Chinese Gastric Cancer Patients Research Articles

Identification of common genetic variants in KCNQ family genes associated with gastric cancer survival in a Chinese population.

KCNQ family genes ( KCNQ1-5), encoding voltage-gated K + (Kv) channels, have been revealed to have potential pathophysiological roles in cancers. However, the associations between genetic variants located in KCNQ family genes and gastric cancer survival remain unclear. A large-scale cohort comprising 1,135 Chinese gastric cancer patients was enrolled to identify genetic variants in KCNQ family genes associated with overall survival (OS). Based on the survival evaluation of all five members, KCNQ1 was selected for subsequent genetic analysis. Cox regression models and stepwise Cox regression models were conducted to evaluate survival-related genetic variants. We found that KCNQ1 rs10832417 was associated with increased OS in gastric cancer patients (adjusted hazard ratio (HR) = 0.84, 95% confidence interval (CI): 0.72-0.98, P = 0.023). Subsequently, a nomogram was generated to support the prognostic capacity and clinical translation of rs10832417 variants. The rs10832417 T allele was predicted to increase the minimum free energy (MFE) of the secondary structure. Furthermore, we observed that gastric cancer patients with downregulation of KCNQ1 had poor survival in multiple public datasets. The present study found that KCNQ1 rs10832417 could serve as an independent prognostic predictor of gastric cancer, yielding novel insight into the progression and survival of gastric cancer.

Association of high-risk comorbidity with overall survival among patients with gastric cancer and its sex-specific differences in China: a retrospective observational cohort study

BackgroundConcomitant diseases often occur in cancer patients and are important in decision-making regarding treatments. However, information regarding the prognostic relevance of comorbidities for mortality risk is still limited among Chinese gastric cancer (GC) patients. This study aimed to investigate the association between comorbidities and 3-year mortality risk.MethodsThis retrospective study enrolled 376 GC patients undergoing radical gastrectomy at the Affiliated Zhongshan Hospital of Dalian University from January 2011 to December 2019. Demographic and clinicopathological information and treatment outcomes were collected. Patients were divided into low-, moderate- and high-risk comorbidity groups based on their Charlson Comorbidity Index (CCI) and age-adjusted CCI (ACCI) scores. Kaplan-Meier survival and Cox regression analyses were used to examine 3-year overall survival (OS) and mortality risk for each group.ResultsThe median follow-up time was 43.5 months, and 40.2% (151/376) of GC patients had died at the last follow-up. There were significant differences in OS rates between ACCI-based comorbidity groups (76.56; 64.51; 54.55%, log-rank P = 0.011) but not between CCI-based comorbidity groups (log-rank P = 0.16). The high-risk comorbidity group based on the ACCI remained a significant prognostic factor for 3-year OS in multivariate analysis, with an increased mortality risk (hazard ratio [HR], 1.99; 95% CI, 1.15–3.44). Subgroup analysis revealed that this pattern only held for male GC patients but not for female patients.ConclusionThe present study suggested that high-risk comorbidities were significantly associated with a higher mortality risk, particularly in Chinese male GC patients. Moreover, the ACCI score was an independent prognostic factor of long-term mortality.

Remote modulation of WWOX by an intronic variant associated with survival of Chinese gastric cancer patients.

