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DNA Methylation Signatures Distinguish Extranodal NK/T-cell Lymphoma and EBV-Positive Nodal T/NK-Cell Lymphoma and Identify Prognostic Subgroups

ABSTRACT: Extranodal NK/T-cell lymphoma (ENKTL) and primary Epstein–Barr virus (EBV)-positive nodal T/NK-cell lymphoma (nodal-TNKL) are aggressive lymphomas with overlapping clinicopathologic features but distinct underlying biology. While their genomic landscapes have been increasingly defined, comparative epigenetic characterization remains limited. We performed methylated DNA immunoprecipitation sequencing (MeDIP-seq) on formalin-fixed paraffin-embedded samples from ENKTL, nodal-TNKL, ENKTL cell lines, and control tissues. ENKTL displayed extensive promoter hypermethylation associated with repression of tumor suppressor genes, lineage regulators, and lymphoid signaling genes, including LEF1 and BANK1, together with focal hypomethylation of immune- and interferon-responsive genes such as IFITM1. In contrast, nodal-TNKL showed global hypomethylation, particularly affecting cytotoxicity, immune-response, and antigen-presentation pathways; TET2-mutated cases exhibited locus-specific methylation changes consistent with impaired active demethylation. Across all samples, global DNA methylation levels correlated with genomic instability. Unsupervised clustering identified two epigenetically distinct ENKTL subgroups, one characterized by higher global methylation, TP53 loss, increased copy number alterations and loss of heterozygosity, and significantly poorer overall survival. Together, this study defines fundamental epigenetic differences between ENKTL and nodal-TNKL and links DNA methylation dynamics to genomic instability and clinical outcome, highlighting the value of methylation profiling for refined classification, risk stratification and therapeutic guidance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328647 | GEO | 2026/06/23

REPOSITORIES: GEO

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Project description:Background: NK/T cell lymphoma (NKTCL) is a type of non-Hodgkin's lymphoma that occurs primarily extra nodal. The main treatment methods are radiotherapy and chemotherapy. The 5-year recurrence rate is still high, and there is currently no standard treatment for relapse-resistant patients. Compared with other lymphoid tumors, its malignancy is relatively strong, and the prognosis is not very good. Here, we try to identify the key genes and signaling pathways related to chemotherapy resistance in extra nodal NK/T cell lymphoma. Methods: Firstly, we collect white blood cells from 5 healthy controls and 7 different clinical patients,4 patients were chemotherapy sensitive while 3 patients were chemotherapy resistant. Secondly, after total RNA extraction from those white blood cells, RNA sequence was performed on the Illumina HiSeq platform. Finally, we used qRT-PCR to confirm the expression patterns of different expression genes(DEGs) from the mostly enriched signaling pathways, especially the cancer related genes on the NK/T cell lymphoma clinical individuals. Results: The RNA sequence results displayed 4063 DEGs, including 1128 up regulated and 2935 down regulated genes in the chemotherapy resistance cases of extra nodal NK/T cell lymphoma specimens. Further quantitative gene expression analysis was performed to identify the differential expression pattern in all libraries. And 9 down regulated genes and 10 up regulated genes were confirmed by quantitative real time PCR comparison of chemotherapy resistance in extra nodal NK/T cell lymphoma from 6 clinical specimens. KEGG analysis revealed significant pathway changes, including 6 down regulated and 9 up regulated gene enrichment pathways. The TNF signaling pathway, one of the most extensively regulated, was among the pathways. DEGs and the TNF signaling pathway may be essential in the resistance to chemotherapy in extra nodal NK/T cell lymphoma. Conclusion:Our finding indicated that different genes expression may be important for chemotherapy resistance in extra nodal NK/T cell lymphoma, particularly TNFRSF1B, TRADD2 and MAP3K7.The TNF signaling pathway, a critical signaling pathway, was pinpointed as a potential factor in the emergence of chemotherapy resistance in extra nodal NK/T cell lymphoma.

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DNA Methylation Signatures Distinguish Extranodal NK/T-cell Lymphoma and EBV-Positive Nodal T/NK-Cell Lymphoma and Identify Prognostic Subgroups

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