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Yu X, Shao Y, Dong H, Yan J, Zhang X, Ye G. Molecular subtype of gastric cancer based on apoptosis-related genes reveals differential immune microenvironment and intratumoral microorganisms distribution. BMC Cancer 2025; 25:12. [PMID: 39762768 PMCID: PMC11702164 DOI: 10.1186/s12885-024-13411-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Accepted: 12/30/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Gastric cancer (GC) is known for its high heterogeneity, presenting challenges in current clinical treatment strategies. Accurate subtyping and in-depth analysis of the molecular heterogeneity of GC at the molecular level are still not fully understood. METHODS This study categorized GC into two subtypes based on apoptosis-related genes (ARGs) and investigated differences in tumor immune microenvironment, intratumoral microorganisms distribution, gene expression, and signaling pathways. Key prognostic genes related to apoptosis in GC were identified through random survival forest analysis, and their specific signaling mechanisms were explored. Expression levels of key genes were validated through PCR in paired GC tissues and cancer cell lines. Moreover, biological functions of these key genes were verified in vitro experiments. RESULTS A consistent clustering of GC was conducted using 161 apoptosis-related genes (ARGs), resulting in the identification of two subtypes, C1 and C2. Subsequently, significant differences were found in the tumor immune microenvironment, intratumoral microorganisms, gene expression, signaling pathways, and protein interaction networks between the two subtypes. GPX3, PLAT, and CAV1 were identified as key prognostic genes related to apoptosis in GC, with a focus on their impact on disease progression-related pathways. Furthermore, PCR assays validated that these three key genes exhibited significantly low expression levels in both GC cell lines and tissues. Finally, knocking down key genes expression significantly promoted cell proliferation, colony formation and invasion of GC. CONCLUSIONS Our study conducted a comprehensive analysis of the molecular characteristics of ARGs in GC, revealed their association with the tumor immune microenvironment and intratumoral microorganisms. These findings provide new ideas for the molecular classification of GC.
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Affiliation(s)
- Xuan Yu
- Department of Gastroenterology, the First Affiliated Hospital of Ningbo University, Ningbo, 315020, China
| | - Yongfu Shao
- Department of Gastroenterology, the First Affiliated Hospital of Ningbo University, Ningbo, 315020, China.
- Health Science Center, Ningbo University, Ningbo, 315211, China.
| | - Haotian Dong
- Health Science Center, Ningbo University, Ningbo, 315211, China
| | - Jianing Yan
- Department of Gastroenterology, the First Affiliated Hospital of Ningbo University, Ningbo, 315020, China
| | - Xinjun Zhang
- Department of Gastroenterology, the First Affiliated Hospital of Ningbo University, Ningbo, 315020, China
| | - Guoliang Ye
- Department of Gastroenterology, the First Affiliated Hospital of Ningbo University, Ningbo, 315020, China
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2
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Estaji F, Zibaee S, Torabi M, Moghim S. Epstein-Barr Virus and gastric carcinoma pathogenesis with emphasis on underlying epigenetic mechanisms. Discov Oncol 2024; 15:719. [PMID: 39601901 PMCID: PMC11602878 DOI: 10.1007/s12672-024-01619-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 11/21/2024] [Indexed: 11/29/2024] Open
Abstract
Gastric cancer (GC) remains one of the top causes of cancer-related mortality around the world. The pathogenesis of GC is attributed to lifestyle, family history, genetic mutations, epigenetic alterations, as well as infectious agents such as Epstein-Barr Virus (EBV). EBV, a ubiquitous human gamma herpes virus, with latent asymptomatic infection in more than 95% of the world's population, is able to infect through the oral epithelium. EBV is described as the first virus found in human neoplastic, when it was detected in Burkitt lymphoma tumor biopsy. Nowadays this virus is considered to be involved in various human malignancies such as GC. Despite comprehensive efforts and immense studies, the main underlying mechanism is not well described as there are crucial contradictions regarding the presence of this virus and the prognosis of the disease. Immunological alterations, genetic mutations, and epigenetic modifications are among the most important criteria presented in EBV- associated gastric cancer (EBVaGC), leading to its consideration as a separate subtype with unique clinical, histological, biochemical, and genetic characteristics. The current study aimed to review the association between EBV and GC with an emphasis on the role of epigenetic modifications in the suppression or progression of carcinogenesis. To put all findings in a nutshell, several genes and chromatin mutations, promoter hypermethylation and subsequent silencing of related genes, and histone modifications and aberrant micro RNAs (miRNAs) expression were considered as the major altered mechanisms in the pathogenesis of EBVaGC, most of which able to be suggested as therapeutic targets. However, the current knowledge appeared to be imperfect, hence further studies are encouraged.
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Affiliation(s)
- Fatemeh Estaji
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Saeed Zibaee
- Department of Research and Development of Biological Products, Razi Vaccine and Serum Research Institute, Agricultural Research Education and Extension Organization, Mashhad, Iran
| | - Maryam Torabi
- Department of Biotechnology, Molecular Biology Laboratory of Khorasan Razavi Veterinary Head Office, Mashhad, Iran
| | - Sharareh Moghim
- Department of Bacteriology & Virology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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3
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Ying T, Chen J, Song J, Zhou Y, Bao B, Zheng L. Prognosis of EBV-positive gastric cancer with lymphoid stroma: systematic review and meta-analysis. Scand J Gastroenterol 2024; 59:316-324. [PMID: 38032298 DOI: 10.1080/00365521.2023.2286194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 11/06/2023] [Accepted: 11/15/2023] [Indexed: 12/01/2023]
Abstract
BACKGROUND Although gastric cancer with lymphoid stroma (GCLS) presents better prognosis, uncertainty still exists regarding the association of Epstein-Barr virus (EBV) infection with prognosis of GCLS. Therefore, it is urgent to evaluate the outcome and characteristics of EBV-positive GCLS via a systematic review and meta-analysis. METHODS Three medical databases, with a period ranging from 2000 to so far, were searched for observational studies on EBV infection, clinical characteristics and prognosis. Odds ratio (OR) was used to evaluate the mortality and clinical characteristics of EBV-positive GCLS patients. Egger's test and subgroup analysis were conducted to identify the source of heterogeneity. RESULTS Nine retrospective studies were finally identified, which involved 618 EBV-positive and 153 EBV-negative GCLS patients. The forest plot indicated that EBV-positive GCLS patients had lower mortality (p = .009; 95% CI: 0.15-0.77; I2 = 48.6%). Both of funnel plot and Egger's tests suggested that there was no publication bias. Nonetheless, subgroup analysis indicated that T1-2 stage ratio more than 50% (p < .001; I2 = 6.7%) and male ratio more than 80% (p < .001; I2 = 0.0%) were valuable for eliminating the heterogeneity. Seven studies including valid information showed that TNM stage of EBV-positive and negative GCLS patients was not statistically different (p = .644; 95% CI: 0.50-1.53; I2 = 0.0%). CONCLUSIONS EBV-positive GCLS tends to have lower mortality, suggesting that detection of EBV infection is necessary to predict prognosis of GCLS.
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Affiliation(s)
- Tianxin Ying
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Jie Chen
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Jiyu Song
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Yi Zhou
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Banghe Bao
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
| | - Liduan Zheng
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
- Clinical Center of Human Genomic Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
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4
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Yang X, Wu Y, Wang A, Ma X, Zhou K, Ji K, Ji X, Zhang J, Wu X, Li Z, Bu Z. Immunohistochemical characteristics and potential therapeutic regimens of hepatoid adenocarcinoma of the stomach: a study of 139 cases. J Pathol Clin Res 2024; 10:e343. [PMID: 37974386 PMCID: PMC10766033 DOI: 10.1002/cjp2.343] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2023] [Revised: 08/13/2023] [Accepted: 08/28/2023] [Indexed: 11/19/2023]
Abstract
Hepatoid adenocarcinoma of stomach (HAS) is a special subtype of gastric cancer with poor prognosis. Immunohistochemical analysis could provide important clues for the treatment of HAS. A total of 159 patients were diagnosed as HAS and 139 were enrolled in this study. Statistical differences were determined using relative test methods and survival analyses were performed by the Kaplan-Meier method to find survival differences. All tumors in this study were negative for Epstein-Barr virus-encoded small RNAs (EBERs) and almost all showed no loss of mismatch repair (MMR) proteins and were positive for alpha fetoprotein (AFP or spalt like transcription factor 4 (SALL4). About half of the tumors had a positive programmed death-ligand 1 combined positive score (CPS) and 17.3% were positive for human epidermal growth factor receptor 2 (HER2). In addition, there was a relatively high proportion of cmet expression. We also found that HAS patients with recurrent disease treated by emerging therapy had a better survival than those treated with traditional chemotherapy (p = 0.002, median recurrence-to-death survival: 23 months versus 6 months); HAS patients who received anti-HER2 therapy or harbored MMR deficiency had favorable prognosis. Overall, high proportions of MMR protein proficiency, positivity for AFP or SALL4, overexpression of HER2, CPS and cmet, as well as negative EBER findings, are distinctive characteristics of HAS patients. While negative EBER and MMR proficiency indicate molecular features of HAS, positivity for AFP or SALL4 could aid in the diagnosis of HAS. In addition, HAS patients could benefit from anti-HER2 therapy, immunotherapy, and anti-angiogenesis therapy.
