154 Shared CpG methylation defects in mycosis fungoides and Sézary syndrome

Abstract

Mycosis fungoides (MF) and Sézary syndrome (SS) are related cutaneous T cell lymphomas thought to arise from distinct memory T cell populations. However, a subset of MF patients progress to SS, suggesting that these clinical variants can arise from a common lineage, and may share abnormal epigenetic imprinting with impact on clinical findings. To address this issue, we compared genome-wide CpG methylation profiles of T cells from SS, MF tumors (MFT), MF blood, and psoriasis blood as a disease control. Comparing all differentially methylated positions (DMPs) showed that while 15% of DMPs from SS T cells were shared by MFT-eluted cells, this shared fraction was 69% of all DMPs in MFT-eluted cells. DMPs annotated to CpG islands were more prevalent in the shared DMP group (49%) and non-shared MFT group (44%) compared to the non-shared SS group (7%). Conversely, intergenic DMPs were less prevalent in the shared DMP group (27%) and non-shared MFT group (31%) compared to the non-shared SS group (74%). DMPs located within 200 bp of transcription start sites and in first exons represented a smaller fraction of sites in the non-shared SS group compared to the shared group and non-shared MFT group. For the shared group, hypomethylated DMPs were primarily intergenic (78%), while most hypermethylated DMPs were in GpG islands (58%). Thus, a large majority of abnormally methylated CpG sites in MFT-eluted cells were also abnormally methylated in SS T cells, suggesting that MF and SS share many epigenetic defects. SS is a more advanced stage of disease, and bore many additional DMPs that were not highly affected in MF tumors.