Clinicopathological and genomic features of extrachromosomal DNA in gastric cancer.

Background: Extrachromosomal DNA (ecDNA), a form of circular DNA located outside chromosomes, is a common driver of oncogene amplification. Recent pan-cancer studies have associated ecDNA with cancer progression and poor prognosis. Moreover, its relationship with specific genomic features is becoming increasingly evident. However, the clinicopathological characteristics and underlying genomic mechanisms of ecDNA in gastric cancer remain poorly understood.

Methods: We analyzed whole-genome sequencing data from 81 Japanese gastric cancer samples to identify ecDNA using AmpliconArchitect and AmpliconClassifier. Gene expression profiles were obtained through whole-transcriptome RNA sequencing (RNA-seq).

Results: We found that the frequency of ecDNA occurrence was comparable across cancer stages and had a modest impact on prognosis, suggesting that ecDNA is present in early-stage disease and has a limited role in gastric cancer progression. Several immunomodulatory genes were amplified on ecDNA, and the presence of ecDNA harboring these genes was associated with the suppression of cytotoxic T cell responses, indicating a functional link between ecDNA and immune evasion. ecDNA-positive cases more frequently harbored TP53 mutations and were microsatellite stable compared to ecDNA-negative cases. Finally, ecDNA-positive tumors exhibited a high prevalence of single-base substitution signature 17, implicating that oxidative stress, potentially induced by gastric acid, plays a role in the generation of ecDNA in gastric cancer.

Conclusions: These findings provide insights into the clinicogenomic features of ecDNA in gastric cancer and highlight its potential impact on disease progression and immune modulation.