The protein WWOX was reported to be involved in cancer progression via interaction with mTOR and DNA repair pathway. We previously reported noteworthy association of some single nucleotide polymorphisms (SNPs) in mTOR and DNA repair pathways with gastric cancer (GCa) patients' survival. We hypothesized that genetic variants in WWOX gene could predict the survival of GCa patients. By extracting WWOX genetic variants from our ongoing genome-wide association study including 796 GCa patients from an Eastern Chinese population, we identified 51 out of 1913 SNPs to be significantly associated with survival of GCa patients, which passed the false positive probability tests. In particular, the intronic variant rs9922483, a G>T change, was associated with 21% increased death risk for GCa patients (HR = 1.21, 95% CI = 1.04-1.42, P = .015). This locus was predicted to be involved in potential enhancer by bioinformatics analysis. Genotype-phenotype correlation analysis revealed decreased expression of WWOX by rs9922483 G>T change. Mechanistically, rs9922483 locus may exhibits long-range interaction with WWOX promoter, and the G>T change inhibited the transcriptional activity driven by WWOX promoter in luciferase reporter system. Especially, the G>T change had an allele-specific negative effect on NR3C1 binding, and NR3C1 promoted the expression of WWOX in GCa cells. Further functional analysis indicated an increase in proliferation, migration and invasion of GCa cells by knockdown of WWOX. In conclusion, WWOX genetic variants may modulate survival of Chinese GCa patients by exerting remote regulatory effect on WWOX expression. Our results highlight the cis-regulatory effect of genetic variants on genes and survival modulation for GCa patients.

Co-mutation-based subtyping of Chinese patients with gastric cancer.

e16070 Background: The incidence of gastric cancer is decreasing globally, in contrast, that of Chinese patients has been increased from 35.9% to 48.3%. In-depth investigation of the characteristic of Chinese gastric cancer patients could help to understand the disease mechanism and improve the treatment of gastric cancer. Methods: Tumor tissues were obtained from 96 Chinese gastric cancer patients and tested by high-coverage ( > 1000x) panel sequencing containing 624 cancer-related genes. Genomic mutations including substitutions, insertions, deletions, rearrangements, fusions, and copy number variations were called. Genes were clustered based on their co-mutation relationship in all samples. Patients with gene mutations in each cluster were classified into corresponding groups. The properties of each patient group were characterized, including genomic features, age, gender, stage, LAUREN type, and grade. Results: The most mutated genes were TP53, ERBB4, LRP1B, and CDH1 in our cohort. A higher proportion of female patients had TP53 mutations compared to male patients. Mutations in ALK, KMT2C, and LRP2 were positively associated with microsatellite-instable, and that in ERBB4 and PIK3CA were positively associated with high tumor mutation burden (TMB). Four gene clusters (1, 2, 3, and 4) were identified based on the co-mutation relationship between genes. Cluster 1 included FAT4, APC, OBSCN, and GATA3; Cluster 2 included FGF3, CCND1, FGF19, and GATA4; Cluster 3 included BLK, FAM135B, and DLC1; and Cluster 4 included ATRX, KMT2D, STAG2, and EGFR. Patients were classified into the four patient groups (I, II, III, and IV) accordingly when mutations in the corresponding gene cluster were found. Further association analysis indicated that: Group I was associated with adenocarcinoma subtype; Group II was negatively associated with LAUREN type 2; Group III was associated with high TMB; Cluster IV was associated with microsatellite-instable. Conclusions: This study utilized gene co-mutations to classify gastric cancer patients into subgroups with unique clinical characteristics. Further study on the etiology, treatment, and prognosis of these groups of patients is needed.

Comparison of EQ-5D-5L and EORTC QLU-C10D utilities in gastric cancer patients.

To compare measurement properties of the utility scores derived from various country-specific value sets of EQ-5D-5L (5L) and EORTC QLU-C10D (10D) in gastric cancer patient. The study used cross-sectional data of 243 Chinese gastric cancer patients who completed both 5L and EORTC QLQ-C30. Utility score of QLU-C10D is generated from all the available QLU-C10D value sets currently; the score of 5L is derived from the corresponding 5L value sets for the countries with both the 5L and QLU-C10D value sets and the Chinese 5L value set. Convergent validity was evaluated by testing their correlations with the VAS score. Known-group validity was assessed by comparing the utility scores the patients with different severities. Their relative efficiency (RE) was also compared. Correlation coefficient of 5L and QLU-C10D utility scores with VAS ranged from 0.54 to 0.59, and 0.55 to 0.63, respectively. Both the utility scores were in general able to discriminate the patients with different severities; and 5L utility score had higher RE in the majority of known-groups. EQ-5D-5L and QLU-C10D utility scores were different and, thus, non-swappable. They possess similar convergent validity and known-group validity; while EQ-5D-5L scores may have better discriminative power.

