Noninvasive predictive models based on lifestyle analysis and risk factors for early-onset colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) incidence has increased among patients aged <50 years. Exploring high-risk factors and screening high-risk populations may help lower early-onset CRC (EO-CRC) incidence. We developed noninvasive predictive models for EO-CRC and investigated its risk factors. METHODS: This retrospective multicenter study collected information on 1756 patients (811 patients with EO-CRC and 945 healthy controls) from two medical centers in China. Sociodemographic features, clinical symptoms, medical and family history, lifestyle, and dietary factors were measured. Patients from one cohort were randomly assigned (8:2) to two groups for model establishment and internal validation, and another independent cohort was used for external validation. Multivariable logistic regression, random forest, and eXtreme Gradient Boosting (XGBoost) were performed to establish noninvasive predictive models for EO-CRC. Some variables in the model influenced EO-CRC occurrence and were further analyzed. Multivariable logistic regression analysis yielded adjusted odd ratios (ORs) and 95% confidence intervals (CIs). RESULTS: All three models showed good performance, with areas under the receiver operator characteristic curves (AUCs) of 0.82, 0.84, and 0.82 in the internal and 0.78, 0.79, and 0.78 in the external validation cohorts, respectively. Consumption of sweet (OR 2.70, 95% CI 1.89-3.86, P < 0.001) and fried (OR 2.16, 95% CI 1.29-3.62, P < 0.001) foods ≥3 times per week was significantly associated with EO-CRC occurrence. CONCLUSION: We established noninvasive predictive models for EO-CRC and identified multiple nongenetic risk factors, especially sweet and fried foods. The model has good performance and can help predict the occurrence of EO-CRC in the Chinese population.

MAOA suppresses the growth of gastric cancer by interacting with NDRG1 and regulating the Warburg effect through the PI3K/AKT/mTOR pathway.

OBJECTIVE: Previous studies have indicated that neurotransmitters play important roles in the occurrence and development of gastric cancer. MAOA is an important catecholamine neurotransmitter-degrading enzyme involved in the degradation of norepinephrine, epinephrine and serotonin. To find a potential therapeutic target for the treatment of gastric cancer, the biological functions of MAOA and the underlying mechanism in gastric cancer need to be explored. METHODS: The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO) datasets, Kaplan‒Meier (KM) plotter were used to identify the differentially expressed genes, which mainly involved the degradation and synthesis enzymes of neurotransmitters in gastric cancer. We also investigated the expression pattern of MAOA in human and mouse tissues and cell lines by immunohistochemistry and Western blotting analysis. Western blotting, quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA) and a Seahorse experiment were used to identify the molecular mechanism of cancer cell glycolysis. MAOA expression and patient survival were analysed in the Ren Ji cohort, and univariate and multivariate analyses were performed based on the clinicopathological characteristics of the above samples. RESULTS: MAOA expression was significantly downregulated in gastric cancer tissue and associated with poor patient prognosis. Moreover, the expression level of MAOA in gastric cancer tissue had a close negative correlation with the SUXmax value of PET-CT in patients. MAOA suppressed tumour growth and glycolysis and promoted cancer cell apoptosis. We also reported that MAOA can interact with NDRG1 and regulate glycolysis through suppression of the PI3K/Akt/mTOR pathway. MAOA expression may serve as an independent prognostic factor in gastric cancer patients. CONCLUSIONS: MAOA attenuated glycolysis and inhibited the progression of gastric cancer through the PI3K/Akt/mTOR pathway. Loss of function or downregulation of MAOA can facilitate gastric cancer progression. Overexpression of MAOA and inhibition of the PI3K/Akt/mTOR pathway may provide a potential method for gastric cancer treatment in clinical therapeutic regimens.

HUNK inhibits epithelial-mesenchymal transition of CRC via direct phosphorylation of GEF-H1 and activating RhoA/LIMK-1/CFL-1.

