AUTHOR=Zhong Ce , Wu Chen , Lin Yuan , Lin Dongxin 

TITLE=Refined expression quantitative trait locus analysis on adenocarcinoma at the gastroesophageal junction reveals susceptibility and prognostic markers

JOURNAL=Frontiers in Genetics

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2023.1180500

DOI=10.3389/fgene.2023.1180500

ISSN=1664-8021

ABSTRACT=<p><bold>Objectives:</bold> This study aimed to explore cell type level expression quantitative trait loci (eQTL) in adenocarcinoma at the gastroesophageal junction (ACGEJ) and identify susceptibility and prognosis markers.</p><p><bold>Methods:</bold> Whole-genome sequencing (WGS) was performed on 120 paired samples from Chinese ACGEJ patients. Germline mutations were detected by GATK tools. RNA sequencing (RNA-seq) data on ACGEJ samples were taken from our previous studies. Public single-cell RNA sequencing (scRNA-seq) data were used to produce the proportion of epithelial cells. Matrix eQTL and a linear mixed model were used to identify condition-specific cis-eQTLs. The R package coloc was used to perform co-localization analysis with the public data of genome-wide association studies (GWASs). Log-rank and Cox regression tests were used to identify survival-associated eQTL and genes. Functions of candidate risk loci were explored by experimental validation.</p><p><bold>Results:</bold> Refined eQTL analyses of paired ACGEJ samples were performed and 2,036 potential ACGEJ-specific eQTLs with East Asian specificity were identified in total. ACGEJ-gain eQTLs were enriched at promoter regions more than ACGEJ-loss eQTLs. rs658524 was identified as the top eQTL close to the transcription start site of its paired gene (<italic>CTSW</italic>). rs2240191–<italic>RASAL1</italic>, rs4236599–<italic>FOXP2</italic>, rs4947311–<italic>PSORS1C1</italic>, rs13134812–<italic>LOC391674</italic>, and rs17508585–<italic>CDK13-DT</italic> were identified as ACGEJ-specific susceptibility eQTLs. rs309483–<italic>LINC01355</italic> was associated with the overall survival of ACGEJ patients. We explored functions of candidate eQTLs such as rs658524, rs309483, rs2240191, and rs4947311 by experimental validation.</p><p><bold>Conclusion:</bold> This study provides new risk loci for ACGEJ susceptibility and effective disease prognosis biomarkers.</p>