Global hypomethylation is an independent prognostic factor in diffuse large B cell lymphoma

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

SN - 0361-8609

VL - 92

SP - 689

EP - 694

JO - American Journal of Hematology

JF - American Journal of Hematology

IS - 7

ER -