Efficacy of AS versus SOX regimen as first-line chemotherapy for gastric cancer patients with peritoneal metastasis: a real-world study

BackgroundTo compare the prognosis of first-line systemic chemotherapy of AS (Albumin-bound paclitaxel and S-1) versus SOX (S-1 and oxaliplatin) regimen in Chinese gastric cancer patients with peritoneal metastasis.MethodsThis was a real-world study of gastric cancer patients with peritoneal metastasis who have been treated with AS or SOX regimen as first-line chemotherapy. Patients were matched by the method of propensity score matching (PSM). The primary and secondary endpoints were overall survival (OS) and progress-free survival (PFS).ResultsA total of 108 gastric cancer patients with peritoneal metastasis were enrolled after PSM analysis. There was no significant difference between AS and SOX regimen based on gender, age, ascites, treatment cycles, gastric cancer resection, received checkpoint inhibitors, and HER-2 expression after PSM analysis. The median OS (14.13 vs. 11.17 months, p = 0.0356) and median PFS (10.30 vs. 6.70 months, p = 0.0003) of patients who received AS regimen were longer than those treated by SOX regimen as first-line systemic chemotherapy. In sub-group analysis, the median OS and median PFS were longer for patients in AS regimen than SOX regimen in Lauren diffuse type. The occurrence of toxicity between the two groups was shown no significant difference.ConclusionsThe results verified that AS regimen was more effective than SOX chemotherapy in gastric cancer patients with peritoneal metastasis, especially in Lauren diffuse type.

Integrated DNA and RNA sequencing reveals early drivers involved in metastasis of gastric cancer

Gastric cancer (GC) is the second cause of cancer-related death and metastasis is an important cause of death. Considering difficulties in searching for metastatic driver mutations, we tried a novel strategy here. We conducted an integrative genomic analysis on GC and identified early drivers lead to metastasis. Whole-exome sequencing (WES), transcriptomes sequencing and targeted-exome sequencing (TES) were performed on tumors and matched normal tissues from 432 Chinese GC patients, especially the comparative analysis between higher metastatic-potential (HMP) group with T1 stage and lymph-node metastasis, and lower metastatic-potential (LMP) group without lymph-nodes or distant metastasis. HMP group presented higher mutation load and heterogeneity, enrichment in immunosuppressive signaling, more immune cell infiltration than LMP group. An integrated mRNA-lncRNA signature based on differentially expressed genes was constructed and its prognostic value was better than traditional TNM stage. We identified 176 candidate prometastatic mutations by WES and selected 8 genes for following TES. Mutated TP53 and MADCAM1 were significantly associated with poor metastasis-free survival. We further demonstrated that mutated MADCAM1 could not only directly promote cancer cells migration, but also could trigger tumor metastasis by establishing immunosuppressive microenvironment, including promoting PD-L1-mediated immune escape and reprogramming tumor-associated macrophages by regulating CCL2 through Akt/mTOR axis. In conclusion, GCs with different metastatic-potential are distinguishable at the genetic level and we revealed a number of potential metastatic driver mutations. Driver mutations in early-onset metastatic GC could promote metastasis by establishing an immunosuppressive microenvironment. This study provided possibility for future target therapy of GC.

Radiomics model based on preoperative 18F-fluorodeoxyglucose PET predicts N2-3b lymph node metastasis in gastric cancer patients.

The aim of the study was to construct and validate 18F-fluorodeoxyglucose (18F-FDG) PET-based radiomics nomogram and use it to predict N2-3b lymph node metastasis in Chinese patients with gastric cancer (GC). A total of 127 patients with pathologically confirmed GC who underwent preoperative 18F-FDG PET/CT imaging between January 2014 and September 2020 were enrolled as subjects in this study. We use the LIFEx software to extract PET radiomic features. A radiomics signature (Rad-score) was developed with the least absolute shrinkage and selection operator algorithm. Then a prediction model, which incorporated the Rad-score and independent clinical risk factors, was constructed and presented with a radiomics nomogram. Receiver operating characteristic (ROC) analysis was used to assess the performance of Rad-score and the nomogram. Finally, decision curve analysis (DCA) was applied to evaluate the clinical usefulness of the nomogram. The PET Rad-score, which includes four selected features, was significantly related to pN2-3b (all P < 0.05). The prediction model, which comprised the Rad-score and carcinoembryonic antigen (CEA) level, showed good calibration and discrimination [area under the ROC curve: 0.81(95% confidence interval: 0.74-0.89), P < 0.001)]. The DCA also indicated that the prediction model was clinically useful. This study presents a radiomics nomogram consisting of a radiomics signature based on PET images and CEA level that can be conveniently used for personalized prediction of high-risk N2-3b metastasis in Chinese GC patients.

Microsatellite instability in Chinese gastric cancer and its correlation with clinical characteristics.

Microsatellite instability (MSI) remains a focus of interest in cancer research, but the characteristics of MSI in gastric cancer (GC) are ambiguous. In this retrospective study, we analyzed the prevalence of MSI and the expression of programmed death-ligand 1 (PD-L1) and cluster of differentiation 8 (CD8) cells in Chinese GC patients. A total of 393 GC patients admitted to two centers from January 2010 to December 2017 were enrolled. The prevalence of MSI in this cohort was 3.4% and most frequently occurred in females, patients aged between 59 and 69 years, and patients at a lower clinical stage. All MSI GCs had CD8 expression but lacked PD-L1 expression, indicating that MSI was related to CD8 expression but irrelevant to PD-L1 expression. However, there was no significant difference in the expression of CD8/PD-L1 between MSI GC and microsatellite stable (MSS) GC. Kaplan-Meier survival curves revealed that patients with MSI had a significantly longer overall survival (OS) than patients with MSS. In Chinese GC patients, MSI frequently occurred in females, patients aged between 59 and 69, and patients with lower clinical stages. Patients with MSI-High (MSI-H) and MSI-Low (MSI-L) had a longer OS than patients with MSS. MSI was related to CD8 expression but irrelevant to PD-L1 expression.

Tumor mutation burden is correlated with response and prognosis in microsatellite-stable (MSS) gastric cancer patients undergoing neoadjuvant chemotherapy.

Neoadjuvant chemotherapy (NACT) before radical gastrectomy is preferred for locally advanced gastric cancer (GC). However, clinical practices demonstrate that a considerable proportion of GC patients do not benefit from NACT, largely due to the lack of biomarkers for patient selection and prognosis prediction. A recent study revealed that patients with microsatellite instability-high (MSI-H) may be resistant to NACT, however, most tumors in Chinese GC patients (~ 95%) are characterized by microsatellite stability (MSS). Here, we aimed to discover new molecular biomarkers for this larger population. We performed whole-exome sequencing on 46 clinical samples (pre- and post-treatment) from 30 stage II/III MSS GC patients whose response to NACT was rigorously defined. Serum tumor markers (TMs), including AFP, CEA, CA199, CA724 and CA242 were measured during the course. High tumor mutation burden (TMB-H) and 19q12 amplification (19q12 +) were positively associated with the NACT response. When TMB and 19q12 amplification were jointly analyzed, those with TMB-H or 19q12 + showed favorable response to NACT (p = 0.035). Further, TMB-H was negatively correlated with ypN stage, lymph node metastasis, and macrophage infiltration. Patients with TMB-H showed better disease-free survival (DFS) than those with TMB-L (P = 0.025, HR = 0.1331), and this was further validated using two larger GC datasets: TCGA-STAD (p = 0.004) and ICGC-CN (p = 0.045). The combination of TMB-H and 19q12 + can serve as an early indicator of response to NACT. Superior to traditional clinical indicators, TMB-H is a robust and easily accessible candidate biomarker associated withbetter DFS, and can be evaluated at the time of diagnosis.

