Background Currently available prognostic tools and focused therapeutic methods result in unsatisfactory treatment of gastric cancer (GC). A deeper understanding of human epidermal growth factor receptor 2 (HER2)-coexpressed metabolic pathways may offer novel insights into tumour-intrinsic precision medicine. Methods The integrated multi-omics strategies (including transcriptomics, proteomics and metabolomics) were applied to develop a novel metabolic classifier for gastric cancer. We integrated TCGA-STAD cohort (375 GC samples and 56753 genes) and TCPA-STAD cohort (392 GC samples and 218 proteins), and rated them as transcriptomics and proteomics data, resepectively. 224 matched blood samples of GC patients and healthy individuals were collected to carry out untargeted metabolomics analysis. Results In this study, pan-cancer analysis highlighted the crucial role of ERBB2 in the immune microenvironment and metabolic remodelling. In addition, the metabolic landscape of GC indicated that alanine, aspartate and glutamate (AAG) metabolism was significantly associated with the prevalence and progression of GC. Weighted metabolite correlation network analysis revealed that glycolysis/gluconeogenesis (GG) and AAG metabolism served as HER2-coexpressed metabolic pathways. Consensus clustering was used to stratify patients with GC into four subtypes with different metabolic characteristics (i.e. quiescent, GG, AAG and mixed subtypes). The GG subtype was characterised by a lower level of ERBB2 expression, a higher proportion of the inflammatory phenotype and the worst prognosis. However, contradictory features were found in the mixed subtype with the best prognosis. The GG and mixed subtypes were found to be highly sensitive to chemotherapy, whereas the quiescent and AAG subtypes were more likely to benefit from immunotherapy. Conclusions Transcriptomic and proteomic analyses highlighted the close association of HER-2 level with the immune status and metabolic features of patients with GC. Metabolomics analysis highlighted the co-expressed relationship between alanine, aspartate and glutamate and glycolysis/gluconeogenesis metabolisms and HER2 level in GC. The novel integrated multi-omics strategy used in this study may facilitate the development of a more tailored approach to GC therapy.

/pdf/integration-of-transcriptomics-proteomics-and-metabolomics-2ukl1hrl.pdf

Integration of transcriptomics, proteomics, and metabolomics data to reveal HER2-associated metabolic heterogeneity in gastric cancer with response to immunotherapy and neoadjuvant chemotherapy

The aim of this systematic review and meta-analysis is to the summarize the evidence on programmed cell death protein ligand 1 (PD-L1) in Epstein-Barr virus associated gastric cancer (EBVaGC) and to estimate the expression rate of PD-L1 among this subtype of Gastric Cancer (GC).For this study, PubMed®, EMBASE® and Web of Science® databases were searched for articles published until 1st November 2021. A total of 43 eligible publications with a total of 11,327 patients were included analysis based on inclusion and exclusion criteria. A total of 41 publications present data for proportion estimation and 33 for comparison of PD-L1 between EBV positive and negative GC. DerSimonian-Laird random-effects model was used for meta-analysis.The analysis showed that in EBVaGC the pooled positivity rate for PD-L1 was 54.6% (p < 0.001), with a high heterogeneity between the included studies, which was associated with variation on positivity criteria for PD-L1 expression. Overall, the study reveals an increased association between PD-L1 and EBVaGC (OR = 6.36, 95% CI 3.91-10.3, p < 0.001). Furthermore, the study revealed that GC with lymphoid stroma (GCLS) is highly associated with EBV (OR = 17.4, 95% CI 6.83-44.1, p < 0.001), with a pooled EBV positivity rate of 52.9% (p < 0.001).Patients with EBVaGC tend to show higher PD-L1 expression, which enhances EBV positivity as a promising marker for patient selection for immunotherapy targeted agents. A uniform criteria for PD-L1 positivity in tumor cells is needed, as well as further prospective studies to validate our findings and their prognostic significance. 

/pdf/pd-l1-expression-in-ebv-associated-gastric-cancer-a-1yv488g4.pdf

PD-L1 expression in EBV associated gastric cancer: a systematic review and meta-analysis

Background
Gastric cancer (GC) is the fourth most common cancer worldwide, characterized by multifactorial pathogenesis and a heterogeneous geographic distribution. The complexity of this malignancy has evolved, with environmental and genetic factors and treatment strategies being more studied.


Aims
We aimed to group and organize the clinicopathological and epidemiological features of GC in the Arab World and compare with data from Western countries.


Methods
To obtain the highest number of topic-related articles, an extensive electronic search was conducted in the PubMed MEDLINE and Cochrane databases up to March 2022 using Boolean operators with a combination of keywords and MeSH terms. A total of 42 articles were retained after screening in accordance with the objectives of the study. The estimated age-standardized incidence rates in the Arab World were collected from the GLOBOCAN 2020 database.


Results
A total of 46 articles were retrieved from 11 countries in the Arab World. Epidemiological elements were collected, especially tumour attributes, risk factors and population characteristics, in addition to some therapeutic strategies. Results were regrouped by theme and then organized in tables and charts, allowing a global and regional approach to the subject.


Conclusion
This review shows that the Arab World is considered a low-rate GC incidence region, presenting almost the same tumour characteristics as the Western countries. The lack of GC data in the Arab World should trigger a rise in research on this type of malignancy to better understand the subject.

Gastric cancer in the Arab World: a systematic review.

