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The Androgen Receptor Gene is Preferentially Hypermethylated in Follicular Non-Hodgkin’s Lymphomas

Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, Missouri 65203 [H. Y., P. Y., T. H-M. H., H. S., C. W. C.]; Department of Life Sciences and Institute of Biomedicine, National Chung Hsing University, 402 Taichung, Taiwan [C-M. C.]; and Epigenomics, AG, Berlin D-10435, Germany [M. B., I. N., S. M., K. B.]

ABSTRACT

This investigation examined promoter DNA methylation of the androgen receptor (AR) gene in non-Hodgkin’s lymphoma (NHL) representing different stages of B-cell differentiation. Steroid hormones are important endocrine messengers with a broad range of physiological functions, including regulation of B-cell lymphopoiesis. Some of these effects are mediated via specific receptors such as AR that can act as a ligand-dependent transcription factor for other genes. DNA was isolated from 76 NHL specimens representing pregerminal center, germinal center, and postgerminal center states of differentiation. Initial methylation data were obtained from oligonucleotide microarrays and was confirmed and extended using methylation-specific PCR. Methylation of the AR gene promoter was present in a nonrandom pattern. Those tumors derived from pregerminal center or postgerminal center stages showed virtually no methylation and expressed AR mRNA. Cases of germinal center origin, mainly follicular lymphomas and some diffuse large B-cell lymphomas, showed hypermethylation. Studies with NHL cell lines revealed that demethylation or reversal of histone deacetylation partially restored AR expression but reversal of both simultaneously provided a synergistic release from suppression. Promoter methylation of AR occurs in a differentiation stage-selective manner; those cases arising in the germinal center are preferentially methylated. Full re-expression of AR requires both demethylation and reacetylation, a finding that may affect treatment decisions.

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