Epithelial-mesenchymal transition (EMT) is associated with the invasive and metastatic phenotypes in colorectal cancer (CRC). However, the mechanisms underlying EMT in CRC are not completely understood. In this study, we find that HUNK inhibits EMT and metastasis of CRC cells via its substrate GEF-H1 in a kinase-dependent manner. Mechanistically, HUNK directly phosphorylates GEF-H1 at serine 645 (S645) site, which activates RhoA and consequently leads to a cascade of phosphorylation of LIMK-1/CFL-1, thereby stabilizing F-actin and inhibiting EMT. Clinically, the levels of both HUNK expression and phosphorylation S645 of GEH-H1 are not only downregulated in CRC tissues with metastasis compared with that without metastasis, but also positively correlated among these tissues. Our findings highlight the importance of HUNK kinase direct phosphorylation of GEF-H1 in regulation of EMT and metastasis of CRC.

Microbiota-derived tryptophan catabolites mediate the chemopreventive effects of statins on colorectal cancer.

Epidemiological studies have indicated an association between statin use and reduced incidence of colorectal cancer (CRC), and work in preclinical models has demonstrated a potential chemopreventive effect. Statins are also associated with reduced dysbiosis in the gut microbiome, yet the role of the gut microbiome in the protective effect of statins in CRC is unclear. Here we validated the chemopreventive role of statins by retrospectively analysing a cohort of patients who underwent colonoscopies. This was confirmed in preclinical models and patient cohorts, and we found that reduced tumour burden was partly due to statin modulation of the gut microbiota. Specifically, the gut commensal Lactobacillus reuteri was increased as a result of increased microbial tryptophan availability in the gut after atorvastatin treatment. Our in vivo studies further revealed that L. reuteri administration suppressed colorectal tumorigenesis via the tryptophan catabolite, indole-3-lactic acid (ILA). ILA exerted anti-tumorigenic effects by downregulating the IL-17 signalling pathway. This microbial metabolite inhibited T helper 17 cell differentiation by targeting the nuclear receptor, RAR-related orphan receptor γt (RORγt). Together, our study provides insights into an anti-cancer mechanism driven by statin use and suggests that interventions with L. reuteri or ILA could complement chemoprevention strategies for CRC.

Progressive abdominal pain with acute exacerbation due to retroperitoneal follicular dendritic cell sarcoma: a case report with targeted genomic sequencing analysis.

BACKGROUND: Follicular dendritic cell sarcoma (FDCS) is a rare malignancy that arises from follicular dendritic cells and typically presents as a slow-growing painless mass without specific symptoms. Here we report an unusual case of a 55-year-old female with retroperitoneal FDCS who presented with progressive abdominal pain onset and acute exacerbation. METHODS: On CTA, a middle-upper abdominal mass (58*40 mm) was shown with multiple enlarged lymph nodes. After en-bloc resection of the tumor, the patient recovered completely from her symptoms and was discharged without complication. One month later, the patient returned for follow-up and the relevant tests were completed. RESULTS: In this case, CA724 elevated significantly and seemed to be associated with tumor progression. The results of positron emission tomography/computed tomography (PET/CT) and radiological examinations, including magnetic resonance imaging (MRI) and computed tomography angiography (CTA), were discussed to improve our understanding of diagnostic tools on FDCS. Targeted genomic sequencing analysis revealed three novel gene mutations, EPHA3 (nonsense mutation), DDR2 (SNV), and BIRC3 (InDel). CONCLUSION: We reported an unusual case of retroperitoneal FDCS with acute exacerbated abdominal pain. The interpretations of CA724, PET/CT, as well as imaging results deserve further investigation in FDCS. Genomic sequencing revealed three novel gene mutations in FDCS, including EPHA3 (nonsense mutation), DDR2 (SNV), and BIRC3 (InDel).

Recent advances in multidisciplinary therapy for adenocarcinoma of the esophagus and esophagogastric junction.

Esophageal adenocarcinoma (EAC) and adenocarcinoma of the esophagogastric junction (EGJA) have long been associated with poor prognosis. With changes in the spectrum of the disease caused by economic development and demographic changes, the incidence of EAC and EGJA continues to increase, making them worthy of more attention from clinicians. For a long time, surgery has been the mainstay treatment for EAC and EGJA. With advanced techniques, endoscopic therapy, radiotherapy, chemotherapy, and other treatment methods have been developed, providing additional treatment options for patients with EAC and EGJA. In recent decades, the emergence of multidisciplinary therapy (MDT) has enabled the comprehensive treatment of tumors and made the treatment more flexible and diversified, which is conducive to achieving standardized and individualized treatment of EAC and EGJA to obtain a better prognosis. This review discusses recent advances in EAC and EGJA treatment in the surgical-centered MDT mode in recent years.

