Hypermethylation of DAPK1 is an independent prognostic factor predicting survival in diffuse large B-cell lymphoma
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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
Lasse Sommer Kristensen, e-mail: firstname.lastname@example.org
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
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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