High-throughput sequencing unveils HBV DNA integration and its oncogenic role in gastric cancer

Growing evidence showed an association between hepatitis B virus (HBV) infection and gastric cancer (GC). HBV DNA integration is one of the key mechanisms contributing to hepatocellular carcinoma (HCC) development. However, the status of HBV integration in GC has not been studied yet. In this study, HBV DNA was detected in 7/10 GC and 8/10 para-tumor tissues. By high-throughput viral integration detection and long-read sequencing, a total of 176 and 260 HBV integration breakpoints were identified from GC and para-tumor tissues, respectively. In the HBV genome, the breakpoints were more frequently occurred at X gene and C gene. In the host genome, these breakpoints distribution was correlated with CpG islands. Seven protein-coding genes and one non-coding RNA genes were inserted by HBV DNA for more than once in different samples. Combined with the bioinformatics analysis and functional experiments, we highlight SPRY3 and CHD6 , as potential driver genes for GC. Besides, we also revealed the spatial relationship of HBV integration and its various structural variations. Taken together, our results first indicated that HBV DNA can integrate in GC. These findings provide insight into the HBV integration and its oncogenic progression in GC.