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Lymphoma

DNA methylation profiles in diffuse large B-cell lymphoma and their relationship to gene expression status

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.

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Acknowledgements

We thank Drs Larry Brody (NIH), Darren Magda (Pharmacyclics Inc.) for valuable discussion, and Lou Staudt and Sandeep Dave (NCI) for access to the Affymetrix gene expression data.

Acknowledgement of Funding Support: This study was funded by NIH Grants P50-HG002790 and P30-CA014089, and United States Public Health Service Grants CA36727 and CA84967 awarded by the Department of Health and Human Services, National Cancer Institute. TCG is a grantee of the Mantle Cell Lymphoma Research Program of the Lymphoma Research Foundation. This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. This investigation was conducted in a facility constructed with support from Research Facilities Improvement Program Grant Number C06 (RR10600-01, CA62528-01 and RR14514-01) from the National Center for Research Resources, National Institutes of Health.

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Correspondence to J G Hacia.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Pike, B., Greiner, T., Wang, X. et al. DNA methylation profiles in diffuse large B-cell lymphoma and their relationship to gene expression status. Leukemia 22, 1035–1043 (2008). https://doi.org/10.1038/leu.2008.18

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