Delivery of LINC00589 via mesoporous silica nanoparticles inhibits peritoneal metastasis in gastric cancer.

Peritoneal metastasis is one of the common forms of metastasis in gastric cancer (GC). In this study, we identified the expression pattern of LINC00589 in GC patients and investigate the biological function in GC cells. RNA-pulldown assay was performed to explore the underlying molecular mechanism. Further, we utilize polyethyleneimine-modified mesoporous silica nanoparticles (PMSNs) as the nanocarriers for delivery of LINC00589 encoding plasmid and tested its therapeutic potential for GC with peritoneal dissemination. We revealed that LINC00589 was downregulated in GC tissues and suppressed the metastatic ability of GC cells. Mechanistically, LINC00589 exerted tumor suppressive function by promoting hnRNPA1 protein ubiquitination and proteasomal degradation, thus blocking alternative splicing of PKM to PKM2. Furthermore, LINC00589 delivered by PMSNs could suppress the peritoneal metastasis of GC in vivo and in vitro. This work may provide a new treatment option in GC peritoneal metastasis.

Efficacy and Safety of Camrelizumab in Combination with Docetaxel + S-1 Sequenced by Camrelizumab + S-1 for Stage III (PD-1+/MSI-H/EBV+/dMMR) Gastric Cancer: Study Protocol for a Single-Center, Prospective, Open-Label, Single-Arm Trial.

Background: Gastric cancer occupies the fourth highest morbidity rate of cancers worldwide. A higher incidence of gastric cancer had been found in East Asia compared to the other regions. Gastrectomy with radical lymph node dissection is the cornerstone of curative treatment for Stage III gastric cancer, and postoperative systemic chemotherapy with docetaxel, S-1 improved patients' disease-free survival rates. However, advances in immunotherapy bring innovations in the management of patients with gastric cancer. The objective of this study was to explore the efficacy and safety of camrelizumab in combination with docetaxel + S-1, sequenced by camrelizumab + S-1 in stage III gastric cancer patients who are EBV positive, with defective mismatch repair and CPS ≥5. Methods and analysis: This prospective, open-label, single-arm trial was performed at Renji Hospital. In this study, a total of 70 adult patients aged 18-80 years with Stage III (PD-1+/MSI-H/EBV+/dMMR) gastric cancer confirmed by post-operative pathology will be enrolled after screening. Participants will receive the specific chemotherapy regimen until 1 year after the operation or until tumor recurrence or metastasis. The primary outcome is the 3-year disease-free survival rate measured by the Clopper-Pearson method and 95% confidence intervals. The secondary outcomes include overall survival, incidence and severity of adverse effects, and laboratory abnormalities. The data will be analyzed by the Kaplan-Meier method and log-rank test. The patients will be followed up every 3 months with imaging investigation until clinical remission. Ethics and dissemination: All participants will provide informed consent. The protocol has been approved by the Shanghai Jiaotong University School of Medicine, Renji Hospital Ethics Committee (KY2019-191). The results will be disseminated through peer-reviewed manuscripts, reports and presentations. Clinical Trial Registration: ClinicalTrials.gov, identifier: ChiCTR1900027123. Registration date November 2019; first enrolment December 2019; expected end date December 2021; trial status: Ongoing. Brief Abstract: A clinical trial for Stage III (PD-1+/MSI-H/EBV+/dMMR) gastric cancer patients who accepted anti-PD-1 therapy combined with docetaxel + S-1 as the first-line treatment and explored improvements in three-year disease-free survival rate.

The nerve-tumour regulatory axis GDNF-GFRA1 promotes tumour dormancy, imatinib resistance and local recurrence of gastrointestinal stromal tumours by achieving autophagic flux.

