Abstract 491P
Background
Esophageal squamous cell carcinoma (ESCC) and cardia gastric adenocarcinoma (CGA) remain major health burdens and co-occur geographically worldwide. Most of cases are diagnosed at advanced stages and carry a dismal prognosis. However, biomarkers for early detection of ESCC and CGA are still lacking.
Methods
DNA methylation profiling of 36 paired CGA and non-tumor adjacent tissues (NAT) was performed using HM850K methylation arrays. We identified differentially methylated CpG sites (DMCs) between CGA/ESCC and NAT by combined analyses of in-house data and Gene Expression Omnibus database. Candidate DMCs were validated by pyrosequencing on paired tumor and NAT from 50 CGA and 50 ESCC patients, and mRNA expression of their target genes was detected by quantitative real-time RT-PCR. An independent cohort of 438 CGA, ESCC, high- and low-grade dysplasia (HGD/LGD), and normal control biopsies was tested for selected DMCs using pyrosequencing.
Results
We identified and validated three CGA-specific, two ESCC-specific, and one tumor-shared DMCs, which were significantly hypermethylated with lower expression of their located genes in tumor compared with NAT samples. Using these DMCs, we developed a CGA-specific 4-marker panel (cg27284428, cg11798358, cg07880787, and cg00585116) achieving AUC of 0.995 (95% CI: 0.982-1.000) and 0.962 (95% CI: 0.920-1.000) for early-stage and all-stage CGA, respectively, and an ESCC-specific 3-marker panel (cg14633892, cg04415798, and cg00585116) with an AUC of 0.970 (95%CI: 0.939-1.000) and 0.978 (95%CI: 0.958-0.999) for detecting early-stage and all-stage ESCC, respectively. We then evaluated the performance of DMCs for detecting cancerous and precancerous lesions, the CGA-specific 4-marker panel discriminated cardia HGD/CGA patients from cardia LGD/normal controls with AUC of 0.917, and the ESCC-specific 3-marker panel distinguished esophageal HGD/ESCC with AUC of 0.865.
Conclusions
Collectively, novel DNA methylation markers could differentiate CGA/ESCC and HGD from LGD and normal controls with promising accuracy. Our findings pave the way for targeted DNA methylation assays in future minimally invasive cancer screening methods.
Legal entity responsible for the study
The authors.
Funding
National Natural Science Foundation of China (81974493).
Disclosure
All authors have declared no conflicts of interest.