title: Hypermethylation of DAPK1 is an independent prognostic factor predicting survival in diffuse large B-cell lymphoma.
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.
authors.affiliation: Department of Haematology, Rigshospitalet, Blegdamsvej 9, 2100-DK, Copenhagen, Denmark.
authors.forename: Lasse Sommer
authors.initials: LS
authors.lastname: Kristensen
authors.affiliation: Department of Haematology, Rigshospitalet, Blegdamsvej 9, 2100-DK, Copenhagen, Denmark.
authors.forename: Fazila
authors.initials: F
authors.lastname: Asmar
authors.affiliation: Department of Haematology, Rigshospitalet, Blegdamsvej 9, 2100-DK, Copenhagen, Denmark.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Dimopoulos
authors.affiliation: Department of Haematology, Aalborg University Hospital, Mølleparkvej 4, 9000-DK, Aalborg, Denmark.
authors.forename: Mette Kathrine
authors.initials: MK
authors.lastname: Nygaard
authors.affiliation: Department of Haematology, Rigshospitalet, Blegdamsvej 9, 2100-DK, Copenhagen, Denmark.
authors.forename: Derya
authors.initials: D
authors.lastname: Aslan
authors.affiliation: Department of Haematology, Rigshospitalet, Blegdamsvej 9, 2100-DK, Copenhagen, Denmark.
authors.forename: Jakob Werner
authors.initials: JW
authors.lastname: Hansen
authors.affiliation: Department of Pathology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ralfkiaer
authors.affiliation: Department of Haematology, Rigshospitalet, Blegdamsvej 9, 2100-DK, Copenhagen, Denmark.
authors.forename: Kirsten
authors.initials: K
authors.lastname: Grønbæk
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage; D017209:Apoptosis / Q000235:genetics; D015331:Cohort Studies; D019175:DNA Methylation; D064550:Death-Associated Protein Kinases / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic; D000069283:Rituximab; D016019:Survival Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D055815:Young Adult
chemical_list: D058846:Antibodies, Monoclonal, Murine-Derived; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000069283:Rituximab; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases