Background Reversible N⁶-methyladenosine (m⁶A) modifications in messenger RNAs can be categorized under the field of “RNA epigenetics.” However, the potential role of m⁶A-related genes in gastric cancer (GC) prognosis has not been systematically researched. Aims This study was aimed at providing insights into the prognostic role of m⁶A-related gene expression, at both mRNA and protein levels. Methods Kaplan–Meier (KM) plotter database and The Cancer Genome Atlas (TCGA) database were used to explore the prognostic significance of individual m⁶A-related genes in overall survival (OS) and progression-free survival at the mRNA level. For independent validation, the protein level of genes significantly associated with prognosis in both databases was further detected in 450 paired GC and corresponding adjacent non-tumor tissues using tissue microarray (TMA)-based immunohistochemistry (IHC). The relationship between the FTO and ALKBH1 expression and the clinicopathological characteristics was explored. Results Among nine m⁶A-related genes, aberrantly high mRNA expression of FTO and ALKBH1 was associated with poor OS in the KM and TCGA cohorts. However, the TMA-IHC indicated that protein expression of FTO and ALKBH1 was markedly downregulated in GC tissues. A lower protein level of ALKBH1 was closely correlated with larger tumor sizes (≥ 5 cm) and more advanced TNM stages, while lower FTO protein expression was associated with shorter OS in GC patients. Conclusions Aberrant expression of demethylase genes, FTO and ALKBH1, has a distinct prognostic value in GC patients, indicating that FTO and ALKBH1 may play vital roles in GC progression and metastasis.

Background: Because of dismal prognosis in gastric cancer, identifying relevant prognostic factors is necessary. Phosphoserine phosphatase (PSPH) exhibits different expression patterns in many cancers and has been reported to affect the prognosis of patients with cancer. In this study, we examined the prognostic role of metabolic gene PSPH in gastric cancer based on the TCGA dataset and our hospital–based cohort cases. Methods: We collected and analysed RNA-seq data of Pan-cancer and gastric cancer in the TCGA dataset and PSPH expression data obtained from immunohistochemical analysis of 243 patients with gastric cancer from Sun Yat-sen University cancer center. Further, Kaplan–Meier survival analysis and Cox analysis were used to assess the effect of PSPH on prognosis. The ESTIMATE and Cibersort algorithms were used to elucidate the relationship between PSPH and the abundance of immune cells using the TCGA dataset. Results: We observed that PSPH expression displayed considerably high in gastric cancer and it was significantly associated with inferior prognosis (P = 0.043). Surprisingly, there was a significant relationship between lower immune scores and high expression of PSPH (P < 0.05). Furthermore, patients with a low amount of immune cells exhibited poor prognosis (P = 0.046). The expression of PSPH significantly increased in activated memory CD4 T cells, resting NK cells and M0 macrophages (P = 0.037, < 0.001, and 0.005, respectively). Conclusions: This study highlighted that PSPH influences the prognosis of patients with gastric cancer, and this is associated with the infiltration of tumour immune cells, indicating that PSPH may be a new immune-related target for treating gastric cancer.

Lauren-classification and human epidermal growth factor receptor 2 (HER2) status are two important pathological features of gastric cancer patients. The prognostic value of HER2 in gastric cancer remains controversial. Intestinal type gastric cancer has better prognosis and higher HER2 positive proportion. What is the interaction between these two factors? We hypothesized that a combination of Lauren-classification and human epidermal growth factor receptor 2 (HER2) status (L-H status) might be more meaningful than either factor alone.