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Affiliation(s)
- Xuesong Yang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center of Gastrointestinal CancerPeking University Cancer Hospital & InstituteBeijingPR China
| | - Yan Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of PathologyPeking University Cancer Hospital & InstituteBeijingPR China
| | - Anqiang Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center of Gastrointestinal CancerPeking University Cancer Hospital & InstituteBeijingPR China
| | - Xiuli Ma
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of PathologyPeking University Cancer Hospital & InstituteBeijingPR China
| | - Kai Zhou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center of Gastrointestinal CancerPeking University Cancer Hospital & InstituteBeijingPR China
| | - Ke Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center of Gastrointestinal CancerPeking University Cancer Hospital & InstituteBeijingPR China
| | - Xin Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center of Gastrointestinal CancerPeking University Cancer Hospital & InstituteBeijingPR China
| | - Ji Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center of Gastrointestinal CancerPeking University Cancer Hospital & InstituteBeijingPR China
| | - Xiaojiang Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center of Gastrointestinal CancerPeking University Cancer Hospital & InstituteBeijingPR China
| | - ZhongWu Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of PathologyPeking University Cancer Hospital & InstituteBeijingPR China
| | - Zhaode Bu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Center of Gastrointestinal CancerPeking University Cancer Hospital & InstituteBeijingPR China
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Zebardast A, Latifi T, shirzad M, Goodarzi G, Ebrahimi Fana S, Samavarchi Tehrani S, Yahyapour Y. Critical involvement of circular RNAs in virus-associated cancers. Genes Dis 2023; 10:2296-2305. [PMID: 37554189 PMCID: PMC10404876 DOI: 10.1016/j.gendis.2022.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 03/25/2022] [Accepted: 04/06/2022] [Indexed: 12/09/2022] Open
Abstract
Virus-related cancer is cancer where viral infection leads to the malignant transformation of the host's infected cells. Seven viruses (e.g., human papillomavirus (HPV), Epstein-Barr virus (EBV), Kaposi's sarcoma herpesvirus (KSHV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human T-lymphotropic virus (HTLV), and Merkel cell polyomavirus (MCV)) that infect humans have been identified as an oncogene and have been associated with several human malignancies. Recently, growing attention has been attracted to exploring the pathogenesis of virus-related cancers. One of the most mysterious molecules involved in carcinogenesis and progression of virus-related cancers is circular RNAs (circRNA). These emerging non-coding RNAs (ncRNAs), due to the absence of 5' and 3' ends, have high stability than linear RNAs and are found in some species across the eukaryotic organisms. Compelling evidence has revealed that viruses also encode a repertoire of circRNAs, as well as dysregulation of these viral circRNAs play a critical role in the pathogenesis and progression of different types of virus-related cancers. Therefore, understanding the exact role and function of the virally encoded circRNAs with virus-associated cancers will open a new road for increasing our knowledge about the RNA world. Hence, in this review, we will focus on emerging roles of virus-encoded circRNAs in multiple cancers, including cervical cancer, gastric cancer, Merkel cell carcinoma, nasopharyngeal carcinoma, Kaposi cancer, and liver cancer.
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Affiliation(s)
- Arghavan Zebardast
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Tayebeh Latifi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Moein shirzad
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol 47176, Iran
| | - Golnaz Goodarzi
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
- Student Scientific Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Saeed Ebrahimi Fana
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
- Student Scientific Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Sadra Samavarchi Tehrani
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran 1417613151, Iran
- Student Scientific Research Center, Tehran University of Medical Sciences, Tehran 1417613151, Iran
| | - Yousef Yahyapour
- Infectious Diseases and Tropical Medicine Research Center, Health Research Institute, Babol University of Medical Sciences, Babol 47176, Iran
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Flavokawain B Weakens Gastric Cancer Progression via the TGF-β1/SMAD4 Pathway and Attenuates M2 Macrophage Polarization. J Immunol Res 2022; 2022:4903333. [PMID: 35879950 PMCID: PMC9308533 DOI: 10.1155/2022/4903333] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 05/30/2022] [Accepted: 06/08/2022] [Indexed: 11/30/2022] Open
Abstract
This study was designed to observe the treatment effects of flavokawain B (FKB) on gastric cancer both in SGC-7901 cells and nude mice. When SGC-7901 cells were exposed to 10 μg/mL FKB, cellular proliferative and apoptotic capacities and cell cycle were detected utilizing CCK-8 and flow cytometry assays. The results showed that FKB treatment induced cell apoptosis and G2/M arrest and suppressed cell proliferation for SGC-7901 cells. Western blot results showed that FKB upregulated proapoptotic proteins as well as downregulated antiapoptotic and cell cycle-related proteins in SGC-7901 cells. SMAD4, TGF-β1, and TSPAN12 proteins were tested in FKB-induced SGC-7901 cells. Following exposure to FKB, SMAD4, TGF-β1, and TSPAN12 expression was augmented in SGC-7901 cells. si-SMAD4 transfection weakened cell apoptosis and accelerated cell proliferation. Furthermore, FKB reversed the change in apoptotic and cell cycle-related proteins induced by si-SMAD4. A nude mouse tumorigenesis model was constructed, which was treated by FKB. In the nude mouse tumorigenesis model, FKB activated the TSPAN12 expression and TGF-β1/SMAD4 pathway. Also, FKB treatment prolonged the survival time of nude mice and lowered tumor weight. iNOS and CD86 expression was significantly enhanced, and Arg-1 and CD206 expression was significantly decreased in THP-1 cells cultured in conditioned media from FKB-treated SGC-7901 cells. Additionally, FKB-treated SGC-7901 cells weakened macrophage migration. Collectively, this evidence suggested that FKB accelerated apoptosis and suppressed the proliferation of gastric cancer cells and attenuated M2 macrophage polarization, thereby exerting an anticancer effect on gastric cancer.
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7
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Establishment and Validation for Predicting the Lymph Node Metastasis in Early Gastric Adenocarcinoma. JOURNAL OF HEALTHCARE ENGINEERING 2022; 2022:8399822. [PMID: 35812896 PMCID: PMC9259240 DOI: 10.1155/2022/8399822] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/26/2022] [Accepted: 06/06/2022] [Indexed: 12/24/2022]
Abstract
Lymph node metastasis (LNM) is considered to be one of the important factors in determining the optimal treatment for early gastric cancer (EGC). This study aimed to develop and validate a nomogram to predict LNM in patients with EGC. A total of 842 cases from the Surveillance, Epidemiology, and End Results (SEER) database were divided into training and testing sets with a ratio of 6 : 4 for model development. Clinical data (494 patients) from the hospital were used for external validation. Univariate and multivariate logistic regression analyses were used to identify the predictors using the training set. Logistic regression, LASSO regression, ridge regression, and elastic-net regression methods were used to construct the model. The performance of the model was quantified by calculating the area under the receiver operating characteristic curve (AUC) with 95% confidence intervals (CIs). Results showed that T stage, tumor size, and tumor grade were independent predictors of LNM in EGC patients. The AUC of the logistic regression model was 0.766 (95% CI, 0.709-0.823), which was slightly higher than that of the other models. However, the AUC of the logistic regression model in external validation was 0.625 (95% CI, 0.537-0.678). A nomogram was drawn to predict LNM in EGC patients based on the logistic regression model. Further validation based on gender, age, and grade indicated that the logistic regression predictive model had good adaptability to the population with grade III tumors, with an AUC of 0.803 (95% CI, 0.606-0.999). Our nomogram showed a good predictive ability and may provide a tool for clinicians to predict LNM in EGC patients.
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8
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Chen ZD, Zhang PF, Xi HQ, Wei B, Chen L, Tang Y. Recent Advances in the Diagnosis, Staging, Treatment, and Prognosis of Advanced Gastric Cancer: A Literature Review. Front Med (Lausanne) 2021; 8:744839. [PMID: 34765619 PMCID: PMC8575714 DOI: 10.3389/fmed.2021.744839] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 09/30/2021] [Indexed: 01/06/2023] Open
Abstract
Gastric cancer is one of the most common cause of cancer related deaths worldwide which results in malignant tumors in the digestive tract. The only radical treatment option available is surgical resection. Recently, the implementation of neoadjuvant chemotherapy resulted in 5-year survival rates of 95% for early gastric cancer. The main reason of treatment failure is that early diagnosis is minimal, with many patients presenting advanced stages. Hence, the greatest benefit of radical resection is missed. Consequently, the main therapeutic approach for advanced gastric cancer is combined surgery with neoadjuvant chemotherapy, targeted therapy, or immunotherapy. In this review, we will discuss the various treatment options for advanced gastric cancer. Clinical practice and clinical research is the most practical way of reaching new advents in terms of patients' characteristics, optimum drug choice, and better prognosis. With the recent advances in gastric cancer diagnosis, staging, treatment, and prognosis, we are evident that the improvement of survival in this patient population is just a matter of time.
