Epigenetic aberrations in natural killer/T-cell lymphoma: diagnostic, prognostic and therapeutic implications

Abstract

Natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy that usually presents in the upper aerodigestive tract. This malignancy shows substantial geographic variability in incidence, and is characterized by Epstein-Barr virus (EBV) infections. Epigenetic aberrations may dysregulate the expression of genes involved in different hallmarks of cancer. A growing body of evidence underscores the importance of epigenetic aberrations in the pathogenesis of NKTCL. Promoter hypermethylation is a common epigenetic mechanism for the inactivation of tumour suppressor genes. Several epigenetically silenced tumour suppressor candidates (e.g. PRDM1, BIM) were identified in this aggressive cancer using locus-specific and genome-wide promoter methylation analyses. Importantly, genes involved in epigenetic modifications were identified to be mutated (e.g. KMT2D) or methylated (e.g. TET2) in NKTCL patients, which may contribute to pathogenesis through global alterations in chromatin states. Cancer-associated microRNAs, some of which are expressed by EBV, and long noncoding RNAs have been observed to be dysregulated in NKTCL. This review focuses on studies investigating epigenetic aberrations in NKTCL to bolster our overall understanding of the role of these abnormalities in disease pathobiology. We also discuss the potential of these epigenetic aberrations to improve diagnosis and prognosis as well as reveal novel targets of therapy for NKTCL.

Current Progress in Investigating Mature T- and NK-Cell Lymphoma Gene Aberrations by Next-Generation Sequencing (NGS)

“…These findings align with recent NGS studies showing that KMT2D genes are new NKTCL drivers. 52 Chromatin reshaping genes TP53 and ARID1A, which have also been reported in recent studies using NGS, also showed mutations. Further mutations were detected in 18 new genetic candidates whose molecular activity may be linked to the progression of cancer and suggests that these genes may lead to numerous oncogenic instances.…”

Indolent T-Cell Lymphoproliferative Disease of the GI Tract: Insights for Better Diagnosis, Prognosis, and Appropriate Therapy

“…Given the lack of response of this GI T-LPD case to a variety of therapeutics, high expression of PD-L1 could be responsible for this patient's poor prognosis as EBV-encoded LMP1 upregulated PD-L1, and elevated PD-L1 resulted in adverse clinical course in NKTCL cases (10). EBV-induced epigenomic aberrations were reported in EBV + malignancies (11). If these epigenomic changes are also present in EBV + GI T-LPD cases, it will be worthwhile to address whether they affect patient survival or not.…”

Rational Targets of Therapy in Extranodal NK/T-Cell Lymphoma

“…Epigenetic aberrations play a critical role in tumorigenesis by silencing tumor suppressor genes and altering the regulation of oncogenes. A cohesive understanding of how epigenetic changes drive the ENKTL clone is starting to emerge [32].…”