Lymph node metastasis risk factors and applicability of endoscopic submucosal dissection in mixed-type early gastric cancer in Chinese patients.

To analyze the risk factors of lymph node metastasis (LNM) of mixed-type early gastric cancer (EGC), and to explore whether endoscopic submucosal dissection (ESD) is applicable to mixed-type EGC in Chinese patients. A total of 812 EGC patients were included. We classified the lesions into four types: pure moderately differentiated (PMD) adenocarcinoma, mixed predominantly moderately differentiated (MMD) type, mixed predominantly poorly differentiated (MPD) type, and pure poorly differentiated (PPD) adenocarcinoma. LNM risk factors in EGC were evaluated by univariate and multivariate analyses, and the feasibility of ESD in mixed-type EGC was estimated. The LNM rate in mixed-type EGC was 24.7% (68/275). Tumor size [odds ratio (OR) =1.419, P=0.008], MPD (OR =3.278, P=0.002), submucosal invasion ≥500 µm (OR =5.059, P=0.002), and lymphovascular invasion (LVI) (OR =5.836, P<0.001) were independent predictors of LNM in mixed-type EGC. LNM was more common in MMD patients than in PMD patients who met the expanded indications for ESD of differentiated EGC (0.0% vs. 7.84%, P=0.005). Tumor size, histology, invasion depth, and LVI are independent risk factors for LNM in mixed-type EGC. The absolute indications for ESD are applicable to MMD, and the feasibility of the expanded indications for ESD in MMD and MPD requires further investigation in Chinese patients.

A multicenter study assessing the prevalence of germline genetic alterations in Chinese gastric-cancer patients.

BackgroundApproximately 10% of patients with gastric cancer (GC) have a genetic predisposition toward the disease. However, there is scant knowledge regarding germline mutations in predisposing genes in the Chinese GC population. This study aimed to determine the spectrum and distribution of predisposing gene mutations among Chinese GC patients known to have hereditary high-risk factors for cancer.MethodsA total of 40 GC patients from 40 families were recruited from seven medical institutions in China. Next-generation sequencing was performed on 171 genes associated with cancer predisposition. For probands carrying pathogenic/likely pathogenic germline variants, Sanger sequencing was applied to validate the variants in the probands as well as their relatives.ResultsAccording to sequencing results, 25.0% (10/40) of the patients carried a combined total of 10 pathogenic or likely pathogenic germline variants involving nine different genes: CDH1 (n = 1), MLH1 (n = 1), MSH2 (n = 1), CHEK2 (n = 1), BLM (n = 1), EXT2 (n = 1), PALB2 (n = 1), ERCC2 (n = 1), and SPINK1 (n = 2). In addition, 129 variants of uncertain significance were identified in 27 patients.ConclusionsThis study indicates that approximately one in every four Chinese GC patients with hereditary high risk factors may harbor pathogenic/likely pathogenic germline alterations in cancer-susceptibility genes. The results further indicate a unique genetic background for GC among Chinese patients.

Integrated DNA and RNA sequencing to reveal early drivers of metastasis in gastric cancer.

