Missing link: Viral RNA signatures in circulating exosomes as early diagnostic biomarkers for gastrointestinal cancers

Table 1 Exosomal viral RNA biomarkers in gastrointestinal cancers

Virus type	Exosomal marker(s)	Associated GI cancer(s)	Diagnostic utility/clinical relevance
Epstein-Barr virus	Epstein-Barr virus-encoded small RNAs (EBERs), specific microRNAs (miR-BARTs, miR-BART7-3p, BART13-3p), viral proteins (EBNA1, LMP2A)	Gastric cancer (EBVaGC), nasopharyngeal carcinoma	Exosomal viral RNAs influence host gene expression, promoting cell proliferation and survival. EBERs and LMP2A in exosomes correlate with poorer outcomes in EBVaGC. miR-BART7-3p is a highly specific biomarker for gastric cancer. BART13-3p distinguishes cancerous from benign EBV infections in nasopharyngeal carcinoma
Hepatitis B virus	Viral nucleic acids (e.g., HBV DNA, HBV RNA, HBx RNA), viral proteins (e.g., HBsAg, HBx protein), miRNAs (e.g., miR-212)	Hepatocellular carcinoma	Exosomal viral components induce chronic inflammation, fibrosis, and cellular transformation. Their systemic dissemination can facilitate metastasis. Exosomes from infected cells contain HBV DNA, RNA, and proteins. Exosomal miR-212 is upregulated in HBV-hepatocellular carcinoma
Hepatitis C virus	Viral nucleic acids (e.g., HCV RNA, replication-competent viral RNA), viral proteins (e.g., HCV core protein, E2 envelope protein), miRNAs (e.g., miR-122)	Hepatocellular carcinoma	Exosomal viral components induce chronic inflammation, fibrosis, and cellular transformation. Exosomes from infected patients contain HCV RNA, mediating viral receptor-independent transmission. HCV RNA in exosomes can associate with Ago2, HSP90, and miR-122
Human papillomavirus	Viral oncoproteins (E6 and E7), viral RNAs	Anal cancers, colorectal cancers (to a lesser extent)	Exosomal transfer contributes to immune evasion by modulating antigen presentation and promotes cell proliferation. Detecting these signatures offers a non-invasive tool for identifying HPV-associated GI malignancies

EBERs: Epstein-Barr virus-encoded small RNAs; BART: Bam HI fragment A rightward transcript; EBNA1: Epstein-Barr nuclear antigen 1; LMP2A: Latent membrane protein 2A; HBV: Hepatitis B virus; HBx: Hepatitis B virus X protein; HBsAg: Hepatitis B surface antigen; miRNA: MicroRNA; HCV: Hepatitis C virus; EBVaGC: Epstein-Barr virus is a leading etiological agent in a subset of gastric cancers; Ago2: Argonaute 2; HSP90: Heat shock protein 90; HPV: Human papillomavirus; GI: Gastrointestinal.