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Affiliation(s)
- Zhi-da Chen
- Department of General Surgery, First Medical Center of Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Peng-Fei Zhang
- Department of Oncology, First Medical Center of Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Hong-Qing Xi
- Department of General Surgery, First Medical Center of Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Bo Wei
- Department of General Surgery, First Medical Center of Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Lin Chen
- Department of General Surgery, First Medical Center of Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
| | - Yun Tang
- Department of General Surgery, First Medical Center of Chinese People's Liberation Army of China (PLA) General Hospital, Beijing, China
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9
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Ramos MFKP, Pereira MA, de Mello ES, Cirqueira CDS, Zilberstein B, Alves VAF, Ribeiro-Junior U, Cecconello I. Gastric cancer molecular classification based on immunohistochemistry and in situ hybridization: Analysis in western patients after curative-intent surgery. World J Clin Oncol 2021; 12:688-701. [PMID: 34513602 PMCID: PMC8394162 DOI: 10.5306/wjco.v12.i8.688] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/09/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is a highly heterogeneous disease, and the identification of molecular subtyping of gastric adenocarcinoma emerged as a promising option to define therapeutic strategies and prognostic subgroups. However, the costs and technical complexity of molecular methodologies remains an obstacle to its adoption, and their clinical significance by other approaches needs further evidence.
AIM To evaluate the clinicopathological characteristics and long-term survival of GC based on the subgroups of molecular classification by immunohistochemistry (IHC) and in situ hybridization (ISH).
METHODS We retrospectively evaluated all patients who underwent D2-gastrectomy between 2009 and 2016 in a Western cohort of GC patients treated with curative intent. Microsatellite instability (MSI) status, E-cadherin, and p53 expression were analyzed by IHC, and Epstein-Barr virus (EBV) by ISH. Tissue microarrays were constructed for analysis. Clinicopathological characteristics and survival of GC were evaluated according to subtypes defined by The Cancer Genome Atlas (TCGA) Research Network Group and Asian Cancer Research Group (ACRG) classification systems.
RESULTS A total of 287 GC patients were included. Based on IHC and ISH analysis, five profiles were defined as follows: E-cadherin aberrant (9.1%), MSI (20.9%), p53 aberrant (36.6%), EBV positivity (10.5%), and p53 normal (31%), which corresponded to tumors that showed no alteration in another profile. A flowchart according to the TCGA and ACRG classifications were used to define the subtypes, where clinical and pathological characteristics associated with GC subtypes were evidenced. Proximal location (P < 0.001), total gastrectomy (P = 0.001), and intense inflammatory infiltrate (P < 0.001) were characteristics related to EBV subtype. MSI subtype was predominantly associated with advanced age (P = 0.017) and the presence of comorbidities (P = 0.011). While Laurén diffuse type (P < 0.001) and advanced stage (P = 0.029) were related to genomically stable (GS) subtype. GS tumors and microsatellite stable/epithelial to mesenchymal transition phenotype subtype had worse disease-free survival (DFS) and overall survival (OS) than other subtypes. Conversely, MSI subtype of GC had better survival in both classifications. Type of gastrectomy, pT and the TCGA subtypes were independent factors associated to DFS and OS.
CONCLUSION The IHC/ISH analysis was able to distinguish immunophenotypic groups of GC with distinct characteristics and prognosis, resembling the subtypes of the molecular classifications. Accordingly, this method of classification may represent a viable option for use in a clinical setting.
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Affiliation(s)
- Marcus Fernando Kodama Pertille Ramos
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01249000, Brazil
| | - Marina Alessandra Pereira
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01249000, Brazil
| | - Evandro Sobroza de Mello
- Department of Pathology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo 01249000, Brazil
| | | | - Bruno Zilberstein
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01249000, Brazil
| | - Venancio Avancini Ferreira Alves
- Department of Pathology, Instituto do Cancer, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, São Paulo 01249000, Brazil
| | - Ulysses Ribeiro-Junior
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01249000, Brazil
| | - Ivan Cecconello
- Department of Gastroenterology, Instituto do Cancer, Hospital das Clinicas, HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo 01249000, Brazil
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10
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Guo J, Zhong X, Tan Q, Yang S, Liao J, Zhuge J, Hong Z, Deng Q, Zuo Q. miR-301a-3p induced by endoplasmic reticulum stress mediates the occurrence and transmission of trastuzumab resistance in HER2-positive gastric cancer. Cell Death Dis 2021; 12:696. [PMID: 34257270 PMCID: PMC8277821 DOI: 10.1038/s41419-021-03991-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 06/24/2021] [Accepted: 07/01/2021] [Indexed: 12/21/2022]
Abstract
Trastuzumab resistance negatively influences the clinical efficacy of the therapy for human epidermal growth factor receptor 2 (HER2) positive gastric cancer (GC), and the underlying mechanisms remain elusive. Exploring the mechanisms and finding effective approaches to address trastuzumab resistance are of great necessity. Here, we confirmed that endoplasmic reticulum (ER) stress-induced trastuzumab resistance by up-regulating miR-301a-3p in HER2-positive GC cells. Moreover, we elucidated that miR-301a-3p mediated trastuzumab resistance by down-regulating the expression of leucine-rich repeats and immunoglobulin-like domains containing protein 1 (LRIG1) and subsequently activating the expression of insulin-like growth factor 1 receptor (IGF-1R) and fibroblast growth factor receptor 1 (FGFR1) under ER stress. We also found that intercellular transfer of miR-301a-3p by exosomes disseminated trastuzumab resistance. The present study demonstrated that exosomal miR-301a-3p could serve as a non-invasive biomarker for trastuzumab resistance, which was maybe a novel potential therapeutic target to overcome trastuzumab resistance and improve the curative effect of trastuzumab in HER2-positive GC patients.
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MESH Headings
- Animals
- Antineoplastic Agents, Immunological/pharmacology
- Apoptosis/drug effects
- Cell Line, Tumor
- Drug Resistance, Neoplasm/genetics
- Endoplasmic Reticulum Stress/drug effects
- Gene Expression Regulation, Neoplastic
- Humans
- Male
- Membrane Glycoproteins/genetics
- Membrane Glycoproteins/metabolism
- Mice, Inbred BALB C
- Mice, Nude
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Receptor, ErbB-2/antagonists & inhibitors
- Receptor, ErbB-2/metabolism
- Receptor, Fibroblast Growth Factor, Type 1/genetics
- Receptor, Fibroblast Growth Factor, Type 1/metabolism
- Receptor, IGF Type 1/genetics
- Receptor, IGF Type 1/metabolism
- Signal Transduction
- Stomach Neoplasms/drug therapy
- Stomach Neoplasms/genetics
- Stomach Neoplasms/metabolism
- Stomach Neoplasms/pathology
- Trastuzumab/pharmacology
- Tumor Burden/drug effects
- Xenograft Model Antitumor Assays
- Mice
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Affiliation(s)
- Jing Guo
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China, 510515
- Department of Internal Medicine, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, China, 510080
| | - Xuxian Zhong
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China, 510515
| | - Qinglin Tan
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China, 510515
- Department of Oncology, Dongguan People's Hospital, Southern Medical University, Dongguan, Guangdong Province, China, 523059
| | - Shengnan Yang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China, 510515
| | - Jiaqi Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China, 510515
| | - Jinke Zhuge
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China, 510515
| | - Ziyang Hong
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China, 510515
| | - Qiong Deng
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China, 510515
| | - Qiang Zuo
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China, 510515.
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11
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Li L, Wang X. Identification of gastric cancer subtypes based on pathway clustering. NPJ Precis Oncol 2021; 5:46. [PMID: 34079012 PMCID: PMC8172826 DOI: 10.1038/s41698-021-00186-z] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 05/13/2021] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is highly heterogeneous in the stromal and immune microenvironment, genome instability (GI), and oncogenic signatures. However, a classification of GC by combining these features remains lacking. Using the consensus clustering algorithm, we clustered GCs based on the activities of 15 pathways associated with immune, DNA repair, oncogenic, and stromal signatures in three GC datasets. We identified three GC subtypes: immunity-deprived (ImD), stroma-enriched (StE), and immunity-enriched (ImE). ImD showed low immune infiltration, high DNA damage repair activity, high tumor aneuploidy level, high intratumor heterogeneity (ITH), and frequent TP53 mutations. StE displayed high stromal signatures, low DNA damage repair activity, genomic stability, low ITH, and poor prognosis. ImE had strong immune infiltration, high DNA damage repair activity, high tumor mutation burden, prevalence of microsatellite instability, frequent ARID1A mutations, elevated PD-L1 expression, and favorable prognosis. Based on the expression levels of four genes (TAP2, SERPINB5, LTBP1, and LAMC1) in immune, DNA repair, oncogenic, and stromal pathways, we developed a prognostic model (IDOScore). The IDOScore was an adverse prognostic factor and correlated inversely with immunotherapy response in cancer. Our identification of new GC subtypes provides novel insights into tumor biology and has potential clinical implications for the management of GCs.