e16096 Background: Gastric cancer (GC) is the second cause of cancer-related death and metastasis is an important cause of death. Considering difficulties in searching for metastatic driver mutations, we tried a novel strategy to identify early drivers in primary gastric tumors. In this study, we conducted an integrative genomic analysis on GC patients and identified early drivers that lead to metastases. Methods: Tumors and matched normal tissues from 400 Chinese GC patients were characterized by whole-exome sequencing (WES), transcriptome sequencing and targeted exome sequencing (TES), especially the comparative analysis results between higher metastatic potential (HMP) group with T1 stage and lymph-node metastases, and lower metastatic potential (LMP) group without lymph-nodes or distant metastases. Functional experiments on candidate driver mutations were applied in GC cell lines to explore their roles in metastasis and immune escape. Results: HMP group presented higher mutation load and heterogeneity, enrichment in immunosuppressive signaling, lower tumor purity, more stromal and immune cell infiltration than LMP group. We identified 262 differentially expressed mRNA, lncRNA and miRNA between HMP and LMP group (with more than twice proportion of 2-fold increased or decreased tumor than normal tissue in HMP than LMP group, and with significantly 2-fold higher or lower in HMP tumors than LMP tumors). 168 candidate prometastatic mutations were found by WES and 8 were selected for following TES to detect their association with distant metastasis. We found that four candidate mutations were related to distant metastasis and mutated TP53 and MADCAM1 were significantly associated with poor metastasis-free survival. It’s worth noting that though with low mutational rate, MADCAM1 mutations were only observed in patients with metastasis within three years after surgery or at diagnosis. We demonstrated that MADCAM1-mutated proteins act as GOF mutants and could not only directly promote cancer cells migration, but also could trigger tumor metastasis by establishing complicated immunosuppressive microenvironment, including promoting PD-L1-mediated immune escape and reprogramming tumor-associated macrophages (TAMs). Conclusions: Our results showed that the GCs with different metastatic potential are distinguishable at the genetic level. A number of potential metastatic driver mutations was revealed in this study including known cancer-associated genes TP53. We also discovered some novel driver mutations, such as MADCAM1. The results indicate driver mutations in early-onset metastatic GC could promote metastasis not only by directly empower cancer cells to disseminate but also by establishing an immunosuppressive microenvironment. This study increased the understanding of molecular landscape of GC patients and provided possibility for future target therapy.

Amplification of the human epidermal growth factor receptor 2 (HER2) gene is associated with a microsatellite stable status in Chinese gastric cancer patients.

Gastric cancer (GC) is one of the most common cancers worldwide. However, little is known about the combination of HER2 amplification and microsatellite instability (MSI) status in GC. This study aimed to analyze the correlation of HER2 amplification with microsatellite instability (MSI) status, clinical characteristics, and the tumor mutational burden (TMB) of patients. A total of 192 gastric cancer (GC) patients were enrolled in this cohort. To analyze genomic alterations (GAs), deep sequencing was performed on 450 target cancer genes. TMB was measured by an in-house algorithm. MSI status was inferred based on the MANTIS (Microsatellite Analysis for Normal-Tumor InStability) score. The most frequently amplified genes in the GC patients included cyclin E1 (CCNE1), human epidermal growth factor receptor 2 (HER2), fibroblast growth factor receptor 2 (FGFR2), cyclin D1 (CCND1), fibroblast growth factor 19 (FGF19), fibroblast growth factor 3 (FGF3), and fibroblast growth factor 4 (FGF4). The frequency of HER2 amplification was 9.38% (18/192). HER2 amplification was higher in females than in males (14.52% vs. 6.92%, respectively, P=0.091), however, MSI was higher in males compared to females (7.69% vs. 4.84%, respectively, P=0.46). HER2 amplification was higher in metastatic loci compared to primary lesions (23.08% vs. 8.38%, respectively, P=0.079) and was lower in patients with high TMB (TMB-H) compared to those with low TMB (TMB-L) (4.0% vs. 11.35%, respectively, P=0.12). While the frequency of MSI in metastatic foci was higher than that in primary lesions (15.38% vs. 6.15%, respectively, P=0.48), MSI status was highly associated with TMB-H (20% vs. 0%, respectively, P=3.66×10-7). Furthermore, HER2 amplification was negatively correlated with MSI status in Chinese GC patients. HER2 amplification was negatively correlated with TMB-H and MSI status, and MSI status was significantly associated with TMB-H in Chinese GC patients. These data suggested that HER2 amplification might be a negative indicator for GC immunotherapy.

