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

Rainer Claus, David M. Lucas, Amy S. Ruppert, Katie E. Williams, Daniel Weng, Kara Patterson, Manuela Zucknick, Christopher C. Oakes, Laura Z. Rassenti, Andrew W. Greaves, Susan Geyer, William G. Wierda, Jennifer R. Brown, John G. Gribben, Jacqueline C. Barrientos, Kanti R. Rai, Neil E. Kay, Thomas J. Kipps, Peter Shields, Weiqiang ZhaoMichael R. Grever, Christoph Plass, John C. Byrd

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

ZAP-70methylation 223 nucleotides downstreamof transcription start (CpG1223) predicts outcome in chronic lymphocytic leukemia (CLL), but its impact relative toCD38 and ZAP-70 expression or immunoglobulin heavy chain variable region (IGHV) status is uncertain. Additionally, standardizing ZAP-70 expression analysis has been unsuccessful. CpG1 223 methylation was quantitatively determined in 295 untreated CLL cases using MassARRAY. Impact on clinical outcome vs CD38 and ZAP-70 expression and IGHV statuswasevaluated.Cases with low methylation (<20%) had significantly shortened time to first treatment (TT) and overall survival (OS) (P< .0001). For TT, low methylation defined a large subset of ZAP-70 protein-negative cases with significantly shortened TT (median, 8.0 vs 3.9 years for high vs low methylation; hazard ratio [HR] 5 0.43; 95% confidence interval [CI], 0.25-0.74). Conversely, 16 ZAP-70 protein-positive cases with high methylation had poor outcome (median, 1.1 vs 2.3 years for high vs low methylation; HR51.62; 95% CI, 0.87-3.03). For OS, ZAP-70 methylation was the strongest risk factor; CD38 and ZAP-70 expression or IGHV status did not significantly improve OS prediction. A pyrosequencing assay was established that reproduced the MassARRAY data (k coefficient > 0.90). Thus, ZAP-70 CpG1223 methylation represents a superior biomarker for TT and OS that can be feasibly measured, supporting its use in risk-stratifying CLL.

Original languageEnglish (US)
Pages (from-to)42-48
Number of pages7
JournalBlood
Volume124
Issue number1
DOIs
StatePublished - Jul 3 2014

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'Validation of ZAP-70 methylation and its relative significance in predicting outcome in chronic lymphocytic leukemia'. Together they form a unique fingerprint.

  • Cite this

    Claus, R., Lucas, D. M., Ruppert, A. S., Williams, K. E., Weng, D., Patterson, K., Zucknick, M., Oakes, C. C., Rassenti, L. Z., Greaves, A. W., Geyer, S., Wierda, W. G., Brown, J. R., Gribben, J. G., Barrientos, J. C., Rai, K. R., Kay, N. E., Kipps, T. J., Shields, P., ... Byrd, J. C. (2014). Validation of ZAP-70 methylation and its relative significance in predicting outcome in chronic lymphocytic leukemia. Blood, 124(1), 42-48. https://doi.org/10.1182/blood-2014-02-555722