Complete surgical resection, accessible therapeutic targets and effective tyrosine kinase inhibitors (TKIs) have not completely cured gastrointestinal stromal tumours (GISTs), with most patients suffering from residual tumours and recurrence. The existence of nerve infiltration in GIST provides a way for tumour cells to escape local resection and systemic targeted therapy, which may challenge the previous understanding of its behaviour patterns and inspire the development of more radical excision and more precise targeted therapy. Moreover, tumour dormancy has emerged as a major cause of drug resistance and tumour relapse. Among these pathways, the nerve-tumour regulatory axis GDNF-GFRA1 is activated in GISTs, assists tumour cells in achieving dormancy and protects them from apoptosis under environmental stress by enhancing autophagic flux. The concrete mechanism is that the GDNF-regulating interaction between GFRA1 and the lysosomal calcium channel MCOLN1 activates Ca2+-dependent TFEB signalling. Activated TFEB transcriptionally regulates intracellular lysosome levels, which could achieve feedback upregulation of cellular autophagy flux during TKI treatment. This dormancy-transition axis fills parts of the mechanistic vacancy before the onset of secondary mutations, and strategies for TKIs combined with targeting GFRA1-dependent autophagy have distinct promise as prospective clinical therapies.

Neutrophil extracellular traps promote metastasis in gastric cancer patients with postoperative abdominal infectious complications.

Postoperative abdominal infectious complication (AIC) is associated with metastasis in locally advanced gastric cancer (GC) patients after radical gastrectomy. However, the underlying mechanism remains unclear. Herein, we report that neutrophil extracellular traps (NETs), the DNA meshes released by neutrophils in response to infection, could promote GC cells proliferation, invasion, migration and epithelial-mesenchymal transition dependent on TGF-ß signaling. Then we model nude mice with cecal puncture without ligation to simulate postoperative AIC and find that NETs in peripheral blood and ascites fluid facilitate GC cells extravasation and implantation into liver and peritoneum for proliferation and metastasis. Notably, TGF-ß signaling inhibitor LY 2157299 could effectively impede liver and peritoneal metastasis but not concurrently aggravate sepsis in those AIC-bearing nude mice. These findings implicate that targeting downstream effectors of NETs such as TGF-ß signaling might provide potential therapeutic prospect to reduce the risk of GC metastasis.

Long Non-Coding RNA NRON promotes Tumor Proliferation by regulating ALKBH5 and Nanog in Gastric Cancer.

Long non-coding RNAs (lncRNAs) act as tumor suppressors or oncogenes in tumor development and progression. In this study, we explored the expression and biological role of lncRNA NRON in gastric cancer (GC). We observed that lncNRON was upregulated in GC tissues and cell lines, and high lncNRON expression was associated with malignant features and poor prognosis in GC patients. LncNRON was found to promote the proliferation and tumorigenicity of GC cells. Mechanistically, lncNRON exerted its oncogenic functions by binding to the N6-methyladenosine eraser ALKHB5 and mediating Nanog mRNA decay. In conclusion, our results suggest that lncNRON serves as an oncogenic lncRNA in GC and thus may be a promising prognostic factor and potential therapeutic target for GC patients.

Essential role of ALKBH5-mediated RNA demethylation modification in bile acid-induced gastric intestinal metaplasia.

Bile acid reflux and subsequent caudal-related homeobox 2 (CDX2) activation contribute to gastric intestinal metaplasia (IM), a precursor of gastric cancer; however, the mechanism underlying this phenomenon is unclear. Here, we demonstrate that alkylation repair homolog protein 5 (ALKBH5), a major RNA N6-adenosine demethylase, is required for bile acid-induced gastric IM. Mechanistically, we revealed the N6-methyladenosine (m6A) modification profile in gastric IM for the first time and identified ZNF333 as a novel m6A target of ALKBH5. ALKBH5 was shown to demethylate ZNF333 mRNA, leading to enhanced ZNF333 expression by abolishing m6A-YTHDF2-dependent mRNA degradation. In addition, ALKBH5 activated CDX2 and downstream intestinal markers by targeting the ZNF333/CYLD axis and activating NF-κB signaling. Reciprocally, p65, the key transcription factor of the canonical NF-κB pathway, enhanced the transcription activity of ALKBH5 in the nucleus, thus forming a positive feedforward circuit. Furthermore, ALKBH5 levels were positively correlated with ZNF333 and CDX2 levels in IM tissues, indicating significant clinical relevance. Collectively, our findings suggest that an m6A modification-associated positive feedforward loop between ALKBH5 and NF-κB signaling is involved in generating the IM phenotype of gastric epithelial cells. Targeting the ALKBH5/ZNF333/CYLD/CDX2 axis may be a useful therapeutic strategy for gastric IM in patients with bile regurgitation.