Genomic variants in Fas-mediated apoptosis pathway predict a poor response to Platinum-based Chemotherapy for Chinese Gastric Cancer Patients.

Platinum-based adjuvant chemotherapy is very common for gastric cancer (GC) patients, but the chemotherapy sensitivity is very heterogeneous. The genomic variants and the gene-gene interactions involved in Fas-mediated apoptosis pathway including Fas (FAS 1377 G > A and 670 A > G), FasL (FASL 844 C > T) and caspase-8 (CASP8 -652 6N ins > del or I > D), may paly vital roles in the response to platinum-based treatment. In our investigation, 662 stage II-III postoperative GC patients were enrolled between 1998 and 2006. 261 patients accepted platinum-based regimens and the remaining 401 were not. The log rank tests, Kaplan Meier plots, Pearson chi-square tests, Student t-tests and Cox regression analyses were performed. For the chemotherapy cohort, FAS 1377 G > A or FAS 670 A > G variants alone was related with inferior survival, and a greater than additive effect was identified when patients simultaneously carrying FAS 1377 GA and FAS 670 GA genotypes. But the poor response was neutralized when patients simultaneously carrying FASL 844 C > T or CASP8 -652 6N ins > del mutations. Our study suggested that FAS 1377 G > A and FAS 670 A > G variants may serve as potential biomarkers to predict the response to platinum-based adjuvant chemotherapy, and the gene-gene interactions involved in Fas-mediated apoptosis pathway may enhance or neutralize the chemosensitivity.

Efficacy of Postoperative FOLFOX Versus XELOX Chemotherapy for Gastric Cancer and Prognostic Value of Platelet-Lymphocyte Ratio in Patients Receiving XELOX.

BackgroundSurgery combined with postoperative chemotherapy is an effective method for treating patients with gastric cancer (GC) in Asia. The important roles of systemic inflammatory response in chemotherapy have been gradually verified. The purpose of this study was to assess the difference in clinical effectiveness of FOLFOX (oxaliplatin + leucovorin + 5-fluorouracil) and XELOX (oxaliplatin + capecitabine), and the prognostic value of postoperative platelet–lymphocyte ratio (PLR) in the XELOX group.MethodsPatients who received radical gastrectomy combined with postoperative chemotherapy between 2004 and 2014 were consecutively selected into the FOLFOX and XELOX groups. Group bias was reduced through propensity score matching, which resulted in 278 patients in each group. Cut-off values of systemic immune inflammation (SII) score and PLR were obtained by receiver operating characteristic curve. Kaplan–Meier and Log-rank tests were used to analyze overall survival. The chi-square test was used to analyze the association between clinical characteristics and inflammatory indexes. Univariate and multivariate analyses based on Cox regression analysis showed independent risk factors for prognosis. The nomogram was made by R studio.ResultsPatients receiving XELOX postoperative chemotherapy had better survival than those receiving FOLFOX (P < 0.001), especially for stage III GC (P = 0.002). Preoperative SII was an independent risk factor for prognosis in the FOLFOX group, and PLR of the second postoperative chemotherapy regimen in the XELOX group, combined with tumor size and pTNM stage, could construct a nomogram for evaluating recurrence and prognosis.ConclusionXELOX is better than FOLFOX for treatment of GC in Chinese patients, and a nomogram constructed by PLR, tumor size and pTNM stage can predict recurrence and prognosis.

Identification of "regulation of RhoA activity panel" as a prognostic and predictive biomarker for gastric cancer.

