BOB.1-positive Classical Hodgkin’s Lymphoma Carries Hypermethylation of Its Promoter as Epigenetic Marker of Gene-silencing Memory

Abstract

Analysis of archival formalin-fixed, paraffin-embedded (FFPE) pathological specimens of three case of Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) and three cases of classical Hodgkin lymphoma (CHL) revealed that hypermethylation of the BOB.1 gene promoter was exclusively observed in CHL. A discrepancy was observed, however, between the methylation status of the BOB.1 gene promoter and its expression in the EBV-positive mixed cellular CHL (MCCHL). Since MCCHL lacks the typical B-cell phenotype even in the presence of abundant BOB.1 transcription factors, functional activity of BOB.1 may be lost or reduced by a mechanism other than epigenetic gene silencing. When some tumor-suppressor gene products have lost their biological function, impact or significance of derepression of such genes may be little. Therefore, when interpreting immunohistochemical results for diagnostic or research purposes, it must be borne in mind that apparent positive immunostaining can merely be the result of chromatin remodeling and that such transient expression often has little functional significance. Any apparent positive immunohistochemical result needs to be interpreted carefully with the help of the hypermethylation status as a molecular marker of gene silencing memory.

New molecular targets in Hodgkin and Reed-Sternberg cells

“…Subsequent analysis indicated that DNA methylation is directly involved in the control of some of these genes, while in case of others, the expression could be dependent on additional genetic encoding, i.e. some master transcription factors (69)(70)(71)(72)(73). Array-based genome-wide study of DNA methylation in HL cell lines (74) led to the identification of hypermethylation on 383 CpG islands, corresponding to 329 genes which were commonly associated with characteristic changes for germinal center derived B-cell lymphoma (gcdBCL).…”

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“…Immunohistochemistry enables us to describe protein expression in cells, but Watanabe et al [4] give a warning: protein expression does not always mean that a protein is really active. They had found not only high BOB.1 protein expression in HL but also hypermethylation of its promoter.…”

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“…But they are usually either weakly or partially expressed. This feature can be used in the differential diagnosis (7)(8)(9)(10).…”