Norepinephrine Enhances Aerobic Glycolysis and May Act as a Predictive Factor for Immunotherapy in Gastric Cancer.

METHODS: Monoamine neurotransmitters were detected in gastric cancer tissue and paired normal tissue, and The Cancer Genome Atlas was used to identify differentially expressed norepinephrine-degrading and synthetic enzymes. Quantitative real-time PCR and the Seahorse assay were used to determine the effect of norepinephrine on gastric cancer cell glycolysis. MAOA expression in cancer tissues was analyzed by immunohistochemistry and was compared with the patient SUVmax value of PET-CT and other clinicopathological characteristics. RESULTS: The norepinephrine levels were markedly high in gastric cancer tissue, while the norepinephrine-degrading enzymes MAOA and MAOB showed low expression. High norepinephrine levels were associated with activated glycolysis. The MAOA or MAOB expression levels in tumor tissue were closely correlated with the patient SUV max values of PET-CT and immunotherapy evaluation indices, such as PD-L1 and the microsatellite status. CONCLUSIONS: Norepinephrine shows relatively higher expression in gastric cancer tissue than in normal tissue, and its expression level is associated with the glycolysis levels in patients. The norepinephrine-degrading enzymes MAOA and MAOB have significant expression differences in cancer and normal tissue, and their missing or low expression may predict immune therapy outcomes for gastric cancer patients. High norepinephrine levels with metabolic abnormalities may be more suitable for metabolic targeted therapy or immunotherapy.

Hypoxic gastric cancer-derived exosomes promote progression and metastasis via MiR-301a-3p/PHD3/HIF-1α positive feedback loop.

Hypoxic tumor microenvironment(TME) is a universal feature in solid carcinoma and is associated with unfavorable prognosis. Tumor-derived exosomes are now significantly implicating in mediating cellular communication and interactions in TME. The aim of this study was to identify exosomal miR-301a-3p involved in gastric cancer(GC) progression and metastasis. Here, we found hypoxia promote GC exosomes release and miR-301a-3p expression in an HIF-1α-dependent manner. In hypoxic TME, enriched miR-301a-3p could be transmitted between GC cells via exosomes and then contributed to inhibit HIF-1α degradation through targeting PHD3, that were capable to hydroxylate HIF-1α subunits to ubiquitinate degradation. This synergistical positive feedback loop between HIF-1α and miR-301a-3p facilitated GC proliferation, invasion, migration, and epithelial-mesenchymal transition. In clinical samples, we further discovered circulating exosomal miR-301a-3p in serum was positively related with peritoneal metastasis. Collectively, these data indicate that GC cells could generate miR-301a-3p-rich exosomes in the hypoxic TME, which then help to HIF-1α accumulation and promote GC malignant behaviors and metastasis. Exosomal miR-301a-3p/HIF-1α signaling axis may serve as a promising predictor and potential therapeutic target of GC with metastasis.

The Association Between Immune Characteristic and Clinical Pathology in Chinese Patients with Adenocarcinoma of Esophagogastric Junction.

PURPOSE: Adenocarcinoma of the esophagogastric junction (AEG) patient immune characteristics were analyzed in this study, and these features were compared with patient clinical pathology and prognosis. PATIENTS AND METHODS: The clinicopathological data and prognostic information of 96 AEG patients who were admitted to Ren Ji Hospital between December 2008 and December 2015 were collected. PD-1/PD-L1, Tim-3/Gal-9, and CD3/CD8/Foxp3 expression in these patients, as well as the correlation of the expression of these molecules with clinicopathological data and survival time, were analyzed. Comparisons of count data were performed using the chi-square test or Fisher's exact test. The survival rate and survival curves were calculated and drawn, respectively, with the Kaplan-Meier method, and the Log rank test was used for survival analysis. RESULTS: The positive rate for PD-L1 and Gal-9 in these AEG patients was 30.21% and 31.25%, respectively. Tim-3 positivity had a close relationship with patient Siewert type. CD8+ T cell infiltration and patient TNM stage, as well as CD3+CD8+ T cell infiltration and patient Lauren type, had a close relationship based on analysis of the correlation between immune factor expression and clinicopathological data. The group with high CD8+ T cell infiltration had an improved survival rate, while the combined analysis of Tim-3 and Gal-9 expression showed that the double-positive group had a significantly poorer prognosis than groups with other Tim-3 and Gal-9 expression patterns. The PD-L1 expression level had a close relationship with T cell infiltration in AEG patients, especially CD3+ and CD8+ T cell infiltration. CONCLUSION: Tim-3 expression was higher in patients with Siewert type I tumors than in patients with tumors of other Siewert types. Patients with high CD8+ T cell infiltration had a better prognosis than patients with low CD8+ T cell infiltration, and CD8+ T cell infiltration was closely related to AEG patient TNM stage. The Tim-3 and Gal-9 double-positive group showed poor prognosis, and immune therapy could be recommended for these AEG patients.

