Distinct genomic, transcriptomic, and immune profiles for tumor and non-tumor mucosal regions in gastric cancer

Background: Local recurrence Metachronous cancer frequently develops after following endoscopic resection for early gastric cancer by field cancerization. Thus, understanding the nature of cancer-prone environments is important to establish effective strategies to prevent recurrence. We hypothesized that the molecular/immune profiles in non-tumor (cancer-prone) tissue differ according to the relative distance from the gastric tumor, which could be used to predict the risk of cancer development. Methods: We performed whole-exome and transcriptome sequencing of 16 early gastric cancer samples with paired non-tumor mucosa samples 1 cm (non-tumor 1 cm) and 3 cm (non-tumor 3 cm) away from the tumor. Analyses were performed to compare the mutational signatures, pathways, and immune cell profiles among groups. Results: The expression of programmed death-ligand 1 was decreased in tumors, whereas the expression of the epithelial-mesenchymal transition signature, mesenchymal signature, and proliferation signature was increased compared with that in the non-tumor mucosa. In immune cell profiling, the numbers of M0 macrophages, M1 macrophages, neutrophils, and eosinophils increased, whereas plasma cell numbers decreased in the tumor compared with those in the non-tumor mucosa. Whole-exome sequencing revealed mutations in both the tumor and non-tumor mucosa. TTN was the most frequently altered gene in tumors (31%) and was the second most frequently altered gene in non-tumor 1 cm (25%) samples; however, the mutation rate was significantly lower in non-tumor 3 cm (12%) samples (P = 0.0046). TP53 mutations were mainly observed in the tumor (50%) and in 6.3% of non-tumor 1 cm samples, with no such mutations detected in non-tumor 3 cm samples. Loss of heterozygosity and large-scale transitions were also significantly increased in tumor and non-tumor 1 cm samples compared with those in non-tumor 3 cm samples. Gene expression profiling revealed a similar gene expression pattern between non-tumor 1 cm and tumor samples, but this pattern differed from that of non-tumor 3 cm samples. Similarly, the distribution of certain immune cells in the non-tumor 3 cm samples was different from that in the non-tumor 1 cm and tumor samples. Conclusion: Non-tumor mucosa at 1 cm and 3 cm from the tumor harbored different genomic, transcriptomic, and immune cell profiles. The non-tumor mucosa closer to the tumor (1 cm) exhibited genomic and transcriptomic features that were more similar to those of the tumor. These findings can offer clinical guidance for acquiring a safe horizontal margin in endoscopic resectiony for early gastric cancer.