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IGHV-associated methylation signatures more accurately predict clinical outcomes of chronic lymphocytic leukemia patients than IGHV mutation load

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Dianna Hussmann
  • ,
  • Anna Starnawska
  • Louise Kristensen, University of Southern Denmark, Denmark
  • Iben Daugaard
  • Astrid Thomsen, Aarhus University, Denmark
  • Tina Kjeldsen
  • Christine Søholm Hansen, iPSYCH -The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Statens Serum Institut
  • ,
  • Jonas Bybjerg-Grauholm, Statens Serum Institut, iPSYCH -The Lundbeck Foundation Initiative for Integrative Psychiatric Research
  • ,
  • Karina Dalsgaard Johansen, Denmark
  • Maja Ludvigsen
  • Thomas Kristensen, University of Southern Denmark, Denmark
  • Thomas Stauffer Larsen, University of Southern Denmark
  • ,
  • Michael Boe Møller, University of Southern Denmark, Denmark
  • Charlotte Guldborg Nyvold, University of Southern Denmark, Denmark
  • Lise Lotte Hansen
  • Tomasz K Wojdacz

Currently, no molecular biomarker indices 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 procedure to stratify patients based on methylation signatures associated with mutation load of the IGHV gene. This procedure allowed us to predict the time to treatment with a hazard ratio (HR) of 8.34 (95% confidence interval [CI]: 4.54-15.30), as opposed to a HR of 4.35 (95% CI: 2.60-7.28) using IGHV mutation status. Detailed evaluation of 17 cases for which the two classification procedures gave discrepant results showed that these cases were incorrectly classified using IGHV status. Moreover, methylation-based classification stratified patients with different overall survival (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 whom information on time to treatment, overall survival and relapse was available. Despite 450K array methylation data not containing all the biomarkers used in our classification procedure, methylation signatures again stratified patients with significantly better accuracy than did IGHV mutation load regarding all available clinical outcomes. Thus, stratification using IGHV-associated methylation signatures may provide better prognostic power than IGHV mutation status.

Original languageEnglish
Pages (from-to)877-886
Number of pages10
Publication statusPublished - Apr 2022

    Research areas

  • Humans, Immunoglobulin Heavy Chains/genetics, Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis, Methylation, Mutation, Prognosis

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