Global hypomethylation is an independent prognostic factor in diffuse large B cell lymphoma
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Global hypomethylation is an independent prognostic factor in diffuse large B cell lymphoma. / Wedge, Eileen; Hansen, Jakob Werner; Garde, Christian; Asmar, Fazila; Tholstrup, Dorte; Kristensen, Søren Sommer; Munch-Petersen, Helga D; Ralfkiaer, Elisabeth; Brown, Peter; Grønbaek, Kirsten; Kristensen, Lasse Sommer.
In: American Journal of Hematology, Vol. 92, No. 7, 07.2017, p. 689-694.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Global hypomethylation is an independent prognostic factor in diffuse large B cell lymphoma
AU - Wedge, Eileen
AU - Hansen, Jakob Werner
AU - Garde, Christian
AU - Asmar, Fazila
AU - Tholstrup, Dorte
AU - Kristensen, Søren Sommer
AU - Munch-Petersen, Helga D
AU - Ralfkiaer, Elisabeth
AU - Brown, Peter
AU - Grønbaek, Kirsten
AU - Kristensen, Lasse Sommer
N1 - © 2017 Wiley Periodicals, Inc.
PY - 2017/7
Y1 - 2017/7
N2 - Global hypomethylation has been linked to disease progression in several cancers, but has not been reported for Diffuse Large B Cell Lymphoma (DLBCL). This study aimed to assess global methylation in DLBCL and describe its prognostic value. Mean LINE1 methylation, a validated surrogate measure for global methylation, was measured in DNA from 67 tumor biopsies. Additionally, cell-free circulating DNA (cfDNA) in plasma samples from 74 patients was tested to assess the feasibility of global hypomethylation as a biomarker in liquid biopsies. LINE1 methylation was assessed using a commercially available kit, based on pyrosequencing of PCR amplified bisulfite-treated DNA. Global hypomethylation was detected in a subset of cases and was associated with poor overall survival in both tumor biopsies (P = .001) and cfDNA (P = .009). It was the strongest risk factor in multivariate analysis in both biopsies (HR: 10.65, CI: 2.03-55.81, P = .005) and cfDNA (HR: 11.87, CI: 2.80-50.20, P = .001), outperforming conventional clinical risk factors. Finally, hierarchical cluster analyses were performed for the cfDNA samples using previously published gene-specific methylation data. This analysis shows that global hypomethylation co-occurs with other epigenetic abnormalities, including DAPK1 promoter hypermethylation. In conclusion, we have shown that global hypomethylation is strongly associated with poor survival in DLBCL both when present in tumor biopsy DNA and when detected in plasma cfDNA, and has potential for clinical application as a prognostic biomarker.
AB - Global hypomethylation has been linked to disease progression in several cancers, but has not been reported for Diffuse Large B Cell Lymphoma (DLBCL). This study aimed to assess global methylation in DLBCL and describe its prognostic value. Mean LINE1 methylation, a validated surrogate measure for global methylation, was measured in DNA from 67 tumor biopsies. Additionally, cell-free circulating DNA (cfDNA) in plasma samples from 74 patients was tested to assess the feasibility of global hypomethylation as a biomarker in liquid biopsies. LINE1 methylation was assessed using a commercially available kit, based on pyrosequencing of PCR amplified bisulfite-treated DNA. Global hypomethylation was detected in a subset of cases and was associated with poor overall survival in both tumor biopsies (P = .001) and cfDNA (P = .009). It was the strongest risk factor in multivariate analysis in both biopsies (HR: 10.65, CI: 2.03-55.81, P = .005) and cfDNA (HR: 11.87, CI: 2.80-50.20, P = .001), outperforming conventional clinical risk factors. Finally, hierarchical cluster analyses were performed for the cfDNA samples using previously published gene-specific methylation data. This analysis shows that global hypomethylation co-occurs with other epigenetic abnormalities, including DAPK1 promoter hypermethylation. In conclusion, we have shown that global hypomethylation is strongly associated with poor survival in DLBCL both when present in tumor biopsy DNA and when detected in plasma cfDNA, and has potential for clinical application as a prognostic biomarker.
KW - Adult
KW - Aged
KW - Biomarkers, Tumor
KW - Biopsy
KW - Cluster Analysis
KW - DNA Methylation
KW - DNA, Neoplasm
KW - Death-Associated Protein Kinases
KW - Epigenesis, Genetic
KW - Female
KW - Humans
KW - Kaplan-Meier Estimate
KW - Long Interspersed Nucleotide Elements
KW - Lymphoma, Large B-Cell, Diffuse
KW - Male
KW - Middle Aged
KW - Neoplasm Staging
KW - Prognosis
KW - Promoter Regions, Genetic
KW - Proportional Hazards Models
KW - Retrospective Studies
KW - Journal Article
U2 - 10.1002/ajh.24751
DO - 10.1002/ajh.24751
M3 - Journal article
C2 - 28378885
VL - 92
SP - 689
EP - 694
JO - American Journal of Hematology
JF - American Journal of Hematology
SN - 0361-8609
IS - 7
ER -
ID: 183005893