phenotype (CIMP) groups were identified. Patients with a CIMP negative profile had an inferior response to treatment compared to CIMP positive patients (3-year cumulative incidence of relapse (CIR3y) rate: 29% vs. 6%, p=0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high risk T-ALL patients (MRD â?¥0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs CIMP positive 12%; p=0.02). These groups did not differ regarding ETP-phenotype, but the CIMP negative group was younger (p=0.02) and had higher white blood cell count at diagnosis (p=0.004) compared with the CIMP positive group. Conclusions: CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision-making. Bisulphite converted DNA from T-ALL samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip

ORGANISM(S): Homo sapiens

SUBMITTER: Sofie Degerman

PROVIDER: E-GEOD-69954 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia.

Borssén Magnus M Haider Zahra Z Landfors Mattias M Norén-Nyström Ulrika U Schmiegelow Kjeld K Åsberg Ann E AE Kanerva Jukka J Madsen Hans O HO Marquart Hanne H Heyman Mats M Hultdin Magnus M Roos Göran G Forestier Erik E Degerman Sofie S

Pediatric blood & cancer 20160229 7

<h4>Background</h4>Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype d ...[more]

PMID: 26928953

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Project description:The outcome of patients with anaplastic gliomas varies considerably depending on histology and single molecular markers such as codeletion of 1p/19q and mutations of the isocitrate dehydrogenase (IDH) gene. Whether a molecularly-based classification of anaplastic gliomas based on large scale genomic or epigenomic analyses is superior to histopathology, may reflect distinct biological subtypes, predict outcome and guide therapy decisions had yet to be determined. Epigenome-wide DNA methylation analysis, which also allows for the detection of copy-number aberrations, was performed in a cohort of 228 patients with anaplastic gliomas (astrocytomas, oligoastrocytomas and oligodendrogliomas), including 115 patients of the NOA-04 trial. We further compared these tumors with a group of 55 glioblastomas. Unsupervised clustering demonstrated two main groups based on IDH mutation status: CpG island methylator phenotype (CIMP) positive (77.5%) or negative (22.5%). CIMP+ (IDH mutant) tumors showed a further separation based on copy-number status of chromosome arms 1p and 19q, but not based on histopathology. CIMP- (IDH wild type) tumors on the other hand showed hallmark copy-number alterations of glioblastomas. These tumors clustered together with CIMP- glioblastomas without forming separate groups based on WHO grade. There was no Tumor classification based on CIMP and 1p/19q status was significantly associated with survival allowing a better prediction of outcome than the current histopathological classification alone: Patients with CIMP+ tumors with 1p/19q codeletion had the best prognosis, followed by patients with CIMP+ but intact 1p/19q status. Patients with CIMP- anaplastic gliomas had the worst prognosis. Collectively, our data suggest that anaplastic gliomas can be grouped into three molecular subtypes with clear association to underlying biology and clinical outcome based on IDH and 1p/19q status. The data do not provide a molecular basis for the diagnosis of anaplastic oligoastrocytoma. We investigated a subset of 228 anaplastic gliomas using the Illumina 450k methylation array.

Dataset Information

DNA methylation adds prognostic value to minimal residual disease status in pediatric T-cell acute lymphoblastic leukemia

Publications

DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia.

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