1. ¹Department of Biochemistry and Molecular Biology, University of Southern California, Los Angeles, CA, USA
2. ²Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
3. ³Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
4. ⁴Department of Surgery, University of Southern California, Los Angeles, CA, USA
5. ⁵Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
6. ⁶Department of Pathology, Norwegian Radium Hospital, University of Oslo, Oslo, Norway

Correspondence: Professor JG Hacia, Department of Biochemistry and Molecular Biology, University of Southern California, 2250 Alcazar Street, IGM 240, Los Angeles, CA 90089, USA. E-mail: hacia@hsc.usc.edu

Received 26 May 2007; Revised 11 January 2008; Accepted 18 January 2008; Published online 21 February 2008.

Abstract

In an initial epigenetic characterization of diffuse large B-cell lymphoma (DLBCL), we evaluated the DNA methylation levels of over 500 CpG islands. Twelve CpG islands (AR, CDKN1C, DLC1, DRD2, GATA4, GDNF, GRIN2B, MTHFR, MYOD1, NEUROD1, ONECUT2 and TFAP2A) showed significant methylation in over 85% of tumors. Interestingly, the methylation levels of a CpG island proximal to FLJ21062 differed between the activated B-cell-like (ABC-DLBCL) and germinal center B-cell-like (GCB-DLBCL) subtypes. In addition, we compared the methylation and expression status of 67 genes proximal (within 500 bp) to the methylation assays. We frequently observed that hypermethylated CpG islands are proximal to genes that are expressed at low or undetectable levels in tumors. However, many of these same genes were also poorly expressed in DLBCL tumors where their cognate CpG islands were hypomethylated. Nevertheless, the proportional reductions in BNIP3, MGMT, RBP1, GATA4, IGSF4, CRABP1 and FLJ21062 expression with increasing methylation suggest that epigenetic processes strongly influence these genes. Lastly, the moderate expression of several genes proximal to hypermethylated CpG tracts suggests that DNA methylation assays are not always accurate predictors of gene silencing. Overall, further investigation of the highlighted CpG islands as potential clinical biomarkers is warranted.