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Affiliation(s)
- Lin Li
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Big Data Research Institute, China Pharmaceutical University, Nanjing, China
| | - Xiaosheng Wang
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
- Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China.
- Big Data Research Institute, China Pharmaceutical University, Nanjing, China.
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12
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Yang K, Lu L, Liu H, Wang X, Gao Y, Yang L, Li Y, Su M, Jin M, Khan S. A comprehensive update on early gastric cancer: defining terms, etiology, and alarming risk factors. Expert Rev Gastroenterol Hepatol 2021; 15:255-273. [PMID: 33121300 DOI: 10.1080/17474124.2021.1845140] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Early gastric cancer (EGC) is a well-defined gastric malignancy that is limited to the mucosa or submucosa, irrespective of lymph node metastasis. At an early stage, gastric cancer often does not cause symptoms until it becomes advanced, and it is a heterogeneous disease and usually encountered in its late stages. AREA COVERED This comprehensive review will provide a novel insight into the evaluation of EGC epidemiology, defining terms, extensive etiology and risk factors, and timely diagnosis since prevention is an essential approach for controlling this cancer and reducing its morbidity and mortality. EXPERT OPINION The causative manner of EGC is complex and multifactorial. In recent years, researchers have made significant contributions to understanding the etiology and pathogenesis of EGC, and standardization in the evaluation of disease activity. Though the incidence of this cancer is steadily declining in some advanced societies owing to appropriate interventions, there remains a serious threat to health in developing nations. Early detection of resectable gastric cancer is crucial for better patient outcomes.
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Affiliation(s)
- Kuo Yang
- Department of Digestive Diseases, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital , Tianjin, PR, China
| | - Lijie Lu
- Department of Digestive Diseases, Dongfang Hospital of Beijing University of Chinese Medicine , Beijing, PR, China
| | - Huayi Liu
- Department of Digestive Diseases, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital , Tianjin, PR, China
| | - Xiujuan Wang
- Department of Digestive Diseases, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital , Tianjin, PR, China
| | - Ying Gao
- Department of Digestive Diseases, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital , Tianjin, PR, China
| | - Liu Yang
- Department of Digestive Diseases, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital , Tianjin, PR, China
| | - Yupeng Li
- Department of Digestive Diseases, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital , Tianjin, PR, China
| | - Meiling Su
- Department of Digestive Diseases, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital , Tianjin, PR, China
| | - Ming Jin
- Department of Digestive Diseases, Tianjin Academy of Traditional Chinese Medicine Affiliated Hospital , Tianjin, PR, China
| | - Samiullah Khan
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital , Tianjin, PR, China
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13
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Zebardast A, Tehrani SS, Latifi T, Sadeghi F. Critical review of Epstein-Barr virus microRNAs relation with EBV-associated gastric cancer. J Cell Physiol 2021; 236:6136-6153. [PMID: 33507558 DOI: 10.1002/jcp.30297] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 12/29/2020] [Accepted: 01/15/2021] [Indexed: 12/24/2022]
Abstract
Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is regarded as the most prevalent malignant tumor triggered by EBV infection. In recent years, increasing attention has been considered to recognize more about the disease process's exact mechanisms. There is accumulating evidence that showing epigenetic modifications play critical roles in the EBVaGC pathogenesis. MicroRNAs (miRNAs), as critical epigenetic modulators, are single-strand short noncoding RNA (length ~ <200 bp), which regulate gene expression through binding to the 3'-untranslated region (3'-UTR) of target RNA transcripts and either degrade or repress their activities. In the latest research on EBV, it was found that this virus could encode miRNAs. Mechanistically, EBV-encoded miRNAs are involved in carcinogenesis and the progression of EBV-associated malignancies. Moreover, these miRNAs implicated in immune evasion, identification of pattern recognition receptors, regulation of lymphocyte activation and lethality, modulation of infected host cell antigen, maintain of EBV infection status, promotion of cell proliferation, invasion and migration, and reduction of apoptosis. As good news, not only has recent data demonstrated the crucial function of EBV-encoded miRNAs in the pathogenesis of EBVaGC, but it has also been revealed that aberrant expression of exosomal miRNAs in EBVaGC has made them biomarkers for detection of EBVaGC. Regarding these substantial characterizes, the critical role of EBV-encoded miRNAs has been a hot topic in research. In this review, we will focus on the multiple mechanisms involved in EBVaGC caused by EBV-encoded miRNAs and briefly discuss their potential application in the clinic as a diagnostic biomarker.
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Affiliation(s)
- Arghavan Zebardast
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Sadra S Tehrani
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Department of Microbiology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Tayebeh Latifi
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Farzin Sadeghi
- Department of Microbiology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
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14
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MULTIFACTOR ANALYSIS OF THE ONCOPROTEINS EXPRESSION DEPENDENCE IN GASTRIC CANCER. WORLD OF MEDICINE AND BIOLOGY 2021. [DOI: 10.26724/2079-8334-2021-1-75-79-84] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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15
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Satala CB, Jung I, Stefan-van Staden RI, Kovacs Z, Molnar C, Bara T, Fulop ZZ, Gurzu S. HER2 Heterogeneity in Gastric Cancer: A Comparative Study, Using Two Commercial Antibodies. JOURNAL OF ONCOLOGY 2020; 2020:8860174. [PMID: 33144857 PMCID: PMC7596543 DOI: 10.1155/2020/8860174] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 10/08/2020] [Accepted: 10/12/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although amplification of the gene encoding human epidermal growth factor receptor 2 (HER2) is used as an indicator for response to trastuzumab, the reported response rate is low, and few patients with gastric cancer (GC) benefit from this individualized therapy. The aim of this study was to examine the expression of c-erbB-2 oncoprotein (HER2), in GC samples, using two commercial immunohistochemical (IHC) antibodies, and to validate the results by checking HER2 gene amplification by fluorescence in situ hybridization (FISH). METHODS We assessed the IHC expression of HER2 using the polyclonal antibody from Dako and CB11 clone from Leica, in 93 consecutive cases of GC samples. In all of the cases, FISH analysis was also performed using the BOND-MAX platform. RESULTS No significant difference was observed between the two HER2 antibodies. Of the 93 cases, 22.58% demonstrated at least focal and 1+ HER2 positivity. Seven cases (7.53%) exhibited 3+ expression, and another 7 carcinomas (7.53%) were equivocal (2+). HER2 amplification was seen in 11 cases (11.83%), 10 of which were differentiated adenocarcinomas. In 5 of the cases, 2-5 sections were examined, which proved the extremely high intratumorally/intraglandular heterogeneity. FISH heterogeneity was higher in cases with only 2+ positivity on IHC assessment, compared with those showing at least one small focus of 3+ overexpression. HER2 amplification proved to be an independent negative prognostic factor. CONCLUSIONS Due to the highly heterogeneous aspect of GC, at least 3-4 slides should be assessed by IHC, before considering a tumor to be HER2-negative. In cases with small 3+ foci representing less than 5% of tumor and in equivocal (2+) cases, FISH analysis remains the gold standard method.
