Heterogeneity in Gastric Cancer: From Pure Morphology to Molecular Classifications

Gullo, Irene; Carneiro, Fátima; Oliveira, Carla; Almeida, Gabriela M.

doi:10.1159/000473881

Cited by 108 publications

(127 citation statements)

References 107 publications

(149 reference statements)

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“…Although GC incidence and mortality has decreased throughout the years and novel therapies have been developed, less than one fifth of advanced GC patients survive 5 years post disease diagnosis [2,3]. Late diagnosis and high intra/inter-tumor heterogeneity likely explain this dismal prognosis and therapeutic failure [4]. Given the non-curative nature of gastric surgery in patients with advanced cancer, two targeted therapies have been approved to treat these patients: the monoclonal antibodies Trastuzumab (anti-HER2) and Ramucirumab (anti-VEGFR2) [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Integrated Analysis of Structural Variation and RNA Expression of FGFR2 and Its Splicing Modulator ESRP1 Highlight the ESRP1amp-FGFR2norm-FGFR2-IIIchigh Axis in Diffuse Gastric Cancer

Teles

Oliveira

Ferreira

et al. 2019

Cancers

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Gastric Cancer (GC) is one of the most common and deadliest types of cancer in the world. To improve GC prognosis, increasing efforts are being made to develop new targeted therapies. Although FGFR2 genetic amplification and protein overexpression in GC have been targeted in clinical trials, so far no improvement in patient overall survival has been found. To address this issue, we studied genetic and epigenetic events affecting FGFR2 and its splicing regulator ESRP1 in GC that could be used as new therapeutic targets or predictive biomarkers. We performed copy number variation (CNV), DNA methylation, and RNA expression analyses of FGFR2/ESRP1 across several cohorts. We discovered that both genes were frequently amplified and demethylated in GC, resulting in increased ESRP1 expression and of a specific FGFR2 isoform: FGFR2-IIIb. We also showed that ESRP1 amplification in GC correlated with a significant decreased expression of FGFR2-IIIc, an alternative FGFR2 splicing isoform. Furthermore, when we performed a survival analysis, we observed that patients harboring diffuse-type tumors with low FGFR2-IIIc expression revealed a better overall survival than patients with FGFR2-IIIc high-expressing diffuse tumors. Our results encourage further studies on the role of ESRP1 in GC and support FGFR2-IIIc as a relevant biomarker in GC.

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Section: Introductionmentioning

confidence: 99%

Integrated Analysis of Structural Variation and RNA Expression of FGFR2 and Its Splicing Modulator ESRP1 Highlight the ESRP1amp-FGFR2norm-FGFR2-IIIchigh Axis in Diffuse Gastric Cancer

Teles

Oliveira

Ferreira

et al. 2019

Cancers

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“…STAD is a highly heterogeneous cancer, and tumor heterogeneity is instrumental in immune evasion [24][25][26][27][28] . In fact, several studies have shown that tumor infiltrating immune cells are prognostic markers for cancer progression [29][30][31] .…”

Section: Discussionmentioning

confidence: 99%

VGLL3 is a prognostic biomarker and correlated with clinical pathologic features and immune infiltrates in stomach adenocarcinoma

