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Aberrant methylation of cell-free circulating DNA in plasma predicts poor outcome in diffuse large B cell lymphoma

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ABSTRACT

Background: The prognostic value of aberrant DNA methylation of cell-free circulating DNA in plasma has not previously been evaluated in diffuse large B cell lymphoma (DLBCL). The aim of this study was to investigate if aberrant promoter DNA methylation can be detected in plasma from DLBCL patients and to evaluate this as a prognostic marker. Furthermore, we wanted to follow possible changes in methylation levels during treatment. Seventy-four patients were enrolled in the study, of which 59 received rituximab and CHOP-like chemotherapy. Plasma samples were collected from all patients at the time of diagnosis and from 14 healthy individuals used as controls. In addition, plasma samples were collected during and after treatment for surviving patients. In total, 158 plasma samples were analyzed for DNA methylation in the promoter regions of DAPK (DAPK1), DBC1, MIR34A, and MIR34B/C using pyrosequencing.

Results: Aberrant methylation levels at the time of diagnosis were detected in 19, 16, 8, and 10 % of the DLBCL plasma samples for DAPK1, DBC1, MIR34A, and MIR34B/C, respectively. DAPK1 methylation levels were significantly correlated with DBC1 and MIR34B/C methylation levels (P < 0.001). For the entire cohort, 5-year overall survival (OS) rates were significantly lower in the groups carrying aberrant DAPK1 (P = 0.004) and DBC1 (P = 0.044) methylation, respectively. DAPK1 methylation status were significantly correlated with stage (P = 0.015), as all patients with aberrant DAPK1 methylation were stages III and IV. Multivariate analysis identified DAPK1 as an independent prognostic factor for OS with a hazard ratio of 8.9 (95 % CI 2.7–29.3, P < 0.0007). Patients with DAPK1 methylated cell-free circulating DNA at time of diagnosis, who became long-term survivors, lost the aberrant methylation after treatment initiation. Conversely, patients that maintained or regained aberrant DAPK1 methylation died soon thereafter.

Conclusions: Aberrant promoter methylation of cell-free circulating DNA can be detected in plasma from DLBCL patients and hold promise as an easily accessible marker for evaluating response to treatment and for prognostication. In particular, aberrant DAPK1 methylation in plasma was an independent prognostic marker that may also be used to assess treatment response.

Electronic supplementary material: The online version of this article (doi:10.1186/s13148-016-0261-y) contains supplementary material, which is available to authorized users.

No MeSH data available.


Overall survival of the entire cohort according to methylation status. aDAPK1. bDBC1. cMIR34A. dMIR34B/C
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Fig3: Overall survival of the entire cohort according to methylation status. aDAPK1. bDBC1. cMIR34A. dMIR34B/C

Mentions: When analyzing all patients, the 5-year OS rates were 35.7 and 70.0 % in the DAPK1 methylated group and unmethylated group, respectively. The hazard ratio for death in the methylated group was 3.08 (95 % CI, 1.37 to 6.93; P = 0.004). The 5-year OS rates were 41.7 and 67.8 % in the DBC1 methylated and unmethylated group, respectively. The hazard ratio for death in the methylated group was 2.38 (95 % CI, 1.00 to 5.66; P = 0.044). The 5-year OS rates were 83.3 and 60.9 % in the MIR34A methylated and unmethylated group, respectively. The hazard ratio for death in the methylated group was 0.40 (95 % CI, 0.05 to 2.93; P = 0.348). The 5-year OS rates were 50.0 and 67.9 % in the MIR34B/C methylated and unmethylated group, respectively. The hazard ratio for death in the methylated group was 1.64 (95 % CI, 0.48 to 5.60; P = 0.426) (Fig. 3).Fig. 3


Aberrant methylation of cell-free circulating DNA in plasma predicts poor outcome in diffuse large B cell lymphoma
Overall survival of the entire cohort according to methylation status. aDAPK1. bDBC1. cMIR34A. dMIR34B/C
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC5015248&req=5

Fig3: Overall survival of the entire cohort according to methylation status. aDAPK1. bDBC1. cMIR34A. dMIR34B/C
Mentions: When analyzing all patients, the 5-year OS rates were 35.7 and 70.0 % in the DAPK1 methylated group and unmethylated group, respectively. The hazard ratio for death in the methylated group was 3.08 (95 % CI, 1.37 to 6.93; P = 0.004). The 5-year OS rates were 41.7 and 67.8 % in the DBC1 methylated and unmethylated group, respectively. The hazard ratio for death in the methylated group was 2.38 (95 % CI, 1.00 to 5.66; P = 0.044). The 5-year OS rates were 83.3 and 60.9 % in the MIR34A methylated and unmethylated group, respectively. The hazard ratio for death in the methylated group was 0.40 (95 % CI, 0.05 to 2.93; P = 0.348). The 5-year OS rates were 50.0 and 67.9 % in the MIR34B/C methylated and unmethylated group, respectively. The hazard ratio for death in the methylated group was 1.64 (95 % CI, 0.48 to 5.60; P = 0.426) (Fig. 3).Fig. 3

View Article: PubMed Central - PubMed

ABSTRACT

Background: The prognostic value of aberrant DNA methylation of cell-free circulating DNA in plasma has not previously been evaluated in diffuse large B cell lymphoma (DLBCL). The aim of this study was to investigate if aberrant promoter DNA methylation can be detected in plasma from DLBCL patients and to evaluate this as a prognostic marker. Furthermore, we wanted to follow possible changes in methylation levels during treatment. Seventy-four patients were enrolled in the study, of which 59 received rituximab and CHOP-like chemotherapy. Plasma samples were collected from all patients at the time of diagnosis and from 14 healthy individuals used as controls. In addition, plasma samples were collected during and after treatment for surviving patients. In total, 158 plasma samples were analyzed for DNA methylation in the promoter regions of DAPK (DAPK1), DBC1, MIR34A, and MIR34B/C using pyrosequencing.

Results: Aberrant methylation levels at the time of diagnosis were detected in 19, 16, 8, and 10 % of the DLBCL plasma samples for DAPK1, DBC1, MIR34A, and MIR34B/C, respectively. DAPK1 methylation levels were significantly correlated with DBC1 and MIR34B/C methylation levels (P < 0.001). For the entire cohort, 5-year overall survival (OS) rates were significantly lower in the groups carrying aberrant DAPK1 (P = 0.004) and DBC1 (P = 0.044) methylation, respectively. DAPK1 methylation status were significantly correlated with stage (P = 0.015), as all patients with aberrant DAPK1 methylation were stages III and IV. Multivariate analysis identified DAPK1 as an independent prognostic factor for OS with a hazard ratio of 8.9 (95 % CI 2.7–29.3, P < 0.0007). Patients with DAPK1 methylated cell-free circulating DNA at time of diagnosis, who became long-term survivors, lost the aberrant methylation after treatment initiation. Conversely, patients that maintained or regained aberrant DAPK1 methylation died soon thereafter.

Conclusions: Aberrant promoter methylation of cell-free circulating DNA can be detected in plasma from DLBCL patients and hold promise as an easily accessible marker for evaluating response to treatment and for prognostication. In particular, aberrant DAPK1 methylation in plasma was an independent prognostic marker that may also be used to assess treatment response.

Electronic supplementary material: The online version of this article (doi:10.1186/s13148-016-0261-y) contains supplementary material, which is available to authorized users.

No MeSH data available.