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Validation of DNA methylation biomarkers for diagnosis of acute lymphoblastic leukemia.

Publication ,  Journal Article
Chatterton, Z; Burke, D; Emslie, KR; Craig, JM; Ng, J; Ashley, DM; Mechinaud, F; Saffery, R; Wong, NC
Published in: Clin Chem
July 2014

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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Published In

Clin Chem

DOI

EISSN

1530-8561

Publication Date

July 2014

Volume

60

Issue

7

Start / End Page

995 / 1003

Location

England

Related Subject Headings

  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Reference Standards
  • Promoter Regions, Genetic
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Neoplasm, Residual
  • Male
  • Limit of Detection
  • Infant
  • Humans
  • Homeodomain Proteins
 

Citation

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MLA
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Chatterton, Z., Burke, D., Emslie, K. R., Craig, J. M., Ng, J., Ashley, D. M., … Wong, N. C. (2014). Validation of DNA methylation biomarkers for diagnosis of acute lymphoblastic leukemia. Clin Chem, 60(7), 995–1003. https://doi.org/10.1373/clinchem.2013.219956
Chatterton, Zac, Daniel Burke, Kerry R. Emslie, Jeffery M. Craig, Jane Ng, David M. Ashley, Francoise Mechinaud, Richard Saffery, and Nicholas C. Wong. “Validation of DNA methylation biomarkers for diagnosis of acute lymphoblastic leukemia.Clin Chem 60, no. 7 (July 2014): 995–1003. https://doi.org/10.1373/clinchem.2013.219956.
Chatterton Z, Burke D, Emslie KR, Craig JM, Ng J, Ashley DM, et al. Validation of DNA methylation biomarkers for diagnosis of acute lymphoblastic leukemia. Clin Chem. 2014 Jul;60(7):995–1003.
Chatterton, Zac, et al. “Validation of DNA methylation biomarkers for diagnosis of acute lymphoblastic leukemia.Clin Chem, vol. 60, no. 7, July 2014, pp. 995–1003. Pubmed, doi:10.1373/clinchem.2013.219956.
Chatterton Z, Burke D, Emslie KR, Craig JM, Ng J, Ashley DM, Mechinaud F, Saffery R, Wong NC. Validation of DNA methylation biomarkers for diagnosis of acute lymphoblastic leukemia. Clin Chem. 2014 Jul;60(7):995–1003.

Published In

Clin Chem

DOI

EISSN

1530-8561

Publication Date

July 2014

Volume

60

Issue

7

Start / End Page

995 / 1003

Location

England

Related Subject Headings

  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Reference Standards
  • Promoter Regions, Genetic
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Neoplasm, Residual
  • Male
  • Limit of Detection
  • Infant
  • Humans
  • Homeodomain Proteins