Should we still use prophylactic drain in gastrectomy for cancer? A systematic review and meta-analysis.

Prophylactic drain in gastrectomy for cancer is still widely used, although some evidence has disputed this practice and spreading enhanced recovery protocol has been pushing towards surgical simplification. This study aimed at assessing the impact of drain placement on important clinical outcomes, evaluating the results of randomised controlled trials (RCTs), or cohort studies whenever information provided by the former was scarce. PubMed, PMC, Cochrane Library, CNKI and Wanfang databases were searched from January 1990 to February 2019, both for RCTs and cohort studies comparing use or avoidance of prophylactic drain in gastric cancer patients undergoing gastrectomy. All RCTs and cohort studies were rated according to Jadad score and Newcastle-Ottawa-Scale, respectively. Meta-analysis was separately performed on RCTs and cohort studies. The following clinical outcomes were considered: anastomotic leak, reoperation rate, additional drain procedure, length of stay, postoperative morbidity, postoperative mortality, readmission rate and drain related complications. Overall, 3 RCTs (330 patients) and 7 cohort studies (2897 patients) were included. Seven studies came from Eastern Countries. Meta-analysis on RCTs evidenced that drain avoidance halves overall morbidity (RR = 0.47, 95%CI 0.26-0.86, p = 0.014) and slightly reduces length of stay (SMD -0.24, 95%CI -0.51-0.03, p = 0.083). Only one postoperative death occurred in the drain group. The other outcomes were either not reported or reported just by one RCT each. Meta-analysis on cohort studies, despite higher statistical power, did not highlight any significant difference. This meta-analysis showed that prophylactic drain avoidance can reduce morbidity and length of stay, while not significantly affecting other major surgical outcomes.

TIGIT and PD-1 may serve as potential prognostic biomarkers for gastric cancer.

Gastric Cancer (GC) is the fifth leading cause of cancer-related death in the world, and in urgent need of specific therapeutic targets to acquire prominent effectiveness. T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) and programmed cell death protein 1 (PD-1) are identified to be abnormally overexpressed in various types of cancers including GC. This study aimed to investigate whether TIGIT and PD-1 could serve as potential prognostic biomarkers for GC. Firstly, TCGA GC dataset analysis and correlation analysis were utilized to inspect the relationship between expression of TIGIT, PD-1 and CD8 + T cells in GC and adjacent normal tissues. Then, flow cytometry was used to verify the data after collecting the peripheral blood, GC and adjacent normal tissues from 150 GC patients. Lastly, quantitative RT-PCR was performed to detect the expression of CD155, CD113, CD112 and TIGIT in six human GC cell lines and 631 GC patients in KM Plotter Database to conduct prognostic analysis. As results, we found that TIGIT and PD-1 were upregulated in GC tissues with high CD8 + T cells infiltration, while correlation analysis indicated they were in high-positive correlation. In addition, the flow cytometry analysis further showed that the high-expression of TIGIT in tumor microenvironment of GC could suppress the function of infiltrative CD8 + T cells, which leads to the escape of GC cells from immune killing. Furthermore, CD155 and CD112 were found abnormally upregulated in GC tissues and cell lines and the high expression of CD155, CD112 and TIGIT demonstrated poor prognosis results. In conclusion, these results provided potential therapeutic targets and prognostic biomarkers for treatment of GC in clinic.

Prognostic and pathological impact of tumor budding in gastric cancer: A systematic review and meta-analysis.

