Table 2.

Molecular biomarkers for ESCC and EAC. Area under the curve (AUC), esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), healthy control (HC), circulating tumor (ct) DNA, Barrett’s esophagus (BE), next-generation sequencing (NGS), variants of unknown significance (VUS), gelsolin (GSN), serum paraoxonase/arylesterase 1 (PON1) and serum paraoxonase/lactonase 3 (PON3), esophageal squamous cell carcinoma (ESCC) and esophagogastric junction adenocarcinoma (EJA), desmoglein-2 (DSG2), tRNA-derived small RNAs (tsRNAs).

Sample Type	EAC/ESCC	Sample Size	Biomarker Type/Observation
Urine [41]	EAC and ESCC	150 HCs and 43 ESCCs 144 HCs and 8 EACs	Significantly higher miR-1273f, miR-619-5p, miR-150-3p, miR-4327, and miR-3135b levels in ESCC and EAC compared with HCs; miR-1273f and miR-619-5p with AUC ≥ 0.80 for diagnosing stage I ESCC, AUC ≥ 0.80 in ESCC, and AUC = 0.80 for EAC
Urine, saliva, and blood [55]	ESCC	72 ESCC patients	Serum cell-free miR-1246 expression in the urine, saliva, and serum may be a useful biomarker for ESCC and urine can be used as a non-invasive sample instead of blood
Plasma [56]	ESCC	16 healthy controls and 66 ESCC patients	Plasma miR-21, miR-31, and miR-375 could be potential biomarkers for the diagnosis of ESCC, while miR-31 and miR-375 have sufficiently high sensitivity and specificity to differentiate ESCC patients from healthy controls
Saliva [57]	EC	miRNA expression profile GSE41268	miR-144, miR-451, miR-98, miR-10b, and miR-363 may serve as biomarkers for EC
Saliva [58]		32 EC patients and 16 healthy controls	Salivary supernatant miR-21 was significantly higher in EC with a sensitivity and specificity of 84.4% and 62.5%, respectively; miR-21 expression does not correlate with EC stage
Saliva [59]	EC	7 EC patients and 3 healthy controls	miR-10b*, miR-144, and miR-451 in the whole saliva and miR-10b*, miR-144, miR-21, and miR-451 in saliva supernatant were significantly upregulated in patients, with sensitivity and specificity ranging between 43.6% and 92.3%
Saliva [60]	ESCC	3 ESCC patients and 3 healthy controls	RNA sequencing of salivary exosomes for identification of tsRNA; tsRNA (tRNA-GlyGCC-5) was significantly enriched in salivary exosomes in ESCC
Plasma [47]	EAC	Patients with stage I to IV EAC 55 tumor and matched normal samples	Detection frequency and quantity of ctDNA increase with stage; ctDNA positively correlates with disease burden; ctDNA levels during the treatment may be useful to determine response and recurrence in some patient
Plasma [48]	EAC	209 blood and tumor samples from 57 EAC patients	Both plasma and tumor samples were sequenced for ctDNA; detectable ctDNA variants in post-treatment plasma samples were associated with worse disease-specific survival; variant allele frequency of ctDNA variants increased with disease recurrence
Plasma [61]	BE EAC	138 patients: EAC = 41 Barrett’s dysplasia = 48 Control = 49	To detect circulating HPV DNA; higher circulating HPV DNA was detected in EAC patients with invasive tumors with submucosal invasion and lymph node metastasis; circulating HPV DNA positivity was associated with tissue HPV positivity and disease severity
Plasma [49]	EAC	40 EAC patients (17 palliative and 23 curative)	Sensitive ctDNA detection has potential for the monitoring and predicting of short overall survival; the presence of ctDNA post-operatively predicts relapse and provides a molecular window before the onset of overt disease
Plasma [62]	EAC	55 EAC patients with advanced disease	ctDNA detection using NGS; 66% of patients had ≥ 1 genomic alteration including VUS and 69.1% had ≥ 1 characterized alteration (excluding VUSs); patients with ≥ 1 characterized alteration had alterations targetable by an FDA-approved therapy theoretically