Background: Identification of activated epidermal growth factor receptor ( EGFR ) mutations and application of EGFR‐tyrosine kinase inhibitors (EGFR‐TKIs) have greatly changed the therapeutic strategies of non‐small‐cell lung cancer (NSCLC). However, the long‐term efficacy of EGFR‐TKI therapy is limited due to the development of drug resistance. The aim of this study was to investigate the correlation between the aberrant alterations of 8 driver genes and the primary resistance to EGFR‐TKIs in advanced NSCLC patients with activated EGFR mutations. Methods: We retrospectively reviewed the clinical data from 416 patients with stage III/IV or recurrent NSCLC who received an initial EGFR‐TKI treatment, from April 2004 and March 2011, at the Sun Yat‐sen University Cancer Center. Several genetic alterations associated with the efficacy of EGFR‐TKIs, including the alterations in BIM , ALK , KRAS , PIK3CA , PTEN , MET , IGF1R , and ROS1 , were detected by the routine clinical technologies. The progression‐free survival (PFS) and overall survival (OS) were compared between different groups using Kaplan–Meier survival analysis with the log‐rank test. A Cox regression model was used to estimate multivariable‐adjusted hazard ratios (HRs) and their 95% confidence intervals (95% CIs) associated with the PFS and OS. Results: Among the investigated patients, 169 NSCLC patients harbored EGFR‐sensitive mutations. EGFR‐mutant patients having PTEN deletion had a shorter PFS and OS than those with intact PTEN ( P = 0.003 for PFS, and P = 0.034 for OS). In the combined molecular analysis of EGFR signaling pathway and resistance genes, we found that EGFR‐mutant patients coexisted with aberrant alterations in EGFR signaling pathway and those having resistant genes had a statistically poorer PFS than those without such alterations ( P < 0.001). A Cox proportional regression model determined that PTEN deletion (HR = 4.29,95% CI = 1.72–10.70) and low PTEN expression (HR = 1.96, 95% CI = 1.22–3.13), MET FISH + (HR = 2.83,95% CI = 1.37–5.86) were independent predictors for PFS in patients with EGFR‐TKI treatment after adjustment for multiple factor. Conclusions: We determined that the coexistence of genetic alterations in cancer genes may explain primary resistance to EGFR‐TKIs.

Background: Genes related to the SWItch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex are frequently mutated across cancers. SWI/SNF-mutant tumors are vulnerable to synthetic lethal inhibitors. However, the landscape of SWI/SNF mutations and their associations with tumor mutational burden (TMB), microsatellite instability (MSI) status, and response to immune checkpoint inhibitors (ICIs) have not been elucidated in large real-world Chinese patient cohorts. Methods: The mutational rates and variation types of six SWI/SNF complex genes (ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, and PBRM1) were analyzed retrospectively by integrating next-generation sequencing data of 4591 cases covering 18 cancer types. Thereafter, characteristics of SWI/SNF mutations were depicted and the TMB and MSI status and therapeutic effects of ICIs in the SWI/SNF-mutant and SWI/SNF-non-mutant groups were compared. Results: SWI/SNF mutations were observed in 21.8% of tumors. Endometrial (54.1%), gallbladder and biliary tract (43.4%), and gastric (33.9%) cancers exhibited remarkably higher SWI/SNF mutational rates than other malignancies. Further, ARID1A was the most frequently mutated SWI/SNF gene, and ARID1A D1850fs was identified as relatively crucial. The TMB value, TMB-high (TMB-H), and MSI-high (MSI-H) proportions corresponding to SWI/SNF-mutant cancers were significantly higher than those corresponding to SWI/SNF-non-mutant cancers (25.8 vs. 5.6 mutations/Mb, 44.3% vs. 10.3%, and 16.0% vs. 0.9%, respectively; all p < 0.0001). Furthermore, these indices were even higher for tumors with co-mutations of SWI/SNF genes and MLL2/3. Regarding immunotherapeutic effects, patients with SWI/SNF variations showed significantly longer progression-free survival (PFS) rates than their SWI/SNF-non-mutant counterparts (hazard ratio [HR], 0.56 [95% confidence interval {CI} 0.44–0.72]; p < 0.0001), and PBRM1 mutations were associated with relatively better ICI treatment outcomes than the other SWI/SNF gene mutations (HR, 0.21 [95% CI 0.12–0.37]; p = 0.0007). Additionally, patients in the SWI/SNF-mutant + TMB-H (HR, 0.48 [95% CI 0.37–0.54]; p < 0.0001) cohorts had longer PFS rates than those in the SWI/SNF-non-mutant + TMB-low cohort. Conclusions: SWI/SNF complex genes are frequently mutated and are closely associated with TMB-H status, MSI-H status, and superior ICI treatment response in several cancers, such as colorectal cancer, gastric cancer, and non-small cell lung cancer. These findings emphasize the necessity and importance of molecular-level detection and interpretation of SWI/SNF complex mutations.