Oncotarget

Research Papers:

Hypermethylation of DAPK1 is an independent prognostic factor predicting survival in diffuse large B-cell lymphoma

Lasse Sommer Kristensen _, Fazila Asmar, Konstantinos Dimopoulos, Mette Kathrine Nygaard, Derya Aslan, Jakob Werner Hansen, Elisabeth Ralfkiaer and Kirsten Grønbæk

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Oncotarget. 2014; 5:9798-9810. https://doi.org/10.18632/oncotarget.2394

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Abstract

Lasse Sommer Kristensen1, Fazila Asmar1, Konstantinos Dimopoulos1, Mette Kathrine Nygaard2, Derya Aslan1, Jakob Werner Hansen1, Elisabeth Ralfkiaer3, Kirsten Grønbæk1

1Department of Haematology, Rigshospitalet, Blegdamsvej 9, 2100-DK, Copenhagen, Denmark

2Department of Haematology, Aalborg University Hospital, Mølleparkvej 4, 9000-DK, Aalborg, Denmark

3Department of Pathology, Rigshospitalet, Copenhagen, Denmark

Correspondence to:

Lasse Sommer Kristensen, e-mail: lasse.sommer.kristensen@regionh.dk

Keywords: Diffuse Large B-Cell Lymphoma, Rituximab, prognostic markers, allele-specific DNA methylation, DAPK, DAPK1, mutations, TP53

Received: August 20, 2014     Accepted: August 21, 2014     Published: November 12, 2014

ABSTRACT

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin’s lymphoma. Improvements in overall survival have been observed with the introduction of rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), however, prognostic markers are still needed. Methylation of the death associated protein kinase (DAPK or DAPK1) gene and TP53 mutations are likely to have prognostic value in DLBCL. We have assessed TP53 mutations and allelic DAPK1 methylation patterns in a cohort of 119 DLBCL patients uniformly treated with R-CHOP-like regimens. We found that DAPK1 promoter methylation was associated with shorter overall survival (p=0.017) and disease-specific survival (p=0.023). In multivariate analyses DAPK1 methylation remained as an independent prognostic factor predicting disease-specific survival (p=0.038). When only considering individuals heterozygous for the rs13300553 SNP monoallelic methylation of the A-allele was associated with shorter overall- and disease-specific survival (p<0.001). Patients carrying both DAPK1 methylation and a TP53 mutation had an inferior survival compared to patients carrying only one of these molecular alterations, however, this was borderline statistically significant. Allele-specific DAPK1 methylation patterns were also studied in a cohort of 67 multiple myeloma patients, and all of the methylated multiple myeloma samples heterozygous for the rs13300553 SNP were methylated on both alleles.


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