A gene panel, including LRP12, is frequently hypermethylated in major types of B-cell lymphoma

Nicole Bethge; Hilde Honne; Kim Andresen; Vera Hilden; Gunhild Trøen; Knut Liestøl; Harald Holte; Jan Delabie; Guro E Lind; Erlend B Smeland

doi:10.1371/journal.pone.0104249

A gene panel, including LRP12, is frequently hypermethylated in major types of B-cell lymphoma

PLoS One. 2014 Sep 16;9(9):e104249. doi: 10.1371/journal.pone.0104249. eCollection 2014.

Authors

Affiliations

¹ Department of Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway.
² Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
³ Department of Pathology, Oslo University Hospital, Oslo, Norway.
⁴ Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; Department of Informatics, University of Oslo, Oslo, Norway.
⁵ Centre for Cancer Biomedicine, University of Oslo, Oslo, Norway; Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers, Tumor / genetics
Case-Control Studies
Cell Line, Tumor
CpG Islands
DNA Methylation*
Epigenesis, Genetic
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Low Density Lipoprotein Receptor-Related Protein-1 / genetics*
Lymphoma, B-Cell / diagnosis
Lymphoma, B-Cell / genetics*
Promoter Regions, Genetic
ROC Curve
Sequence Analysis, DNA

Substances

Biomarkers, Tumor
LRP12 protein, human
Low Density Lipoprotein Receptor-Related Protein-1

Grants and funding

This work was supported by grants from the South-Eastern Norway Regional Health Authority (ES: no. 39232, funding NB as PhD and GEL: no. 39535), and The Norwegian Cancer Society (ES: no. 33260 and GEL: PR-2008-0163). In addition, this work was partly supported by the Research Council of Norway through its Centres of Excellence funding scheme, project number 179571. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.