Molecular subtyping of gastric cancer combining genetic and epigenetic anomalies provides distinct clinicopathological features and prognostic impacts

Tahara, Tomomitsu; Tahara, Sayumi; Horiguchi, Noriyuki; Okubo, Masaaki; Terada, Tsuyoshi; Yamada, Hisakata; Yoshida, Dai; Omori, Takafumi; Osaki, Hayato; Maeda, Keiko; Kamano, Toshiaki; Funasaka, Kohei; Nagasaka, Mitsuo; Nakagawa, Yoshihito; Shibata, Tomoyuki; Ohmiya, Naoki

doi:10.1002/humu.23700

Cited by 16 publications

(15 citation statements)

References 19 publications

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“…The CpG island methylator phenotype (CIMP) and TP53 hot spot mutation status (R175, G245, R248, R273, and R282) were sufficient to predict the prognosis and clinicopathological features of GC. Among these features, patients with the CIMP − TP53 hot spot + subtype presented the worst overall survival [67]. Moreover, Ooi et al selected three oncogenic pathways (NF-κB, Wnt/β-catenin, and proliferation/ stem cells) by analysing a GC pathway heatmap and combined them to predict its prognosis, which was validated in vitro [68].…”

Section: Discussionmentioning

confidence: 99%

Homeobox proteins are potential biomarkers and therapeutic targets in gastric cancer: a systematic review and meta-analysis

Jin

Dai

et al. 2020

BMC Cancer

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Background An increasing number of studies have described the aberrant expression of homeobox (HOX) proteins in gastric cancer (GC), which is critically associated with the prognosis and clinicopathological characteristics of GC. This study was conducted to investigate the clinical value and action mechanisms of HOX proteins in GC. Methods A comprehensive search of PubMed, Embase, Web of Science and Cochrane Library was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. The pooled hazard ratio (HR) with its 95% confidence interval (95% CI) and the pooled odds ratio (OR) with its 95% CI were used to assess the effect of HOX protein expression on the prognosis and clinicopathological features of GC, respectively. Results Nineteen studies containing 3775 patients were selected for this study. Heterogeneity among HRs of overall survival (OS) was markedly high (I2 = 90.5%, p = 0.000). According to the subgroup analysis, increased expression of HOX protein in the downregulated subgroup was associated with a good prognosis for patients with GC (pooled HR: 0.46, 95% CI: 0.36–0.59, I2 = 3.1%, p = 0.377), while overexpression of HOX protein in the upregulated subgroup was correlated with a reduced OS (pooled HR: 2.59, 95% CI: 1.79–3.74, I2 = 73.5%, p = 0.000). The aberrant expression of HOX protein was crucially related to the TNM stage, depth of tumour invasion, tumour size, lymph node metastasis, distant metastasis, vascular invasion, histological differentiation and Lauren classification in patients with GC. In addition, the molecular mechanisms by which HOX proteins regulate tumorigenesis and development of GC were also explored. Conclusions HOX proteins play vital roles in GC progression, which might serve as prognostic markers and therapeutic targets for GC.

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Section: Discussionmentioning

confidence: 99%

Homeobox proteins are potential biomarkers and therapeutic targets in gastric cancer: a systematic review and meta-analysis

Jin

Dai

et al. 2020

BMC Cancer

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“…TNM staging has been widely used for determining GC prognosis 7 - 9 but is limited by the variations among patients with the same tumor stage. Studies have shown that the treatment response and survival rate of GC patients depend not only on tumor staging but also on heterogeneous and epigenetic molecular features 10 - 12 . Biomarkers, especially gene expression in tumor tissues, are reliably related to cancer prognosis and survival 13 - 16 .…”

Section: Introductionmentioning

confidence: 99%

Identification of a Tumor Microenvironment-relevant Gene set-based Prognostic Signature and Related Therapy Targets in Gastric Cancer