RhoA is a member of the RHO family GTPases and is associated with essential functions in gastric cancer. In this study, we identified a gastric cancer biomarker, termed the “regulation of RhoA activity panel” (RRAP). Patients with gastric cancer from The Cancer Genome Atlas database were divided into training (N=160) and validation (N=155) cohorts. A cohort of 109 Chinese gastric cancer patients was utilized as an independent validation. Patients with mutated RRAP showed significantly better overall survival than patients with wild type RRAP. We also analyzed the association between RRAP and the migration capacity, immune-related signatures, and the tumor microenvironment. RRAP-mutant tumors had a significantly lower degree of lymph node metastasis and lower activities of migration-related pathways. These tumors also showed significantly increased immune cell infiltration and cytotoxic activity. Furthermore, two independent patient cohorts who received immune checkpoint blockade therapy were assessed for RRAP mutant status. As expected, for both immunotherapy cohorts, higher response rates to immune checkpoint blockade therapy were observed in patients with RRAP-mutant tumors than in patients with wild type RRAP tumors. Overall, this study indicates that the RRAP gene set is a potential biomarker for gastric cancer prognosis and therapeutic selection.

CD36 upregulates DEK transcription and promotes cell migration and invasion via GSK-3β/β-catenin-mediated epithelial-to-mesenchymal transition in gastric cancer.

Evidence indicates that the lipid scavenger receptor CD36 has pro-metastatic functions in several cancers. Although CD36 expression correlates with an unfavorable prognosis in gastric cancer (GC), its specific contribution to disease onset, progression, and/or metastasis remains unclear. Using bioinformatics analyses, we ascertained that CD36 expression was increased in metastatic GC specimens in The Cancer Genome Atlas and Gene Expression Omnibus databases and correlated with poor prognosis. In addition, higher CD36 expression was associated with lymph node metastasis (p < 0.05) and poor prognosis (p = 0.030) in 79 Chinese GC patients. Basal CD36 expression levels correlated positively with migration, invasion, and expression of epithelial-to-mesenchymal transition (EMT) markers in GC cell lines, a relationship confirmed by knockdown and overexpression experiments. Importantly, analysis of gene expression changes in CD36-knockdown GC cells led us to identify the chromatin-associated protein DEK as a c-Myc target that mediates activation of the GSK-3β/β-catenin signaling pathway to trigger EMT. These findings further our understanding of the mechanisms governing metastatic dissemination of GC cells and suggest the therapeutic potential of strategies targeting CD36.

Functional variation of SLC52A3 rs13042395 predicts survival of Chinese gastric cancer patients.

The solute carrier family 52 member 3 (SLC52A3) gene encodes riboflavin transporter protein which is essential to maintain mitochondrial function in cells. In our research, we found that SLC52A3 rs13042395 C > T variation was significantly associated with poor survival in a 926 Chinese gastric cancer (GCa) patients cohort (CC/CT genotype versus TT genotype, HR = 0.57, 95%CI (0.40‐0.82), log‐rank P = 0.015). The SLC52A3 rs13042395 C > T change led to its increased mRNA expression according to expression quantitative trait loci analysis (P = 0.0029). In vitro, it was revealed that rs13042395 C allele had higher binding affinity to inhibitory transcription factor Meis homeobox 1 (MEIS1) compared with T allele, knock‐down of MEIS1 could up‐regulate SLC52A3, and overexpression of SLC52A3 contributed to the increased ability of proliferation, colony formation, migration and invasion in GCa cells. Subsequently, the bioinformatics analysis combined with experiments in vitro suggested that Gap junction protein alpha 1 (GJA1) was the downstream effector of SLC52A3, SLC52A3 may promote the GCa cells aggressiveness by down‐regulating the GJA1 expression. Overall, SLC52A3 genetic variant rs13042395 C > T change was associated with poorer survival in Chinese GCa patients and increased SLC52A3 expression by interaction with MEIS1. SLC52A3 promoted the GCa cells aggressiveness by down‐regulating the GJA1 expression.

116P PD-L1 expression profile and microsatellite instability status in Chinese gastric cancer patients

116P PD-L1 expression profile and microsatellite instability status in Chinese gastric cancer patients