The gastric adenocarcinoma (GC) represents the third cause of cancer-related mortality worldwide, and available therapeutic options remain sub-optimal. The Fibroblast growth factor receptors (FGFRs) are oncogenic transmembrane tyrosine kinase receptors. FGFR inhibitors have been approved for the treatment of various cancers and a STAT3-dependent regulation of FGFR4 has been documented in the H.pylori infected intestinal GC. Therefore, the modulation of FGFR4 might be useful for the treatment of GC.To investigate wich factors could modulate FGFR4 signalling in GC, we employed RNA-seq analysis on GC patients biopsies, human patients derived organoids (PDOs) and cancer cell lines.We report that FGFR4 expression/function is regulated by the leukemia inhibitory factor (LIF) an IL-6 related oncogenic cytokine, in JAK1/STAT3 dependent manner. The transcriptomic analysis revealed a direct correlation between the expression of LIFR and FGFR4 in the tissue of an exploratory cohort of 31 GC and confirmed these findings by two external validation cohorts of GC. A LIFR inhibitor (LIR-201) abrogates STAT3 phosphorylation induced by LIF as well as recruitment of pSTAT3 to the promoter of FGFR4. Furthermore, inhibition of FGFR4 by roblitinib or siRNA abrogates STAT3 phosphorylation and oncogentic effects of LIF in GC cells, indicating that FGFR4 is a downstream target of LIF/LIFR complex. Treating cells with LIR-201 abrogates oncogenic potential of FGF19, the physiological ligand of FGFR4.Together these data unreveal a previously unregnized regulatory mechanism of FGFR4 by LIF/LIFR and demonstrate that LIF and FGF19 converge on the regulation of oncogenic STAT3 in GC cells. 

The leukemia inhibitory factor regulates fibroblast growth factor receptor 4 transcription in gastric cancer.

Background and Aim: Gastric cancer (GC) is one of the most common infection-related malignancies worldwide. Human Papillomavirus (HPV) and Epstein-Barr virus (EBV) are among the most important viruses affecting many people worldwide. The potential role of these viruses in gastric tissue may explain the possibility of GC, as seen in Helicobacter pylori (H. pylori). This study aimed to systematically investigate the presence of HPV and EBV in GC. Methods: According to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, this study is a systematic review based on reported cases. The keywords HPV, EBV and GC, were searched in PubMed, Web of Science, Scopus, EMBASE and Google scholar databases from 2012 to 2022. Articles were selected and evaluated by five researchers independently. The odds ratio of HPV and EBV viruses in GC was estimated. Data analysis was performed by SPSS (Version 20) software. Results: Sixty studies with 14949 patients were included in the study after obtaining the inclusion criteria. The mean prevalence of HPV and EBV viruses in GC was 10.58% and 8.58%, respectively. The highest prevalence of HPV and EBV were 37.74% and 44.44% in Turkey and Iraq, respectively. The highest odds of HPV and EBV in GC were observed in Asia (17.54%) and Africa (19.02%), respectively. Conclusion: The findings indicate the presence of HPV and EBV in GC in the study areas. However, the present study’s results are insufficient for a more accurate conclusion. Therefore, further studies are necessary for the conclusion in this regard. 

https://www.techscience.com/oncologie/online/detail/18799/pdf

The Presence of Human Papillomavirus and Epstein-Barr Virus Infection in Gastric Cancer: A Systematic Study

Introduction The Cancer Genome Atlas (TCGA) project and Asian Cancer Research Group (ACRG) recently categorized gastric cancer into molecular subtypes. Nevertheless, these classification systems require high cost and sophisticated molecular technologies, preventing their widespread use in the clinic. This study is aimed to generating molecular subtypes of gastric cancer using techniques available in routine diagnostic practice in a series of Moroccan gastric cancer patients. In addition, we assessed the associations between molecular subtypes, clinicopathological features, and prognosis. Methods Ninety-seven gastric cancer cases were classified according to TCGA, ACRG, and integrated classifications using a panel of four molecular markers (EBV, MSI, E-cadherin, and p53). HER2 status and PD-L1 expression were also evaluated. These markers were analyzed using immunohistochemistry (E-cadherin, p53, HER2, and PD-L1), in situ hybridization (EBV and HER2 equivocal cases), and multiplex PCR (MSI). Results Our results showed that the subtypes presented distinct clinicopathological features and prognosis. EBV-positive gastric cancers were found exclusively in male patients. The GS (TCGA classification), MSS/EMT (ACRG classification), and E-cadherin aberrant subtype (integrated classification) presented the Lauren diffuse histology enrichment and tended to be diagnosed at a younger age. The MSI subtype was associated with a better overall survival across all classifications (TCGA, ACRG, and integrated classification). The worst prognosis was observed in the EBV subtype (TCGA and integrated classification) and MSS/EMT subtype (ACRG classification). Discussion/Conclusion. We reported a reproducible and affordable gastric cancer subtyping algorithms that can reproduce the recently recognized TCGA, ACRG, and integrated gastric cancer classifications, using techniques available in routine diagnosis. These simplified classifications can be employed not only for molecular classification but also in predicting the prognosis of gastric cancer patients.

/pdf/reproduction-of-the-cancer-genome-atlas-tcga-and-asian-56msnq28h4.pdf

Reproduction of the Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) Gastric Cancer Molecular Classifications and Their Association with Clinicopathological Characteristics and Overall Survival in Moroccan Patients.

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Reproduction of the Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) Gastric Cancer Molecular Classifications and Their Association with Clinicopathological Characteristics and Overall Survival in Moroccan Patients.