Identification of loci of functional relevance to Barrett’s esophagus and esophageal adenocarcinoma: Cross-referencing of expression quantitative trait loci data from disease-relevant tissues with genetic association data

Abstract

Esophageal adenocarcinoma (EA) and its precancerous condition Barrett’s esophagus (BE) are multifactorial diseases with rising prevalence rates in Western populations. A recent meta-analysis of genome-wide association studies (GWAS) data identified 14 BE/EA risk loci located in non-coding genomic regions. Knowledge about the impact of non-coding variation on disease pathology is incomplete and needs further investigation. The aim of the present study was (i) to identify candidate genes of functional relevance to BE/EA at known risk loci and (ii) to find novel risk loci among the suggestively associated variants through the integration of expression quantitative trait loci (eQTL) and genetic association data. eQTL data from two BE/EA-relevant tissues (esophageal mucosa and gastroesophageal junction) generated within the context of the GTEx project were cross-referenced with the GWAS meta-analysis data. Variants representing an eQTL in at least one of the two tissues were categorized into genome-wide significant loci (P < 5×10−8) and novel candidate loci (5×10−8 ≤ P ≤ 5×10−5). To follow up these novel candidate loci, a genetic association study was performed in a replication cohort comprising 1,993 cases and 967 controls followed by a combined analysis with the GWAS meta-analysis data. The cross-referencing of eQTL and genetic data yielded 2,180 variants that represented 25 loci. Among the previously reported genome-wide significant loci, 22 eQTLs were identified in esophageal mucosa and/or gastroesophageal junction tissue. The regulated genes, most of which have not been linked to BE/EA etiology so far, included C2orf43/LDAH, ZFP57, and SLC9A3. Among the novel candidate loci, replication was achieved for two variants (rs7754014, Pcombined = 3.16×10−7 and rs1540, Pcombined = 4.16×10−6) which represent eQTLs for CFDP1 and SLC22A3, respectively. In summary, the present approach identified candidate genes whose expression was regulated by risk variants in disease-relevant tissues. These findings may facilitate the elucidation of BE/EA pathophysiology.

Decoding common genetic alterations between Barrett's esophagus and esophageal adenocarcinoma: A bioinformatics analysis

“…To further bolster the identification of potential target genes in this specific location, the study integrated publicly available genotype-expression correlation from normal human tissues and performed statistical analyses to assess colocalization [ 42 ]. Similarly, using expression quantitative trait loci (eQTL) data, three BE/ECA-associated genetic variants were reported, including variant rs7754014 on 6q25 represents an eQTL for the gene SLC22A3 in esophageal mucosa, variant rs147462972 on 5p15 defines an eQTL for the gene SLC9A3 in esophageal mucosa, and variant rs1540 on 16q23 regulates the CFDP1 expression in gastroesophageal junction [ 43 ]. Importantly, SLC9A3 overexpression has already been found to be associated with gastroesophageal reflux, which is a contributing factor to the risk of BE and EAC [ 44 ].…”

Sex-Specific Genetic Associations for Barrett’s Esophagus and Esophageal Adenocarcinoma

“…SLC22A3 (solute carrier family 22 member 3) belongs to the solute carrier superfamily and were recently reported to be candidate genes of BE and EA in a study investigating eQTLs in esophageal tissues. 88 In addition, downregulation of SLC22A3 (solute carrier family 22 member 3) could drive early tumor invasion and metastasis in familial esophageal cancer. 89 ISL1 (LIM homeobox 1) encodes LIM-homeodomain transcription factor and promotes tumor progression in multiple cancer types, such as gastric and breast cancer.…”

Cranberry Proanthocyanidins Mitigate Reflux-Induced Transporter Dysregulation in an Esophageal Adenocarcinoma Model

“…The transport of glutamine, a non-essential neutral amino acid, is conducted by SLC families 1, 6, 7 and 38, and the intracellular requirements of this amino acid are necessary for the synthesis of the antioxidant glutathione [40]. With respect to chemotherapeutic treatment of EAC patients, a number of SLC family members, including SLC22A2, are responsible for the uptake of 5-fluorouracil (5-FU), cisplatin, carboplatin, and paclitaxel, and in turn impact cancer cell death, pathological progression, therapeutic efficacy, and patient prognosis [45][46][47][48][49][50][51][52][53][54][55]. ABC transporters are primary active transporters that utilize energy from ATP hydrolysis to move a wide range of substrates generally to the outside of a cell [22].…”

“…Most studies evaluating transporters in the context of esophageal cancer have focused on ESCC and the role of transporters in therapeutic resistance, with fewer studies characterizing transporters linked to EAC. To date, studies have reported transporter dysregulation correlated with progression to EAC, therapeutic resistance or poor patient prognosis [43,46,47,50,51,[53][54][55][61][62][63][64][65][66]. Moreover, ABCB1 was recently identified as a driver gene of EAC supporting a role beyond drug resistance [61].…”