Genome Med. Bai Fan's research group and collaborators revealed the co-evolution characteristics of EB virus-positive gastric cancer tumor cells and EB virus, and discovered potential therapeutic targets

Gastric cancer ranks third in the global mortality rate, and the five-year survival rate of patients is usually less than 40%.

On September 8, 2021, Peking University Biomedical Frontier Innovation Center (BIOPIC), Beijing Future Gene Diagnosis Advanced Innovation Center (ICG) Bai Fan's research group and Sun Yat-sen University Cancer Prevention Center Zhong Qian's research group cooperated in Genome Medicine Published a paper titled The genomic architecture of EBV and infected gastric tissue from precursor lesions to carcinoma in the form of a research long article

Figure 1.

Through whole-exome sequencing, the researchers found that EBVaGCs and high-grade dysplasia (HD) in precancerous lesions are more effective than normal gastric mucosal tissue and low-grade dysplasia (LD).

On the other hand, compared with precancerous lesions, PI3K-Akt, RTK, and JAK pathway-related driver gene copy numbers are significantly increased in EBVaGCs; however, chromatin-related signaling pathways or Notch pathway-related driver gene copy number deletion events are found in cancers.

　　Figure 2.

　　The researchers further performed a clonal analysis of all precancerous lesions and tumor samples of each patient in the cohort, and found that the EBVaGCs of each patient were of monoclonal origin by constructing a phylogenetic tree, and all HDs had the same origin as EBVaGCs (Picture 3)

　　Figure 3.

　　The researchers further analyzed the EBV genome

　　In addition, the EBV sequence in the patient's saliva is also obviously inconsistent with the virus sequence in EBVaGCs, but it is similar to the EBV sequence in normal gastric mucosal tissue and LD

　　Hypermethylation is a significant molecular feature of EBVaGCs.

　　Researchers found that compared with precancerous lesions and other types of gastric cancer, the promoter regions of some genes in the Ras GTPase activator protein (RasGAP) family (including RASA3, RASA4, RASAL3, etc.

　　In order to confirm this view, the researchers compared the methylation and expression levels of RasGAP family genes in the gastric cancer cell line AGS before and after EBV infection, and found that RasGAP family genes showed high methylation and low mRNA levels after EBV infection.

　　Figure 4.

　　By integrating molecular events at different stages of tumor development, the researchers found that EBVaGCs and HD have high-frequency PI3K-Akt pathway genes (PIK3CA/B, PTEN), Wnt pathway genes (CTNNB1, GNAS) and ARID1A mutations and copy numbers Mutations, and these mutations are rare in normal gastric mucosal tissues and LD

　　In order to prove the above conclusions, the researchers combined a series of in vitro and in vivo experiments to confirm that PI3K inhibitors and Wnt pathway inhibitors have a synergistic inhibitory effect on tumor cells with PIK3CA and CTNNB1 double mutations (Figure 5), revealing the simultaneous use of these two Inhibitors of the pathway can be used as a potential treatment strategy for EBVaGCs

　　Figure 5.
Summary of EBVaGC-driven events and clonal evolution models; cell and mouse experiments confirmed that PI3K inhibitors and Wnt pathway inhibitors have a significant synergistic inhibitory effect on tumor cells with PIK3CA and CTNNB1 double mutations

　　Dr.
Chen Zhanghua, Dr.
Chen Xiqian, Peking University Biomedical Frontier Innovation Center, Dr.
Yan Shumei, Dr.
Zhang Qi, and Dr.
Liu Shangxin from Sun Yat-sen University Cancer Center are the co-first authors of this article
.
Peking University BIOPIC researcher Bai Fan and Sun Yat-sen University Cancer Center Researcher Zhong Qian are the co-corresponding authors of the research paper
.
Professor Zeng Musheng from Sun Yat-sen University Cancer Center provided important guidance for this research
.
This research project has received support from the National Natural Science Foundation of China, the Ministry of Science and Technology, Beijing Future Gene Diagnosis High-precision Innovation Center, and the Guangdong Provincial Science and Technology Program
.

　　Link to the paper: https://genomemedicine.
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1186/s13073-021-00963-2