On July 23, Nature published online a study belonging to the Cancer Tumor Genome Atlas (TCGA) program. In it, gastric cancer was divided into four new molecular subtypes with clear genetic characteristics. In order to elaborate the birth and clinical significance of these four new molecular subtypes of gastric cancer, we invited Professor Shmulevich of the Institute of Systems Biology, one of the main leaders of the TCGA research group, and Professor Zhang Wei of M.D. Anderson Cancer Center, a member of the research group, to explain this study in detail. 1. The chromosomal instability (CIN) type is found in the gastroesophageal junction or cardia and is mostly of the intestinal type of the Lauren typology, characterized by a high prevalence of TP53 gene mutations, significant heteroploidy, elevated levels of EGFR (PY1068) phosphorylation due to epidermal growth factor receptor (EGFR) gene amplification, and local amplification of the receptor tyrosine kinase (RTK) gene. Prof. Zhang Wei: In CIN-type gastric cancer, there is targetable RTK gene amplification. As VEGFA gene amplification is more common in this type, the anti-angiogenic effect is obvious. The antibody ramucirumab targeting VEGFR2 can show anti-tumor effect in this type of gastric cancer, but whether its efficacy is determined by VEGFA gene amplification is yet to be verified. 2. Microsatellite instability (MSI) type is found in the gastric sinus or pylorus, mostly in women, with a high age at first diagnosis (median age 72 years). Characterized by increased mutations in repetitive DNA sequences, including mutations in genes encoding targeted oncogenic signaling proteins; with gastric-type CIMP and MHL1 hypermethylation. Prof. Wei Zhang: In MSI-type gastric cancer, BRAFV600E gene mutation was not found in MSI-type colorectal cancer, but replaced by mutations in targetable PIK3CA, ERBB3, ERBB2 and EGFR genes. 3. The genetically stable (GS) type occurs in the gastric sinus or pylorus, with a low age at first diagnosis (median age 59 years), and its histological variants are mostly of the diffuse type of the Lauren typing, characterized by mutations in CDH1, ARID1A, RHOA genes or the phenomenon of RHO family GTPase-activating protein gene fusion (CLDN18-ARHGAP fusion) is common. Prof. Wei Zhang: The RHO family of GTPases regulates myosin dynamics and cellular behavior including adhesion, proliferation and survival. In addition, the RHOA signaling pathway is closely related to tumor cell invasion and metastasis. When expressed in an activated form bound to GTP, RHOA acts as an effector of ROCK1, mDIA and protein kinase N, regulating actin-myosin-based cell contraction and motility, as well as activating STAT3 to promote tumor formation. Structuralmapping analysis revealed that RHOA mutations may be concentrated in two adjacent amino-terminal regions where RHOA interacts with ROCK1 and others, and may activate downstream RHOA signaling. The importance of the RHOA pathway in gastric cancer was further suggested by the discovery of repetitive gene structural alterations, and chromosomal internal translocations of CLDN18 (expressing intercellular tight junctional adhesion protein) and ARHGAP26 [expressing GTPase-activating protein (GAP), which contributes to the conversion of RHO-GTPase to the GDP form to enhance cellular dynamics] were also identified. The identification of these key gene mutations and fusions will provide important clues for future drug development in gastric cancer. 4. Epstein-Barr (EBV) virus-positive type is found in the fundus or gastric body, mostly in males, and is characterized by higher frequency of PIK3CA, ARID1A and BCOR gene mutations, extreme DNA hypermethylation [extreme EBV-CpG island methylation phenotype (CIMP), CDKN2A promoter hypermethylation], JAK2 CD274 and PDCD1LG2 gene amplification, resulting in PD-L1 and PD-L2 immunosuppressive protein overexpression. Prof. Wei Zhang: This subtype highlights the viral origin of gastric cancer, with EBV found in 9% of malignant epithelial cells of gastric cancer. EBV-type gastric cancer has higher levels of DNA hypermethylation (e.g. CIMP) than other cancers (e.g. colorectal cancer, endometrial cancer and glioblastoma) and a high frequency of PIK3CA gene mutations, with 80% having non-silent PIK3CA mutations, while other subtypes are rare this mutation (3% to 42%). The majority of PIK3CA mutations in EBV-negative gastric cancers occurred in the kinase region (exon 20), whereas in EBV types they were mostly disseminated. the efficacy of response to PI3K inhibitors in EBV-positive and -negative gastric cancers will be the focus of future research. In addition, elevated levels of PD-L1/2, an immunosuppressive protein that can serve as a target for enhanced antitumor immune response, suggest that PDL1/2 antagonists may be a new therapeutic option for this type of gastric cancer.