title: A gene panel, including LRP12, is frequently hypermethylated in major types of B-cell lymphoma.
abstract: Epigenetic modifications and DNA methylation in particular, have been recognized as important mechanisms to alter gene expression in malignant cells. Here, we identified candidate genes which were upregulated after an epigenetic treatment of B-cell lymphoma cell lines (Burkitt's lymphoma, BL; Follicular lymphoma, FL; Diffuse large B-cell lymphoma, DLBCL activated B-cell like, ABC; and germinal center like, GCB) and simultaneously expressed at low levels in samples from lymphoma patients. Qualitative methylation analysis of 24 candidate genes in cell lines revealed five methylated genes (BMP7, BMPER, CDH1, DUSP4 and LRP12), which were further subjected to quantitative methylation analysis in clinical samples from 59 lymphoma patients (BL, FL, DLBCL ABC and GCB; and primary mediastinal B-cell lymphoma, PMBL). The genes LRP12 and CDH1 showed the highest methylation frequencies (94% and 92%, respectively). BMPER (58%), DUSP4 (32%) and BMP7 (22%), were also frequently methylated in patient samples. Importantly, all gene promoters were unmethylated in various control samples (CD19+ peripheral blood B cells, peripheral blood mononuclear cells and tonsils) as well as in follicular hyperplasia samples, underscoring a high specificity. The combination of LRP12 and CDH1 methylation could successfully discriminate between the vast majority of the lymphoma and control samples, emphasized by receiver operating characteristic analysis with a c-statistic of 0.999. These two genes represent promising epigenetic markers which may be suitable for monitoring of B-cell lymphoma.
authors.affiliation: Department of Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway.
authors.forename: Nicole
authors.initials: N
authors.lastname: Bethge
authors.affiliation: Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Hilde
authors.initials: H
authors.lastname: Honne
authors.affiliation: Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Kim
authors.initials: K
authors.lastname: Andresen
authors.affiliation: Department of Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway.
authors.forename: Vera
authors.initials: V
authors.lastname: Hilden
authors.affiliation: Department of Pathology, Oslo University Hospital, Oslo, Norway.
authors.forename: Gunhild
authors.initials: G
authors.lastname: Trøen
authors.affiliation: Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; Department of Informatics, University of Oslo, Oslo, Norway.
authors.forename: Knut
authors.initials: K
authors.lastname: Liestøl
authors.affiliation: Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
authors.forename: Harald
authors.initials: H
authors.lastname: Holte
authors.affiliation: Department of Pathology, Oslo University Hospital, Oslo, Norway.
authors.forename: Jan
authors.initials: J
authors.lastname: Delabie
authors.affiliation: Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Guro E
authors.initials: GE
authors.lastname: Lind
authors.affiliation: Department of Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway.
authors.forename: Erlend B
authors.initials: EB
authors.lastname: Smeland
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics*; D016393:Lymphoma, B-Cell / Q000175:diagnosis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012372:ROC Curve; D017422:Sequence Analysis, DNA
chemical_list: D014408:Biomarkers, Tumor; C483993:LRP12 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1