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Title: Validation of DNA methylation biomarkers for diagnosis of acute lymphoblastic leukemia.
Austin Authors: Chatterton, Zac;Burke, Daniel;Emslie, Kerry R;Craig, Jeffery M;Ng, Jane;Ashley, David M;Mechinaud, Francoise;Saffery, Richard;Wong, Nicholas C
Affiliation: Children's Cancer Centre, Royal Children's Hospital, Victoria, Australia
current address: Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY;
National Measurement Institute, Sydney, Australia
Developmental Epigenetics, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Australia
Andrew Love Cancer Centre, Deakin University, Victoria, Australia
current address: Ludwig Institute of Cancer Research, Olivia Newton-John Cancer and Wellness Centre, Austin Hospital, Heidelberg, Victoria, Australia
Cancer and Disease Epigenetics and Department of Paediatrics, University of Melbourne, Melbourne, Australia
Issue Date: 14-May-2014
Publication information: Clinical Chemistry 2014; 60(7): 995-1003
Abstract: DNA methylation biomarkers capable of diagnosis and subtyping have been found for many cancers. Fifteen such markers have previously been identified for pediatric acute lymphoblastic leukemia (ALL). Validation of these markers is necessary to assess their clinical utility for molecular diagnostics. Substantial efficiencies could be achieved with these DNA methylation markers for disease tracking with potential to replace patient-specific genetic testing.We evaluated DNA methylation of promoter regions of TLX3 (T-cell leukemia homeobox) and FOXE3 (forkhead box E3) in bone marrow biopsies from 197 patients classified as leukemic (n = 95) or clear of the disease (n = 102) by MALDI-TOF. Using a single nucleotide extension assay (methylSABER), we tested 10 bone marrow biopsies collected throughout the course of patient chemotherapy. Using reference materials, diagnostic thresholds and limits of detection were characterized for both methods.Reliable detection of DNA methylation of TLX3 and FOXE3 segregated ALL from those clear of disease with minimal false-negative and false-positive results. The limit of detection with MALDI-TOF was 1000-5000 copies of methylated allele. For methylSABER, the limit of detection was 10 copies of methylated TLX3, which enabled monitoring of minimal residual disease in ALL patients.Mass spectrometry procedures can be used to regionally multiplex and detect rare DNA methylation events, establish DNA methylation loci as clinically applicable biomarkers for disease diagnosis, and track pediatric ALL.
Gov't Doc #: 24829271
DOI: 10.1373/clinchem.2013.219956
Journal: Clinical chemistry
Type: Journal Article
Subjects: Adolescent
Case-Control Studies
Child, Preschool
DNA Methylation
False Negative Reactions
False Positive Reactions
Forkhead Transcription Factors.genetics
Gene Dosage
Genetic Markers
Homeodomain Proteins.genetics
Limit of Detection
Neoplasm, Residual.diagnosis.genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma.diagnosis.drug therapy.genetics
Promoter Regions, Genetic
Reference Standards
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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