Abstract
The enhancer of zeste homolog 2 (EZH2) gene encodes a histone methyltransferase that is a catalytic subunit of the Polycomb repressive complex 2 (PRC2) group of proteins that act to repress gene expression. The EZH2 locus is rarely mutated in solid tumors and there is no comprehensive study of EZH2 single nucleotide variants (SNVs) associated with cancer susceptibility, prognosis and response to therapy. Here, for the first time, we review the functional roles of EZH2 DNA variants and propose a putative etiological role in 10 various solid tumors including: esophageal, hepatocellular, oral, urothelial, colorectal, lung and gastric cancers. In particular, we found that the C allele of the EZH2 variant rs3757441 is associated with increased EZH2 RNA expression and poorer prognosis (advanced stage) in at least two malignancies such as colorectal and hepatocellular carcinoma. This suggests that the C allele may be a functional risk variant in multiple malignant tumors. We therefore propose that the rs3757441 single nucleotide variant (SNV) be genotyped and real-time PCR assays be performed in large cohort studies in order to confirm this preliminary finding that could be useful for clinical practice.
Highlights
Polycomb group genes are mainly organized into two multimeric complexes, the Polycomb repressive complex 1 (PRC1) and 2 (PRC2), which are epigenetic repressors in embryonic development, cell fate determination, proliferation, stem cell pluripotency and self-renewal [1]
We found that the C/C genotype at rs3757441 was significantly associated with shorter progression free survival (PFS) and overall survival (OS) (p < 0.01 and p < 0.05, respectively) in metastatic colorectal cancer patients [32,33]
This review has identified 10 enhancer of zeste homolog 2 (EZH2) single nucleotide variants (SNVs) that could potentially predict cancer risk and/or prognosis in 10 types of solid tumors
Summary
Polycomb group genes are mainly organized into two multimeric complexes, the Polycomb repressive complex 1 (PRC1) and 2 (PRC2), which are epigenetic repressors in embryonic development, cell fate determination, proliferation, stem cell pluripotency and self-renewal [1]. (EZH2) functions as part of PRC2 by catalyzing the trimethylation of histone H3 at Lysine 27 (H3K27me3) [2]. This mainly results in Polycomb-dependent chromatin compaction and gene silencing [3]. EZH2 is over-expressed in several types of human cancers and its expression is positively correlated with advanced stages of tumor progression and poor clinical outcome [4]. EZH2 expression and functions vary among solid tumor patients. Emerging evidence indicates that EZH2 SNVs influence tumor initiation, progression and therapeutic response. We aim to discuss the functional and putative etiological roles of EZH2 DNA variants in solid tumors
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