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 Zhao; Michael R. Grever; Christoph Plass; John C. Byrd

doi:10.1182/blood-2014-02-555722

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 journal › Article › peer-review

47 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 language	English (US)
Pages (from-to)	42-48
Number of pages	7
Journal	Blood
Volume	124
Issue number	1
DOIs	https://doi.org/10.1182/blood-2014-02-555722
State	Published - Jul 3 2014

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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10.1182/blood-2014-02-555722

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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

Claus, R, Lucas, DM, Ruppert, AS, Williams, KE, Weng, D, Patterson, K, Zucknick, M, Oakes, CC, Rassenti, LZ, Greaves, AW, Geyer, S, Wierda, WG, Brown, JR, Gribben, JG, Barrientos, JC, Rai, KR, Kay, NE, Kipps, TJ, Shields, P, Zhao, W, Grever, MR, Plass, C & Byrd, JC 2014, 'Validation of ZAP-70 methylation and its relative significance in predicting outcome in chronic lymphocytic leukemia', Blood, vol. 124, no. 1, pp. 42-48. https://doi.org/10.1182/blood-2014-02-555722

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

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.",

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

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doi = "10.1182/blood-2014-02-555722",

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T1 - Validation of ZAP-70 methylation and its relative significance in predicting outcome in chronic lymphocytic leukemia

AU - Claus, Rainer

AU - Lucas, David M.

AU - Ruppert, Amy S.

AU - Williams, Katie E.

AU - Weng, Daniel

AU - Patterson, Kara

AU - Zucknick, Manuela

AU - Oakes, Christopher C.

AU - Rassenti, Laura Z.

AU - Greaves, Andrew W.

AU - Geyer, Susan

AU - Wierda, William G.

AU - Brown, Jennifer R.

AU - Gribben, John G.

AU - Barrientos, Jacqueline C.

AU - Rai, Kanti R.

AU - Kay, Neil E.

AU - Kipps, Thomas J.

AU - Shields, Peter

AU - Zhao, Weiqiang

AU - Grever, Michael R.

AU - Plass, Christoph

AU - Byrd, John C.

PY - 2014/7/3

Y1 - 2014/7/3

N2 - 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.

AB - 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.

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

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