Currently, no molecular biomarker indexes are used in standard care to make treatment decisions at diagnosis of chronic lymphocytic leukemia (CLL). We used Infinium MethylationEPIC array data from diagnostic blood samples of 114 CLL patients, and developed a patient stratification procedure based on methylation signatures associated with mutation load of the IGHV gene. This procedure allowed us to predict the time to treatment (TTT) with HR 8.34 (95% CI, 4.54-15.30), as opposed to HR 4.35 (95% CI, 2.60-7.28) for IGHV mutation status. Detailed evaluation of 17 discrepant cases between the two classification procedures showed that these cases were incorrectly classified using IGHV status. Moreover, methylation-based classification stratified patients with different overall survival (OS) (HR, 1.82; 95% CI, 1.07-3.09), which was not possible using IGHV status. Furthermore, we assessed the performance of the developed classification procedure using published HumanMethylation450 array data for 159 patients for which TTT, OS and relapse were available. Despite that 450K array methylation data did not contain all biomarkers used in our classification procedure, methylation signatures again stratified patients with significantly better accuracy than IGHV mutation load regarding all available clinical outcomes. Thus, stratification using IGHV-associated methylation signatures may provide improved prognostic power than IGHV mutation status.
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