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Affiliation(s)
- Catalin Bogdan Satala
- Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu-Mures, Romania
- Department of Pathology, Clinical County Emergency Hospital, Targu-Mures, Romania
| | - Ioan Jung
- Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu-Mures, Romania
| | - Raluca Ioana Stefan-van Staden
- Laboratory of Electrochemistry and PATLAB, National Institute of Research for Electrochemistry and Condensed Matter, Bucharest, Romania
| | - Zsolt Kovacs
- Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Tirgu-Mures, Romania
| | - Calin Molnar
- Department of Surgery, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Tirgu-Mures, Romania
- Department of Surgery, Clinical County Emergency Hospital, Targu-Mures, Romania
| | - Tivadar Bara
- Department of Surgery, Clinical County Emergency Hospital, Targu-Mures, Romania
| | - Zsolt Zoltan Fulop
- Department of Surgery, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Tirgu-Mures, Romania
- Department of Surgery, Clinical County Emergency Hospital, Targu-Mures, Romania
| | - Simona Gurzu
- Department of Pathology, George Emil Palade University of Medicine, Pharmacy, Sciences and Technology, Targu-Mures, Romania
- Department of Pathology, Clinical County Emergency Hospital, Targu-Mures, Romania
- Department of Pathology, Research Center (CCAMF), Tirgu-Mures, Romania
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16
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Liu Z, Jiang Z, Wu N, Zhou G, Wang X. Classification of gastric cancers based on immunogenomic profiling. Transl Oncol 2020; 14:100888. [PMID: 33096337 PMCID: PMC7576512 DOI: 10.1016/j.tranon.2020.100888] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 09/03/2020] [Accepted: 09/21/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Extensive evidence showed that gastric cancer (GC) is heterogeneous, and many studies have been focused on identifying GC subtypes based on genomic profiles. However, few studies have specifically explored the GC classification and predicted the classification accuracy that may help facilitate the optimal stratification of GC patients responsive to immunotherapy. METHODS Using two publicly available GC genomics datasets, we classified GC on the basis of 797 immune related genes. Unsupervised and supervised machine learning methods were used to predict the classification. RESULTS We identified two GC subtypes that we named as Immunity-High (IM-H) and Immunity- Low (IM-L), and demonstrated that this classification was duplicable and predictable by analyzing other datasets. IM-H subtype was characterized by greater immune cell infiltration, stronger immune activities, lower tumor purity, as well as worse survival prognosis compared to IM-L subtype. Besides the immune signatures, some cancer-associated pathways were hyperactivated in IM-H, including TGF-beta signaling pathway, Focal adhesion, Cell adhesion molecules (CAMs), Calcium signaling pathway, mTOR signaling pathway, MAPK signaling pathway and Wnt signaling pathway. In contrast, IM-L presented depressed immune signatures and increased activation of base excision repair, DNA replication, homologous recombination, non-homologous end-joining and nucleotide excision repair pathways. Furthermore, we identified subtype-specific genomic or clinical features, and subtype-specific gene ontology and networks in IM-H and IM-L subtype. CONCLUSIONS We proposed and validated two reproducible immune molecular subtypes of GC, which has potential clinical implications for GC patient selection of immunotherapy.
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Affiliation(s)
- Zhixian Liu
- The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Jiangsu Cancer Hospital, 42 Baiziting, Nanjing 210009, Jiangsu, China; Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Zehang Jiang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 500040, Guangdong, China; Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China
| | - Nan Wu
- The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Jiangsu Cancer Hospital, 42 Baiziting, Nanjing 210009, Jiangsu, China
| | - Guoren Zhou
- The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Institute of Cancer Research, Jiangsu Cancer Hospital, 42 Baiziting, Nanjing 210009, Jiangsu, China.
| | - Xiaosheng Wang
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing 211198, Jiangsu, China.
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17
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Beeharry MK, Zhang TQ, Liu WT, Gang ZZ. Optimization of perioperative approaches for advanced and late stages of gastric cancer: clinical proposal based on literature evidence, personal experience, and ongoing trials and research. World J Surg Oncol 2020; 18:51. [PMID: 32151257 PMCID: PMC7063816 DOI: 10.1186/s12957-020-01819-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 02/17/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The high incidence of gastric cancer (GC) and paradoxical high prevalence of advanced stage GC, amounting to around 2/3 at time of diagnosis, have urged doctors and researchers around the world not only to ameliorate the detection rate of GC at early stages but also to optimize the clinical management of GC at advanced stages. CONTENT We hereby recommend a more goal-oriented multimodality approach with objectives to increase survival rate and improve survival status. Based on precision and accurate clinical staging at diagnosis, we suggest that advanced stage GC (AGC) patients should be channeled into different treatment plans according to their disease status where they can be subjected to comprehensive measures involving chemo, radio, immunological, or target therapies depending on the pathophysiological behavior of their tumor. Patients assessed as potentially resectable cT4N + M0 can undergo neoadjuvant chemotherapy with intent of tumor downsizing and downgrading followed by surgery with intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) to decrease the incidence of peritoneal dissemination due to surgical trauma and adjuvant chemotherapy and radiation in cases of bulky nodal metastasis. In cases with distal metastasis, conversion therapy is recommended with the possibility of surgery of curative intent in case of favorable response. The options of alternate treatment options such as trans-catheter arterial chemoembolization (TACE) for limited liver lesions or neoadjuvant intraperitoneal plus systemic chemotherapy (NIPS) for peritoneal carcinomatosis have to be negotiated. With surgery as the cornerstone for cancer treatment, there is acknowledgment of the significance of perioperative comprehensive approaches but there has not been some consensus guiding clinical application. Henceforth, in this review, based on past literature, current guidelines and ongoing clinical trials, we have shared a proposal of the current treatment modalities in practice for the advanced stages of gastric cancer. CONCLUSION Even though surgery is the golden standard of radical cancer treatment, clinical reality shows that without proper perioperative management, patients undergoing radical resections manifest high rates of recurrence and metastasis. Hence, in this review, we have outlined a clinical agenda to optimize the management of advanced stage GC with objective to improve survival outcome and quality of life of patients.
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Affiliation(s)
- Maneesh Kumarsing Beeharry
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Tian Qi Zhang
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Wen Tao Liu
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
| | - Zhu Zheng Gang
- Department of Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
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18
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Wang F, Li X, Zhao X, Xue Y. Detection of a 5-circRNA signature to improve prognostic prediction in gastric cancer. J Investig Med 2019; 68:762-769. [PMID: 31672718 DOI: 10.1136/jim-2019-001131] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/02/2019] [Indexed: 01/10/2023]
Abstract
Gastric cancer (GC) is a commonly diagnosed malignancy with a high mortality rate worldwide. Despite advances in therapeutic approaches, the 5-year survival rate of patients with GC remains poor. A type of non-coding RNA, circular RNA (circRNA), has been discovered. Some circRNAs are dysregulated in cancer and may have important functions. Thus, circRNAs could be candidate biomarkers for disease diagnosis and prognosis. Our study used a reannotation framework to derive expression values of circRNAs from microarray data sets. We used an integrated pipeline including differential expression analysis and Cox regression analyses to detect GC-associated circRNA signatures. We validated results with 54 paired gastric tumor and adjacent normal tissues. Five circRNA signatures were highly associated with patient overall survival and disease-free survival. Real-time PCR experiments on hsa_circ_0103398 and hsa_circ_0127859 in tumors and normal tissues showed that these circRNAs were significantly upregulated in GC. High expression of hsa_circ_0103398 and hsa_circ_0127859 was closely associated with unfavorable survival time. Our findings indicated that a 5-circRNA signature might serve as a candidate prognostic biomarker of GC.
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Affiliation(s)
- Fengjiao Wang
- Department of Thoracic Surgery, Cancer Hospital, Harbin Medical University, Harbin, China
| | - Xuexin Li
- Department of Urinary Surgery, Cancer Hospital, Harbin Medical University, Harbin, China
| | - Xingkai Zhao
- The First Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Yingwei Xue
- Department of Gastrointestinal Surgery, Cancer Hospital, Harbin Medical University, Harbin, China
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Barsouk A, Rawla P, Hadjinicolaou AV, Aluru JS, Barsouk A. Targeted Therapies and Immunotherapies in the Treatment of Esophageal Cancers. Med Sci (Basel) 2019; 7:E100. [PMID: 31561465 PMCID: PMC6836115 DOI: 10.3390/medsci7100100] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 09/23/2019] [Accepted: 09/24/2019] [Indexed: 02/08/2023] Open
Abstract
Esophageal cancer (EC) is among the most frequent and deadly cancers around the world. While esophageal adenocarcinoma (EAC) has one of the fastest-growing incidences amongst cancers in the US, it also has one of the lowest survival rates due to the limited effective treatment options. Fortunately, in the past decade, two targeted therapies and an immunotherapy agent have been approved by the FDA for metastatic EAC and esophageal squamous cell carcinoma (ESCC), with several more currently being considered for approval. In terms of immunotherapies, in July 2019, the FDA approved the PD1 inhibitor pembrolizumab for second-line treatment of PDL1-positive, advanced or metastatic ESCC. Two years before, pembrolizumab had been approved for the third-line treatment of PDL1-positive EAC. The PD1 inhibitor nivolumab, which was found in one study to outperform chemotherapy irrespective of PDL1 status, has yet to secure FDA approval. In terms of targeted therapies, although as many as 90% of EC cases show upregulated EGFR, anti-EGFR therapy has not been shown to improve survival. Ramucirumab, an antibody targeting both VEGF and HER2/neu receptors, has been approved for the treatment of refractory EAC, while the anti-HER2 monoclonal antibody (mAb) trastuzumab has been approved as front-line treatment for HER2-positive cases which account for approximately 20% of ECs. Although these targeted therapies and immunotherapies have resulted in significant improvements in survival for specific patient populations that are positive for certain biomarkers, such as PDL1 and HER2/neu, the survival rates remain low for a large proportion of the metastatic EC patient population, necessitating the development of further targeted treatment options.
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Affiliation(s)
- Adam Barsouk
- Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, USA.
| | - Prashanth Rawla
- Department of Medicine, Sovah Health, Martinsville, VA 24112, USA.
| | - Andreas V Hadjinicolaou
- Academic Clinical Post-Doctoral Fellow and Gastroenterology Resident, MRC Cancer Unit and Department of Gastroenterology, University of Cambridge, Cambridge CB2 0XZ, UK.
| | - John Sukumar Aluru
- Senior Research Associate, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02212, USA.
| | - Alexander Barsouk
- Hematologist-Oncologist, Allegheny Health Network, Pittsburgh, PA 15212, USA.