Zhang

Mao

et al. 2020

Sci Rep

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Due to its poor clinical outcome, there is an urgent need to identify novel prognostic markers for stomach adenocarcinoma (STAD). Here, we aimed to explore the relationship between VGLL3 expression and clinico-pathological features, dendritic cells, macrophages, and prognosis of STAD. VGLL3 expression levels were significantly associated with histological grade, T stage, and TNM stage. VGLL3 levels and patient's age were also independent prognostic factors of the clinical outcome of STAD. In addition, VGLL3 was associated with the abundance of macrophages and dendritic cells in tumor infiltrates, of which only VGLL3 and macrophage counts were the independent prognostic factors of immune cell infiltration in the TIMER Database. Extracellular matrix receptor interaction, focal adhesion, pathways in cancer, MAPK, JAK STAT, and WNT signaling pathways were enriched in VGLL3 high-expressing datasets as determined by Gene Set Enrichment Analysis (GSEA), while DNA replication, glyoxylate, and dicarboxylate metabolism, glutathione metabolism, homologous recombination, and glycosylphosphatidylinositol gpi banchor biosynthesis were enriched in VGLL3 low-expressing datasets. Thus, VGLL3 is a novel prognostic biomarker of both the clinical outcome and immune infiltration in STAD, and may therefore be a promising therapeutic target.Despite advances in treatment modalities, gastric cancer remains the most common cause of cancer-related deaths in Asia, and the second most common cause of death worldwide 1 . Around 90% to 95% of gastric cancer cases involve stomach adenocarcinomas (STAD) 2 . Although the survival of STAD patients has greatly improved in the past 20 years due to surgery, chemotherapy and targeted therapy, the prognosis is still unsatisfactory 3 . Poor differentiation, late diagnosis, lack of predictive markers, and ineffective therapeutic targets are key factors that drive STAD metastasis and recurrence 4 . Therefore, it is essential to explore the molecular mechanisms underlying STAD development and progression to identify novel prognostic biomarkers and potential therapeutic targets to treat gastric cancer.Transcription cofactor vestigial-like protein 3 (VGLL3) is a coactivator of mammalian toxicity equivalency factors (TEFs), and was associated with breast cancer, colon cancer, and lung cancer among other malignancies 5-9 . In our previous study, we found that VGLL3 at the protein level as determined by immunohistochemistry (IHC) was a novel prognostic biomarker for gastric cancer in the Chinese population 10 . However, its role at the mRNA level of STAD and immune microenvironment remains to be elucidated. To determine whether VGLL3 was involved in the progression of STAD, the Wilcox test and Kruskal test method were used to analyze the differences in VGLL3 expression in subgroups of clinic-pathological trait. Cox regression and log-rank test were used to evaluate significance of VGLL3 on disease prognosis.Recently, more and more evidence showed immune cell infiltration plays a vital role in predicting overall...

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“…Although surgery has improved the 5 year survival rate of patients with GC, the prognosis is still not optimistic. Gullo et al (15) showed that the prognosis of GC as a highly heterogeneous tumor is closely related to many factors. In addition to the traditional TNM staging system, it is also closely related to the body's immunity, inflammation, and nutrition.…”

Section: Discussionmentioning

confidence: 99%

Value of the preoperative prognostic nutritional index for the evaluation of patient prognosis after radical gastrectomy

et al. 2020

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Preoperative prognostic nutritional index (PNI) has been widely used for the clinical evaluation of patients with cancer. The present study assessed the prognostic value of preoperative PNI in patients after gastric cancer (GC) radical surgery. The clinical case and follow-up data of 170 patients undergoing GC radical surgery were retrospectively analyzed. The receiver operating characteristic (ROC) curve was used to compare the predictive ability of each inflammatory index: The PNI, neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR). The correlation between the preoperative PNI and overall survival (OS) was also analyzed via Kaplan-Meier (K-M) curves and multivariate Cox regression analyses. The results revealed that the optimal PNI cutoff was 46.030. According to this cutoff value, the whole sample was divided into PNI <46.030 (low PNI group) and PNI ≥46.030 (high PNI group). These groups were comprised of 102 and 68 cases, respectively. The area under the curve value of the PNI was 0.725, which was greater than that of traditional inflammatory indices, including the NLR and LMR. K-M survival analysis revealed that the 5 year survival rate of patients in the low PNI group was significantly lower than that of patients in the high PNI group (P<0.01). Univariate analysis and Cox multiple regression model analysis demonstrated that the T stage, N stage, pathological grade and PNI were independent risk factors for the 5 year survival rate after radical gastrectomy (P<0.05). In conclusion, the preoperative PNI is an independent risk factor for 5 year survival after radical gastrectomy and has clinical value for the prognostic evaluation of patients with GC.

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Heterogeneity in Gastric Cancer: From Pure Morphology to Molecular Classifications

Cited by 108 publications

References 107 publications

Integrated Analysis of Structural Variation and RNA Expression of FGFR2 and Its Splicing Modulator ESRP1 Highlight the ESRP1amp-FGFR2norm-FGFR2-IIIchigh Axis in Diffuse Gastric Cancer

Integrated Analysis of Structural Variation and RNA Expression of FGFR2 and Its Splicing Modulator ESRP1 Highlight the ESRP1amp-FGFR2norm-FGFR2-IIIchigh Axis in Diffuse Gastric Cancer

VGLL3 is a prognostic biomarker and correlated with clinical pathologic features and immune infiltrates in stomach adenocarcinoma

Value of the preoperative prognostic nutritional index for the evaluation of patient prognosis after radical gastrectomy

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