BACKGROUND: Tumor budding, is a promising prognostic hallmark in many cancers, and can help us better assess the degree of malignancy in gastric cancer (GC) and in colorectal cancer. In the past few years, several articles on the relationship between tumor budding and GC have been published, but different results have been observed. As the relationship between tumor budding and GC remains controversial, we integrated the data from 7 eligible studies to conduct a systematic review and meta-analysis. AIM: To systematically evaluate the prognostic and pathological impact of tumor budding in GC. METHODS: Literature searches were conducted in the PubMed, Cochrane Library, EMBASE and Web of Science databases, and 7 cohort studies involving 2178 patients met our criteria and included in the analysis. The patients were divided into those with high-grade tumor budding and those with low-grade tumor budding, and the cut-off values for tumor budding varied across the included studies. The hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to estimate the impact of tumor budding on overall survival (OS) in GC patients. The odds ratios (ORs) with 95%CIs were used to determine the correlation between tumor budding and pathological parameters (tumor stage, tumor differentiation, lymphovascular invasion, lymph node metastasis) of GC. RESULTS: Seven studies involving 2178 patients were included in the meta-analysis. The combined ORs suggested that high-grade tumor budding was significantly associated with tumor stage (OR = 6.63, 95%CI: 4.01-10.98, P < 0.01), tumor differentiation (OR = 3.74, 95%CI: 2.68-5.22, P < 0.01), lymphovascular invasion (OR = 7.85, 95%CI: 5.04-12.21, P < 0.01), and lymph node metastasis (OR = 5.75, 95%CI: 3.20-10.32, P < 0.01). Moreover, high-grade tumor budding predicted a poor 5-year OS (HR = 1.79, 95%CI: 1.53-2.05, P < 0.01) in patients with GC and an adverse 5-year OS (HR = 1.93, 95%CI: 1.45-2.42, P < 0.01) in patients with intestinal-type GC. CONCLUSION: High-grade tumor budding suggested a poor prognosis in patients with GC or intestinal-type GC.

Somatic mutation of DNAH genes implicated higher chemotherapy response rate in gastric adenocarcinoma patients.

BACKGROUND: The dynein axonemal heavy chain (DNAH) family of genes encode the dynein axonemal heavy chain, which is involved in cell motility. Genomic variations of DNAH family members have been frequently reported in diverse kinds of malignant tumors. In this study, we analyzed the genomic database to evaluate the mutation status of DNAH genes in gastric adenocarcinoma and further identified the significance of mutant DNAH genes as effective molecular biomarkers for predicting chemotherapy response in gastric cancer patients. METHODS: We analyzed the clinical and genomic data of gastric cancer patients published in The Cancer Genome Atlas (TCGA) project. Data on chemotherapy response, overall survival (OS) and chemotherapy-free survival were retrieved. Then, we verified the results via targeted sequencing of gastric cancer patients with similar clinical characteristics but different chemotherapeutic outcomes. RESULTS: In total, 132 gastric adenocarcinoma patients undergoing chemotherapy treatment from TCGA were included in our study. Somatic mutations in all 13 members of the DNAH family of genes were associated with different chemotherapy responses. Compared with patients with wild-type DNAH genes (n = 59), a significantly higher proportion of those with mutations in DNAH genes (n = 73) (55.9% vs 80.8%) responded to chemotherapy (P = 0.002). Moreover, DNAH mutations were correlated with significantly better OS (P = 0.027), chemotherapy-free survival (P = 0.027), fluoropyrimidine-free survival (P = 0.048) and platinum-free survival (P = 0.014). DNAH mutation status was an independent risk factor for OS (P = 0.015), chemotherapy-free survival (P = 0.015) and platinum-free survival (P = 0.011). We identified somatic mutations in 27 (42.2%) of the 64 stage III gastric adenocarcinoma patients receiving fluoropyrimidine-based chemotherapy by targeted exon sequencing with strict screening conditions. In our own cohort, a significantly higher proportion of patients (n = 32) with DNAH mutations than patients with wild-type DNAH genes (n = 32) had a good prognosis (OS > 48 months) (70.4% vs 35.1%) (P = 0.005). CONCLUSIONS: Dynein axonemal heavy chain gene mutations contribute positively to chemotherapy sensitivity in gastric cancer patients.