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20
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Zeng X, Pan D, Wu H, Chen H, Yuan W, Zhou J, Shen Z, Chen S. Transcriptional activation of ANO1 promotes gastric cancer progression. Biochem Biophys Res Commun 2019; 512:131-136. [PMID: 30871776 DOI: 10.1016/j.bbrc.2019.03.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 03/01/2019] [Indexed: 02/06/2023]
Abstract
The prognosis of gastric cancer (GC) remains poor due to local invasion and distal metastasis. The GC-related molecular mechanisms underlying invasion and metastasis are not well understood. In this study, we investigated the functional role of ANO1 in GC progression. We found that ANO1 is overexpressed in GC tissues and correlated with GC tumor-node-metastasis stage. Knockdown of ANO1 significantly inhibited GC cell migration and invasion in vitro, and loss of ANO1 resulted in inhibition of tumor metastasis in vivo. Mechanistically, SP1 increased ANO1 transcription, recruited MLL1 to the ANO1 promoter region, facilitated H3K4 trimethylation, and subsequently promoted ANO1 expression. Together, our findings provide a mechanistic assessment of ANO1 overexpression, which represents a GC progression-related molecule and a potentially valuable target for future research.
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Affiliation(s)
- Xiaoqing Zeng
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China
| | - Duyi Pan
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China
| | - Hao Wu
- Key Laboratory of Glycoconjugate Research Ministry of Public Health, School of Basic Medical Sciences, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, PR China
| | - Hao Chen
- Department of General Surgery, Zhongshan Hospital of Fudan University, Shanghai, 200032, PR China
| | - Wei Yuan
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China
| | - Ji Zhou
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China
| | - Zhenbin Shen
- Department of General Surgery, Zhongshan Hospital of Fudan University, Shanghai, 200032, PR China.
| | - Shiyao Chen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China; Endoscopy Center, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China.
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21
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Shen L. Liquid biopsy: a powerful tool to monitor trastuzumab resistance in HER2-positive metastatic gastric cancer. Cancer Commun (Lond) 2018; 38:72. [PMID: 30563572 PMCID: PMC6299539 DOI: 10.1186/s40880-018-0344-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 12/07/2018] [Indexed: 12/19/2022] Open
Affiliation(s)
- Lin Shen
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing, 100142, China.
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22
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Lazăr DC, Avram MF, Romoșan I, Cornianu M, Tăban S, Goldiș A. Prognostic significance of tumor immune microenvironment and immunotherapy: Novel insights and future perspectives in gastric cancer. World J Gastroenterol 2018; 24:3583-3616. [PMID: 30166856 PMCID: PMC6113718 DOI: 10.3748/wjg.v24.i32.3583] [Citation(s) in RCA: 110] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Revised: 06/05/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Despite a decrease in gastric cancer incidence, the development of novel biologic agents and combined therapeutic strategies, the prognosis of gastric cancer remains poor. Recently, the introduction of modern immunotherapy, especially using immune checkpoint inhibitors, led to an improved prognosis in many cancers. The use of immunotherapy was also associated with manageable adverse event profiles and promising results in the treatment of patients with gastric cancer, especially in heavily pretreated patients. These data have led to an accelerated approval of some checkpoint inhibitors in this setting. Understanding the complex relationship between the host immune microenvironment and tumor and the immune escape phenomenon leading to cancer occurrence and progression will subsequently lead to the identification of prognostic immune markers. Furthermore, this understanding will result in the discovery of both new mechanisms for blocking tumor immunosuppressive signals and pathways to stimulate the local immune response by targeting and modulating different subsets of immune cells. Due to the molecular heterogeneity of gastric cancers associated with different clinico-biologic parameters, immune markers expression and prognosis, novel immunotherapy algorithms should be personalized and addressed to selected subsets of gastric tumors, which have been proven to elicit the best clinical responses. Future perspectives in the treatment of gastric cancer include tailored dual immunotherapies or a combination of immunotherapy with other targeted agents with synergistic antitumor effects.
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Affiliation(s)
- Daniela Cornelia Lazăr
- Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Mihaela Flavia Avram
- Department of Surgery X, 1st Surgery Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Ioan Romoșan
- Department of Internal Medicine I, University Medical Clinic, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Mărioara Cornianu
- Department of Pathology, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Sorina Tăban
- Department of Pathology, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
| | - Adrian Goldiș
- Department of Gastroenterology and Hepatology, University of Medicine and Pharmacy “Victor Babeş”, Timişoara 300041, Timiş County, Romania
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Jiang Z, Liu Z, Li M, Chen C, Wang X. Immunogenomics Analysis Reveals that TP53 Mutations Inhibit Tumor Immunity in Gastric Cancer. Transl Oncol 2018; 11:1171-1187. [PMID: 30059832 PMCID: PMC6078052 DOI: 10.1016/j.tranon.2018.07.012] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 07/14/2018] [Accepted: 07/16/2018] [Indexed: 12/23/2022] Open
Abstract
Although immunotherapy continues to demonstrate efficacy in a variety of refractory cancers, currently, no any immunotherapeutic strategy is clinically used for gastric cancer (GC) except its microsatellite instable subtype. Thus, it is important to identify molecular biomarkers for predicting the responders to GC immunotherapy. TP53 mutations frequently occur in GC and are associated with unfavorable clinical outcomes in GC. We performed a comprehensive characterization of the associations between TP53 mutations and immune activities in GC based on two large-scale GC cancer genomics data. We compared expression and enrichment levels of 787 immune-related genes and 23 immune gene-sets among TP53-mutated GCs, TP53‐wildtype GCs, and normal tissue, and explored the correlations between p53-mediated pathways and immune activities in GC. Strikingly, almost all analyzed immune gene-sets were significantly downregulated in enrichment levels in TP53-mutated GCs compared to TP53‐wildtype GCs. These less active immune pathways and cell types in TP53-mutated GCs included 15 immune cell types and function, tumor-infiltrating lymphocytes, regulatory T cells, immune checkpoint, cytokine and cytokine receptor, human leukocyte antigen, pro‐inflammatory, and parainflammation. Moreover, we identified a number of p53-mediated pathways and proteins that were significantly associated with immune activities in GC. Furthermore, we demonstrated that the TP53 mutation itself could result in the depressed immune activities in GC and other cancer types. We revealed that chromosomal instability was an important mechanism for the depressed tumor immunity in TP53-mutated cancers. Finally, we showed that immune cell infiltration and immune activities were likely positively associated with survival prognosis in GC. Our findings suggest that p53 may play an important role in activating tumor immunity in GC and other cancer types and that the TP53 mutation status could be useful in stratifying cancer patients responsive to a certain immunotherapy.
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Affiliation(s)
- Zehang Jiang
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, Nanjing 211198, China; Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China
| | - Zhixian Liu
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, Nanjing 211198, China; Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China
| | - Mengyuan Li
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, Nanjing 211198, China; Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China
| | - Cai Chen
- Department of Electrical and Computer Engineering, University of California, San Diego, La Jolla, CA 92093, USA
| | - Xiaosheng Wang
- Biomedical Informatics Research Lab, School of Basic Medicine and Clinical Pharmacy, Nanjing 211198, China; Cancer Genomics Research Center, School of Basic Medicine and Clinical Pharmacy, Nanjing 211198, China; Big Data Research Institute, China Pharmaceutical University, Nanjing 211198, China.
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24
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Alessandrini L, Manchi M, De Re V, Dolcetti R, Canzonieri V. Proposed Molecular and miRNA Classification of Gastric Cancer. Int J Mol Sci 2018; 19:E1683. [PMID: 29882766 PMCID: PMC6032377 DOI: 10.3390/ijms19061683] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 05/30/2018] [Accepted: 06/01/2018] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is a common malignant neoplasm worldwide and one of the main cause of cancer-related deaths. Despite some advances in therapies, long-term survival of patients with advanced disease remains poor. Different types of classification have been used to stratify patients with GC for shaping prognosis and treatment planning. Based on new knowledge of molecular pathways associated with different aspect of GC, new pathogenetic classifications for GC have been and continue to be proposed. These novel classifications create a new paradigm in the definition of cancer biology and allow the identification of relevant GC genomic subsets by using different techniques such as genomic screenings, functional studies and molecular or epigenetic characterization. An improved prognostic classification for GC is essential for the development of a proper therapy for a proper patient population. The aim of this review is to discuss the state-of-the-art on combining histological and molecular classifications of GC to give an overview of the emerging therapeutic possibilities connected to the latest discoveries regarding GC.
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Affiliation(s)
- Lara Alessandrini
- Pathology, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Melissa Manchi
- Pathology, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Valli De Re
- Immunopathology and Cancer Biomarkers, IRCCS CRO National Cancer Institute, 33081 Aviano, Italy.
| | - Riccardo Dolcetti
- The University of Queensland Diamantina Institute, Translational Research Institute, Woolloongabba, QLD 4102, Australia.