Cai

Dong

et al. 2020

Theranostics

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Rationale: The prognosis of gastric cancer (GC) patients is poor, and there is limited therapeutic efficacy due to genetic heterogeneity and difficulty in early-stage screening. Here, we developed and validated an individualized gene set-based prognostic signature for gastric cancer (GPSGC) and further explored survival-related regulatory mechanisms as well as therapeutic targets in GC. Methods: By implementing machine learning, a prognostic model was established based on gastric cancer gene expression datasets from 1699 patients from five independent cohorts with reported full clinical annotations. Analysis of the tumor microenvironment, including stromal and immune subcomponents, cell types, panimmune gene sets, and immunomodulatory genes, was carried out in 834 GC patients from three independent cohorts to explore regulatory survival mechanisms and therapeutic targets related to the GPSGC. To prove the stability and reliability of the GPSGC model and therapeutic targets, multiplex fluorescent immunohistochemistry was conducted with tissue microarrays representing 186 GC patients. Based on multivariate Cox analysis, a nomogram that integrated the GPSGC and other clinical risk factors was constructed with two training cohorts and was verified by two validation cohorts. Results: Through machine learning, we obtained an optimal risk assessment model, the GPSGC, which showed higher accuracy in predicting survival than individual prognostic factors. The impact of the GPSGC score on poor survival of GC patients was probably correlated with the remodeling of stromal components in the tumor microenvironment. Specifically, TGFβ and angiogenesis-related gene sets were significantly associated with the GPSGC risk score and poor outcome. Immunomodulatory gene analysis combined with experimental verification further revealed that TGFβ1 and VEGFB may be developed as potential therapeutic targets of GC patients with poor prognosis according to the GPSGC. Furthermore, we developed a nomogram based on the GPSGC and other clinical variables to predict the 3-year and 5-year overall survival for GC patients, which showed improved prognostic accuracy than clinical characteristics only. Conclusion: As a tumor microenvironment-relevant gene set-based prognostic signature, the GPSGC model provides an effective approach to evaluate GC patient survival outcomes and may prolong overall survival by enabling the selection of individualized targeted therapy.

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“…These 59 published studies [ 5 , 6 , 8 – 13 , 17 – 19 , 22 – 30 , 32 – 70 ], together with our primary study, contained 18,315 GC patients (sFigure 2 ), with a median sample size of 216 (range: 52–1412). The median percentage of H. pylori -positive patients in these studies was 55.4%, ranging from 8.96 to 91.3%.…”

Section: Resultsmentioning

confidence: 99%

Positive H. pylori status predicts better prognosis of non-cardiac gastric cancer patients: results from cohort study and meta-analysis

et al. 2022

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Background Previous researches have associated Helicobacter pylori (H. pylori) with a prognosis of gastric cancer (GC), however, without a concert conclusion. This study aimed to study this issue further by a prospective cohort study and a meta-analysis. Methods Histologically diagnosed gastric cancer (GC) patients were recruited into the primary prospective cohort study between January 2009 to December 2013. All the patients were followed-up periodically to record information on post-surgery therapy and overall survival status. The pre-surgery status of H. pylori was measured by enzyme-linked immunosorbent assay. A meta-analysis was conducted after retrieving related researches in the databases of PubMed and Embase up to April 2020. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were summarized to validate the relationship between H. pylori infection and the survival time of GC patients. I2 statistics and Q test were used to assess the heterogeneity. Sensitivity analyses were performed using Galbraith’s plot, leave-one-out analysis, subgroup analyses and meta-regression to explore the sources of heterogeneity and the stability of the summary results. Results A total of 743 GC patients with radical tumorectomy were included prospectively and 516 (69.4%) were positive on H. pylori. H. pylori-positive patients tended to survive longer than -negative ones (HR 0.92, 95%CI: 0.74–1.15), though the tendency was not statistically significant. Cohort studies on the prognosis of GC were retrieved comprehensively by assessing the full-text and 59 published studies, together with the result of our study, were included in the further meta-analysis. The summarized results related the positive status of H. pylori to better overall survival (HR 0.81, 95%CI: 0.72–0.90) and disease-free survival (HR 0.83, 95%CI: 0.67–0.99). Results from subgroup analyses indicated that the pooled magnitude of this association was relatively lower in studies not referring to H. pylori in title and abstract. Conclusions In conclusion, gastric cancer patients with H. pylori have a better prognosis than patients of H. pylori negative. More stringent surveillance strategies may be necessary for patients with H. pylori negative at cancer diagnosis.

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Molecular subtyping of gastric cancer combining genetic and epigenetic anomalies provides distinct clinicopathological features and prognostic impacts

Cited by 16 publications

References 19 publications

Homeobox proteins are potential biomarkers and therapeutic targets in gastric cancer: a systematic review and meta-analysis

Homeobox proteins are potential biomarkers and therapeutic targets in gastric cancer: a systematic review and meta-analysis

Identification of a Tumor Microenvironment-relevant Gene set-based Prognostic Signature and Related Therapy Targets in Gastric Cancer

Positive H. pylori status predicts better prognosis of non-cardiac gastric cancer patients: results from cohort study and meta-analysis

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