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

TY - JOUR

T1 - Hypermethylation of DAPK1 is an independent prognostic factor predicting survival in diffuse large B-cell lymphoma

AU - Kristensen, Lasse Sommer

AU - Asmar, Fazila

AU - Dimopoulos, Konstantinos

AU - Nygaard, Mette Kathrine

AU - Aslan, Derya

AU - Hansen, Jakob Werner

AU - Ralfkiaer, Elisabeth

AU - Grønbæk, Kirsten

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Alleles

KW - Antibodies, Monoclonal, Murine-Derived

KW - Apoptosis

KW - Cohort Studies

KW - DNA Methylation

KW - Death-Associated Protein Kinases

KW - Female

KW - Genotype

KW - Humans

KW - Lymphoma, Large B-Cell, Diffuse

KW - Male

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Prognosis

KW - Promoter Regions, Genetic

KW - Survival Analysis

KW - Treatment Outcome

KW - Tumor Suppressor Protein p53

KW - Young Adult

U2 - 10.18632/oncotarget.2394

DO - 10.18632/oncotarget.2394

M3 - Journal article

C2 - 25229255

SN - 1949-2553

VL - 5

SP - 9798

EP - 9810

JO - Oncotarget

JF - Oncotarget

IS - 20

ER -