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

Dianna Hussmann; Anna Starnawska; Louise Kristensen; Iben Daugaard; Astrid Thomsen; Tina Kjeldsen; Christine Søholm Hansen; Jonas Bybjerg-Grauholm; Karina Dalsgaard Johansen; Maja Ludvigsen; Thomas Kristensen; Thomas Stauffer Larsen; Michael Boe Møller; Charlotte Guldborg Nyvold; Lise Lotte Hansen; Tomasz K Wojdacz

doi:10.3324/haematol.2021.278477

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

Dianna Hussmann, Anna Starnawska, Louise Kristensen, Iben Daugaard, Astrid Thomsen, Tina Kjeldsen, Christine Søholm Hansen, Jonas Bybjerg-Grauholm, Karina Dalsgaard Johansen, Maja Ludvigsen, Thomas Kristensen, Thomas Stauffer Larsen, Michael Boe Møller, Charlotte Guldborg Nyvold, Lise Lotte Hansen, Tomasz K Wojdacz^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

6 Citations (Scopus)

Abstract

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 language	English
Journal	Haematologica
Volume	107
Issue	4
Pages (from-to)	877-886
Number of pages	10
ISSN	0390-6078
DOIs	https://doi.org/10.3324/haematol.2021.278477
Publication status	Published - Apr 2022

Keywords

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

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Hussmann, D., Starnawska, A., Kristensen, L., Daugaard, I., Thomsen, A., Kjeldsen, T., Hansen, C. S., Bybjerg-Grauholm, J., Dalsgaard Johansen, K., Ludvigsen, M., Kristensen, T., Larsen, T. S., Møller, M. B., Nyvold, C. G., Hansen, L. L., & Wojdacz, T. K. (2022). IGHV-associated methylation signatures more accurately predict clinical outcomes of chronic lymphocytic leukemia patients than IGHV mutation load. Haematologica, 107(4), 877-886. https://doi.org/10.3324/haematol.2021.278477

@article{fb8eb3049b044160b9306f27f47e59cc,

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

abstract = "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.",

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

author = "Dianna Hussmann and Anna Starnawska and Louise Kristensen and Iben Daugaard and Astrid Thomsen and Tina Kjeldsen and Hansen, {Christine S{\o}holm} and Jonas Bybjerg-Grauholm and {Dalsgaard Johansen}, Karina and Maja Ludvigsen and Thomas Kristensen and Larsen, {Thomas Stauffer} and M{\o}ller, {Michael Boe} and Nyvold, {Charlotte Guldborg} and Hansen, {Lise Lotte} and Wojdacz, {Tomasz K}",

year = "2022",

month = apr,

doi = "10.3324/haematol.2021.278477",

language = "English",

volume = "107",

pages = "877--886",

journal = "Haematologica",

issn = "0390-6078",

publisher = "Ferrata Storti Foundation",

number = "4",

}

Hussmann, D, Starnawska, A, Kristensen, L, Daugaard, I, Thomsen, A, Kjeldsen, T, Hansen, CS, Bybjerg-Grauholm, J, Dalsgaard Johansen, K, Ludvigsen, M, Kristensen, T, Larsen, TS, Møller, MB, Nyvold, CG, Hansen, LL & Wojdacz, TK 2022, 'IGHV-associated methylation signatures more accurately predict clinical outcomes of chronic lymphocytic leukemia patients than IGHV mutation load', Haematologica, vol. 107, no. 4, pp. 877-886. https://doi.org/10.3324/haematol.2021.278477

IGHV-associated methylation signatures more accurately predict clinical outcomes of chronic lymphocytic leukemia patients than IGHV mutation load. / Hussmann, Dianna; Starnawska, Anna; Kristensen, Louise et al.
In: Haematologica, Vol. 107, No. 4, 04.2022, p. 877-886.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - IGHV-associated methylation signatures more accurately predict clinical outcomes of chronic lymphocytic leukemia patients than IGHV mutation load

AU - Hussmann, Dianna

AU - Starnawska, Anna

AU - Kristensen, Louise

AU - Daugaard, Iben

AU - Thomsen, Astrid

AU - Kjeldsen, Tina

AU - Hansen, Christine Søholm

AU - Bybjerg-Grauholm, Jonas

AU - Dalsgaard Johansen, Karina

AU - Ludvigsen, Maja

AU - Kristensen, Thomas

AU - Larsen, Thomas Stauffer

AU - Møller, Michael Boe

AU - Nyvold, Charlotte Guldborg

AU - Hansen, Lise Lotte

AU - Wojdacz, Tomasz K

PY - 2022/4

Y1 - 2022/4

N2 - 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.

AB - 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.

KW - Humans

KW - Immunoglobulin Heavy Chains/genetics

KW - Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis

KW - Methylation

KW - Mutation

KW - Prognosis

UR - http://www.scopus.com/inward/record.url?scp=85123163113&partnerID=8YFLogxK

U2 - 10.3324/haematol.2021.278477

DO - 10.3324/haematol.2021.278477

M3 - Journal article

C2 - 34092057

SN - 0390-6078

VL - 107

SP - 877

EP - 886

JO - Haematologica

JF - Haematologica

IS - 4

ER -

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

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Keywords

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