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

Abstract

In early gastric cancer, local recurrence develops after endoscopic resection by field cancerization. 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. For this purpose, we performed whole-exome and transcriptome sequencing of 16 early gastric cancer samples with paired non-tumor mucosa 1 cm (N1) and 3 cm (N3) away from the tumor. The 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 N1 (25 %) samples; however, the mutation rate was significantly lower in N3 (12 %) samples (P = 0.0046). Moreover, the expression levels of TTN mRNA were higher in tumors than in the N1 and N3 samples and were significantly associated with TTN mutations (P = 0.04). TP53 mutations were mainly observed in tumors (50 %) and in 6.3 % of N1, with no mutation detected in N3 samples. Transcriptome sequencing revealed that the expression of the epithelial-mesenchymal transition signature, mesenchymal signature, and proliferation signature was increased in tumors, whereas programmed death-ligand 1 expression was decreased in the non-tumor mucosa. In the tumor, although the numbers of M0/M1 macrophages, neutrophils, and eosinophils increased, plasma cell numbers were markedly decreased compared to non-tumor mucosa. In 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 similar genomic and transcriptomic features. These findings can offer clinical guidance for acquiring a safe horizontal margin in endoscopic resection for early gastric cancer.