Validation of ZAP-70 methylation and its relative significance in predicting outcome in chronic lymphocytic leukemia

ZAP-70 methylation 223 nucleotides downstream of transcription start (CpG+223) predicts outcome in chronic lymphocytic leukemia (CLL), but its impact relative to CD38 and ZAP-70 expression or immunoglobulin heavy chain variable region (IGHV) status is uncertain. Additionally, standardizing ZAP-70 ex...

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Bibliographic Details
Published in:Blood 2014-07, Vol.124 (1), p.42-48
Main Authors: Claus, Rainer, Lucas, David M., Ruppert, Amy S., Williams, Katie E., Weng, Daniel, Patterson, Kara, Zucknick, Manuela, Oakes, Christopher C., Rassenti, Laura Z., Greaves, Andrew W., Geyer, Susan, Wierda, William G., Brown, Jennifer R., Gribben, John G., Barrientos, Jacqueline C., Rai, Kanti R., Kay, Neil E., Kipps, Thomas J., Shields, Peter, Zhao, Weiqiang, Grever, Michael R., Plass, Christoph, Byrd, John C.
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Biomarkers, Tumor - analysis
Clinical Trials and Observations
DNA Methylation - genetics
Female
Humans
Immunoglobulin Variable Region - genetics
Kaplan-Meier Estimate
Leukemia, Lymphocytic, Chronic, B-Cell - genetics
Leukemia, Lymphocytic, Chronic, B-Cell - metabolism
Leukemia, Lymphocytic, Chronic, B-Cell - mortality
Male
Middle Aged
Prognosis
Proportional Hazards Models
Reverse Transcriptase Polymerase Chain Reaction
ZAP-70 Protein-Tyrosine Kinase - genetics
ZAP-70 Protein-Tyrosine Kinase - metabolism
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Summary:ZAP-70 methylation 223 nucleotides downstream of transcription start (CpG+223) predicts outcome in chronic lymphocytic leukemia (CLL), but its impact relative to CD38 and ZAP-70 expression or immunoglobulin heavy chain variable region (IGHV) status is uncertain. Additionally, standardizing ZAP-70 expression analysis has been unsuccessful. CpG+223 methylation was quantitatively determined in 295 untreated CLL cases using MassARRAY. Impact on clinical outcome vs CD38 and ZAP-70 expression and IGHV status was evaluated. Cases with low methylation ( 0.90). Thus, ZAP-70 CpG+223 methylation represents a superior biomarker for TT and OS that can be feasibly measured, supporting its use in risk-stratifying CLL. •Methylation analysis at ZAP-70 CpG+223 in CLL provides superior prognostic information vs IGHV status or CD38 or ZAP-70 expression.•A pyrosequencing method for the feasible assessment of CpG+223 methylation in CLL samples is provided.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2014-02-555722