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25
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Deng X, Xiao Q, Liu F, Zheng C. A gene expression-based risk model reveals prognosis of gastric cancer. PeerJ 2018; 6:e4204. [PMID: 29441228 PMCID: PMC5807894 DOI: 10.7717/peerj.4204] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 12/08/2017] [Indexed: 12/11/2022] Open
Abstract
Background The prognosis of gastric cancer is difficult to determine, although clinical indicators provide valuable evidence. Methods In this study, using screened biomarkers of gastric cancer in combination with random forest variable hunting and multivariable Cox regression, a risk score model was developed to predict the survival of gastric cancer. Survival difference between high/low-risk groups were compared. The relationship between risk score and other clinicopathological indicators was evaluated. Gene set enrichment analysis (GSEA) was used to identify pathways associated with risk scores. Results The patients with high risk scores (median overall survival: 20.2 months, 95% CI [16.9–26.0] months) tend to exhibit early events compared with those with low risk scores (median survival: 70.0 months, 95% CI [46.9–101] months, p = 1.80e–5). Further validation was implemented in another three independent datasets (GSE15459, GSE26253, GSE62254). Correlation analyses between clinical observations and risk scores were performed, and the results indicated that the risk score was not significantly associated with gender, age and primary tumor size but was significantly associated with grade and tumor stage. In addition, the risk score was also not influenced by radiation therapy. Cox multivariate regression and three-year survival nomogram suggest that the risk score is an important indicator of gastric cancer prognosis. GSEA was used to identified KEGG pathways significantly associated with risk score, and signaling pathways involved in focal adhesion and the TGF-beta signaling pathway were identified. Conclusion The risk score model successfully predicted the survival of 1,294 gastric cancer samples from four independent datasets and is among the most important indicators in clinical clinicopathological information for the prognosis of gastric cancer. To our knowledge, it is the first report to predict the survival of gastric cancer using optimized expression panel.
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Affiliation(s)
- Xiaorong Deng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Qun Xiao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Hunan College of Traditional Chinese Medicine, Zhuzhou, Hunan, China
| | - Feng Liu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Cihua Zheng
- Jiangxi Medical College of Nanchang University, Nanchang, Jiangxi, China
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Mihailidou C, Karamouzis MV, Schizas D, Papavassiliou AG. Co-targeting c-Met and DNA double-strand breaks (DSBs): Therapeutic strategies in BRCA-mutated gastric carcinomas. Biochimie 2017; 142:135-143. [PMID: 28890386 DOI: 10.1016/j.biochi.2017.09.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 09/04/2017] [Indexed: 02/06/2023]
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Chen S, Nie RC, OuYang LY, Li YF, Xiang J, Zhou ZW, Chen Y, Peng JS. Nomogram analysis and external validation to predict the risk of lymph node metastasis in gastric cancer. Oncotarget 2017; 8:11380-11388. [PMID: 28077786 PMCID: PMC5355272 DOI: 10.18632/oncotarget.14535] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 12/27/2016] [Indexed: 12/26/2022] Open
Abstract
Aim To identify risk factors for lymph node metastasis using a nomogram for gastric cancer patients to predict lymph node metastasis. Results The Chi-square test and the logistic regression showed that the Boarrmann type, preoperative CA199 level, T stage and N stage by CT scan were independent risk factors. The concordance index (C-index) was 0.786 in the internal validation of the Nomogram model. In the external validation, the C-index was 0.809, and the AUC was 0.894. The total accuracy of the prediction was 82.2%, and the false-negative rate was 5.4% with a cut-off value set at 0.109. Materials and Methods The study consisted of 451 patients with a histological diagnosis of gastric cancer with 0 or 1 lymph node metastasis from the Sun Yat-sen University Cancer Center as the development set, and the validation set consisted of 186 gastric cancer patients from the Sixth Affiliated Hospital of Sun Yat-Sen University. A Chi-square test and a logistic regression analysis were used to compare the clinicopathological variables and lymph node metastasis. The C-index and ROC curve were computed for comparisons of the nomogram's predictive ability. Conclusions We developed and validated a nomogram to predict lymph node metastasis in gastric cancer before surgery. This nomogram can be broadly applied, even in general hospitals, and is useful for decisions regarding treatment programs for patients.
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Affiliation(s)
- Shi Chen
- The 6th Affiliated Hospital, Sun Yat-Sen University, YuanCun ErHeng Road, TianHe District, 510655, Guangzhou, China
| | - Run-Cong Nie
- Department of Gastropancreatic Surgery, Sun Yat-Sen University Cancer Center, 510060, Guangzhou, China
| | - Li-Ying OuYang
- Department of Intensive Care Unit, Sun Yat-Sen University Cancer Center, 510060, Guangzhou, China
| | - Yuan-Fang Li
- Department of Gastropancreatic Surgery, Sun Yat-Sen University Cancer Center, 510060, Guangzhou, China
| | - Jun Xiang
- The 6th Affiliated Hospital, Sun Yat-Sen University, YuanCun ErHeng Road, TianHe District, 510655, Guangzhou, China
| | - Zhi-Wei Zhou
- Department of Gastropancreatic Surgery, Sun Yat-Sen University Cancer Center, 510060, Guangzhou, China
| | - YingBo Chen
- Department of Gastropancreatic Surgery, Sun Yat-Sen University Cancer Center, 510060, Guangzhou, China
| | - Jun-Sheng Peng
- The 6th Affiliated Hospital, Sun Yat-Sen University, YuanCun ErHeng Road, TianHe District, 510655, Guangzhou, China
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Bozkaya Y, Demirci NS, Kurtipek A, Erdem GU, Ozdemir NY, Zengin N. Clinicopathological and prognostic characteristics in patients with AFP-secreting gastric carcinoma. Mol Clin Oncol 2017; 7:267-274. [PMID: 28781800 DOI: 10.3892/mco.2017.1288] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Accepted: 05/16/2017] [Indexed: 12/31/2022] Open
Abstract
The aim of the present study was to determine whether there are any clinicopathological or prognostic differences between patients with α-fetoprotein-secreting gastric carcinoma (AFP-SGC) and non-AFP-SGC. Pathological parameters, clinical parameters, and treatment efficacy were compared in patients with AFP-SGC and non-AFP-SGC. In total, 362 patients (53 with AFP-SGC and 309 with non-AFP-SGC) were included in the present study. Patients with AFP-SGC had significantly higher levels of lymphovascular invasion, perineural invasion (PNI), rate of liver metastasis, and stage IV cancer compared with patients with non-AFP-SGC (P<0.05). The median overall survival (OS) rate was 12.6 months in the AFP-SGC group, and 22.1 months in the non-AFP-SGC group (P<0.001). The median OS and disease free survival (DFS) of patients with stage I-III AFP-SGC were 28.1 and 13.4 months, respectively, whereas for patients with non-AFP-SGC, the OS and DFS were 45.3 and 38.0 months, respectively (P=0.01; P=0.02). The median OS for the stage IV AFP-SGC and non-AFP-SGC groups was 9.3 and 11.5 months, respectively (P=0.14). Multivariate analysis of the entire patient group revealed that the Eastern Cooperative Oncology Group (ECOG) performance score of ≥2, lymph node involvement, presence of PNI, high levels of carcinoembryonic antigen, and distant metastasis were significantly correlated with OS. The lymph node involvement, ECOG performance score of ≥2, AFP-SGC type, and weight loss at diagnosis were also significant factors influencing the DFS in the stage I-III group. In conclusion, patients with AFP-SGC had more aggressive clinicopathological features and biological behavior with an increased tendency of liver metastasis compared with patients with non-AFP-SGC. In the near future, AFP may become an important surrogate marker to manage therapies of patients with gastric cancer.
