Introduction

Gastric cancer is a prevalent malignancy and a leading cause of cancer-related mortality globally.1 Promoter hypermethylation-induced inactivation of tumor suppressor genes, such as PTEN, MDGA2, ZNF331, REC8, and RASSF10, has been implicated in the development of gastric cancer.2, 3, 4, 5, 6 Silencing of tumor suppressors holds diagnostic and prognostic value for gastric cancer patients. Human endogenous retroviruses (HERVs) are remnants of ancient germ line retrovirus infections that date back over a million years.7 HERV integrations can give rise to novel human genes that differ from their non-human counterparts or enable tissue-specific expression of HERV-related genes.8,9 psiTPTE22-HERV represents a recently evolved gene that results from the fusion of HERV and adjacent non-HERV DNA. Notably, the HERV involved is exclusive to humans, rendering psiTPTE22-HERV a human-specific gene.10 Based on a limited sample size, psiTPTE22-HERV was detected in the normal kidney, liver, stomach, and lung tissues, whereas its expression was diminished in the corresponding primary tumor tissues. Bisulfite genomic sequencing confirmed the suppression of psiTPTE22-HERV in kidney cancer owing to promoter DNA methylation. However, as a newly identified gene, the regulatory mechanisms of psiTPTE22-HERV in other cancers and its functional roles remain to be investigated.

The regulatory patterns, functional significance, and mechanisms of psiTPTE22-HERV in various cancers, including gastric cancer, require further exploration. In this study, we investigated the expression, epigenetic regulation, biological functions, molecular mechanisms, and clinical implications of psiTPTE22-HERV in the context of gastric cancer.