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000119761 1001_ $$0P:(DE-HGF)0$$aClaus, Rainer$$b0$$eFirst author
000119761 245__ $$aValidation of ZAP-70 methylation and its relative significance in predicting outcome in chronic lymphocytic leukemia.
000119761 260__ $$aStanford, Calif.$$bHighWire Press$$c2014
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000119761 520__ $$aZAP-70 methylation 223 nucleotides downstream of transcription start (CpG+223) predicts outcome in chronic lymphocytic leukemia (CLL), but its impact relative to CD38 and ZAP-70 expression or immunoglobulin heavy chain variable region (IGHV) status is uncertain. Additionally, standardizing ZAP-70 expression analysis has been unsuccessful. CpG+223 methylation was quantitatively determined in 295 untreated CLL cases using MassARRAY. Impact on clinical outcome vs CD38 and ZAP-70 expression and IGHV status was evaluated. Cases with low methylation (<20%) had significantly shortened time to first treatment (TT) and overall survival (OS) (P < .0001). For TT, low methylation defined a large subset of ZAP-70 protein-negative cases with significantly shortened TT (median, 8.0 vs 3.9 years for high vs low methylation; hazard ratio [HR] = 0.43; 95% confidence interval [CI], 0.25-0.74). Conversely, 16 ZAP-70 protein-positive cases with high methylation had poor outcome (median, 1.1 vs 2.3 years for high vs low methylation; HR = 1.62; 95% CI, 0.87-3.03). For OS, ZAP-70 methylation was the strongest risk factor; CD38 and ZAP-70 expression or IGHV status did not significantly improve OS prediction. A pyrosequencing assay was established that reproduced the MassARRAY data (κ coefficient > 0.90). Thus, ZAP-70 CpG+223 methylation represents a superior biomarker for TT and OS that can be feasibly measured, supporting its use in risk-stratifying CLL.
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000119761 650_7 $$2NLM Chemicals$$aBiomarkers, Tumor
000119761 650_7 $$2NLM Chemicals$$aImmunoglobulin Variable Region
000119761 650_7 $$0EC 2.7.10.2$$2NLM Chemicals$$aZAP-70 Protein-Tyrosine Kinase
000119761 650_7 $$0EC 2.7.10.2$$2NLM Chemicals$$aZAP70 protein, human
000119761 7001_ $$aLucas, David M$$b1
000119761 7001_ $$aRuppert, Amy S$$b2
000119761 7001_ $$aWilliams, Katie E$$b3
000119761 7001_ $$aWeng, Daniel$$b4
000119761 7001_ $$aPatterson, Kara$$b5
000119761 7001_ $$0P:(DE-HGF)0$$aZucknick, Manuela$$b6
000119761 7001_ $$0P:(DE-HGF)0$$aOakes, Christopher C$$b7
000119761 7001_ $$aRassenti, Laura Z$$b8
000119761 7001_ $$aGreaves, Andrew W$$b9
000119761 7001_ $$aGeyer, Susan$$b10
000119761 7001_ $$aWierda, William G$$b11
000119761 7001_ $$aBrown, Jennifer R$$b12
000119761 7001_ $$aGribben, John G$$b13
000119761 7001_ $$aBarrientos, Jacqueline C$$b14
000119761 7001_ $$aRai, Kanti R$$b15
000119761 7001_ $$aKay, Neil E$$b16
000119761 7001_ $$aKipps, Thomas J$$b17
000119761 7001_ $$aShields, Peter$$b18
000119761 7001_ $$aZhao, Weiqiang$$b19
000119761 7001_ $$aGrever, Michael R$$b20
000119761 7001_ $$0P:(DE-He78)4301875630bc997edf491c694ae1f8a9$$aPlass, Christoph$$b21$$udkfz
000119761 7001_ $$aByrd, John C$$b22
000119761 773__ $$0PERI:(DE-600)1468538-3$$a10.1182/blood-2014-02-555722$$gVol. 124, no. 1, p. 42 - 48$$n1$$p42 - 48$$tBlood$$v124$$x1528-0020$$y2014
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