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Affiliation(s)
- Yakup Bozkaya
- Department of Medical Oncology, Ankara Numune Education and Research Hospital, Ankara, Turkey
| | - Nebi Serkan Demirci
- Department of Medical Oncology, Ankara Numune Education and Research Hospital, Ankara, Turkey
| | - Alican Kurtipek
- Department of Internal Medicine, Ankara Numune Education and Research Hospital, Ankara, Turkey
| | - Gökmen Umut Erdem
- Department of Medical Oncology, Ankara Numune Education and Research Hospital, Ankara, Turkey
| | - Nuriye Yildirim Ozdemir
- Department of Medical Oncology, Ankara Numune Education and Research Hospital, Ankara, Turkey
| | - Nurullah Zengin
- Department of Medical Oncology, Ankara Numune Education and Research Hospital, Ankara, Turkey
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Garattini SK, Basile D, Cattaneo M, Fanotto V, Ongaro E, Bonotto M, Negri FV, Berenato R, Ermacora P, Cardellino GG, Giovannoni M, Pella N, Scartozzi M, Antonuzzo L, Silvestris N, Fasola G, Aprile G. Molecular classifications of gastric cancers: Novel insights and possible future applications. World J Gastrointest Oncol 2017; 9:194-208. [PMID: 28567184 PMCID: PMC5434387 DOI: 10.4251/wjgo.v9.i5.194] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2016] [Revised: 12/04/2016] [Accepted: 03/17/2017] [Indexed: 02/05/2023] Open
Abstract
Despite some notable advances in the systemic management of gastric cancer (GC), the prognosis of patients with advanced disease remains overall poor and their chance of cure is anecdotic. In a molecularly selected population, a median overall survival of 13.8 mo has been reached with the use of human epidermal growth factor 2 (HER2) inhibitors in combination with chemotherapy, which has soon after become the standard of care for patients with HER2-overexpressing GC. Moreover, oncologists have recognized the clinical utility of conceiving cancers as a collection of different molecularly-driven entities rather than a single disease. Several molecular drivers have been identified as having crucial roles in other tumors and new molecular classifications have been recently proposed for gastric cancer as well. Not only these classifications allow the identification of different tumor subtypes with unique features, but also they serve as springboard for the development of different therapeutic strategies. Hopefully, the application of standard systemic chemotherapy, specific targeted agents, immunotherapy or even surgery in specific cancer subgroups will help maximizing treatment outcomes and will avoid treating patients with minimal chance to respond, therefore diluting the average benefit. In this review, we aim at elucidating the aspects of GC molecular subtypes, and the possible future applications of such molecular analyses.
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30
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Hou JY, Wang YG, Ma SJ, Yang BY, Li QP. Identification of a prognostic 5-Gene expression signature for gastric cancer. J Cancer Res Clin Oncol 2017; 143:619-629. [PMID: 28035468 DOI: 10.1007/s00432-016-2324-z] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Accepted: 12/16/2016] [Indexed: 12/14/2022]
Abstract
PURPOSE Gastric cancer (GC) is a major tumor throughout the world with remaining high morbidity and mortality. The aim is to generate a gene model to assess the prognoses risk of patients with GC. METHODS Gene expression profiling of gastric cancer patients, GSE62254 (300 samples) and GSE26253 (432 samples), was downloaded from Gene Expression Omnibus (GEO) database. Univariate survival analysis and LASSO (Least Absolute Shrinkage and Selectionator operator) (1000 iterations) of differentially expressed genes in GSE62254 was assessed using survival and glmnet in R package, respectively. Kaplan-Meier analysis on the clustering algorithm from each regression model was performed to calculate the influence to the prognosis. Random samples in GSE26253 were analyzed in multivariate and univariate survival analysis for one thousand times to calculate statistical stability of each regression model. RESULTS A total of 854 Genes were identified differentially expressed in GSE62254, among which 367 Genes were found influencing the prognoses. Six gene clusters were selected with good stability. Hereinto, five or more genes in 11-Gene model, TRPC1, SGCE, TNFRSF11A, LRRN1, HLF, CYS1, PPP1R14A, NOV, NBEA, CES1 and RGN, was available to evaluate the prognostic risk of GC patients in GSE26253 (P = 0.00445). The validity and reliability was validated. CONCLUSION In conclusion, we successfully generated a stable 5-Gene model, which could be utilized to predict prognosis of GC patients and would contribute to postoperational treatment and follow-up strategies.
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Affiliation(s)
- Jun-Yi Hou
- Department of Gastroenterology, Shanghai Sixth People's Hospital East Affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, 201306, China
| | - Yu-Gang Wang
- Department of Gastroenterology, Shanghai Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shi-Jie Ma
- Department of Gastroenterology, Huai'an First People's Hospital, Nanjing Medical University, Huai'an, Jiangsu, China
| | - Bing-Yin Yang
- Department of Gastroenterology, The Second People's Hospital of Huai'an and The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, 223002, China.
| | - Qian-Ping Li
- Department of Cardiothoracic Surgery, Shanghai Sixth People's Hospital East Affiliated to Shanghai University of Medicine & Health Sciences, Shanghai, 201306, China.
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Panarese I, De Vita F, Ronchi A, Romano M, Alfano R, Di Martino N, Zito Marino F, Ferraraccio F, Franco R. Predictive biomarkers along gastric cancer pathogenetic pathways. Expert Rev Anticancer Ther 2017; 17:417-425. [PMID: 28277834 DOI: 10.1080/14737140.2017.1301207] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Gastric cancer is the second leading cause of cancer all over the world. Unfortunately, several gastric cancers are diagnosed in an advanced stage and chemotherapy and/or target therapies remain the only options to treat patients. Areas covered: Herein we evaluate the new molecular proposal of gastric cancer classification, offering the possibility to recognize different pathogenetic mechanisms and molecular biomarkers potentially useful for target therapies. Expert commentary: The possibility of introducing new specific tests for identification of molecular biomarkers critical for targeted therapies response represents the new frontier in the selection of gastric cancer patients to improve their survival. Besides HER2, already used in clinical settings as a target biomarker for biological therapy in gastric cancer patients with tissue cancer cells overexpressing HER2, other promising target biomarkers which are deregulated in gastric cancer, such as MET and FGFR, could be identified in tissue and then used for therapeutic purposes. In addition immunotherapy represents the most promising possibility of advanced gastric cancer treatment. In particular, as in other solid tumors, PD-1/PDL1 pathway has emerged in several clinical trials as an interesting therapeutic target.
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Affiliation(s)
- Iacopo Panarese
- a Pathology Unit, Department of Mental and Physical Health and Preventive Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Ferdinando De Vita
- b Division of Medical Oncology, Department of Internal and Experimental Medicine 'F. Magrassi' , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Andrea Ronchi
- a Pathology Unit, Department of Mental and Physical Health and Preventive Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Marco Romano
- c Division of Hepatogastroenterology, Department of Clinical and Experimental Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Roberto Alfano
- d General Surgery Unit, Department of Anesthesiology , Surgery and Emergency, Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Natale Di Martino
- e Department of Internal Medicine , Surgical, Neurological Metabolic Disease and Geriatric Medicine, Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Federica Zito Marino
- a Pathology Unit, Department of Mental and Physical Health and Preventive Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy.,f Pathology Unit, Istituto dei tumori 'Fondazione G. Pascale'
| | - Francesca Ferraraccio
- a Pathology Unit, Department of Mental and Physical Health and Preventive Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
| | - Renato Franco
- a Pathology Unit, Department of Mental and Physical Health and Preventive Medicine , Università della Campania 'Luigi Vanvitelli,' , Naples , Italy
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朱 晓, 李 夏, 李 素, 于 红. Advances in research of Epstein-Barr virus-associated gastric carcinoma. Shijie Huaren Xiaohua Zazhi 2017; 25:1375. [DOI: 10.11569/wcjd.v25.i15.1375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Xie D, Shang L, Peng L, Li L. Up-regulation of VEZT by small activating RNA inhibits the proliferation, invasion and migration of gastric cancer cells. Biochem Biophys Res Commun 2016; 482:542-548. [PMID: 27856244 DOI: 10.1016/j.bbrc.2016.11.071] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 11/12/2016] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To identify an effective saRNA sequence that can specifically up-regulate VEZT expression and to determine the influence of saRNA had on gastric cancer cell growth, proliferation, invasion and migration. METHODS Three various saRNAs, that target the VEZT gene promoter at different locations relative to the transcription start site were synthesized. A dsControl saRNA was synthesized as a negative control, and a specific shRNA was synthesized to knockdown VEZT and eliminate any off-target effects of the saRNA. Both SGC-7901 and M-28 cells were either transfected with the different saRNAs, or treated with Lipofectamine2000 alone. To determine the most effective saRNA, real-time PCR and Western blot were used to determine the VEZT mRNA and protein content, respectively, of each treatment group. After selection, both cell lines were treated with the chosen saRNA, dsControl or Lipofectamine2000. The saRNA treated cells were divided into two groups: the first group was used immediately in the experiments, and the second group was transfected with shRNA by using RNAi-Mate. The proliferation of cells transfected with saRNA, or saRNA and shRNA, as well as the other control cells, was detected by CCK-8. The invasive and migratory abilities were determined using the transwell chamber assay. RESULTS We identified the most effective saRNA via real-time PCR and Western blot. The selected saRNA inhibited the growth, invasion and migration of GC cells by specially reactivating VEZT. The real-time PCR and Western blot results showed that treatment with saRNA caused a significant up-regulation of VEZT, and an obvious decrease in the proliferative, invasive and migratory abilities; compared with the control groups (P < 0.01); furthermore, there were no significant differences among the control groups (P > 0.05). This phenomenon provides a theoretical basis for saRNA design and gene therapy for gastric cancer.
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Affiliation(s)
- Detian Xie
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250000, Shandong, China
| | - Liang Shang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250000, Shandong, China
| | - Lipan Peng
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250000, Shandong, China
| | - Leping Li
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250000, Shandong, China.
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Yan L. The journey of personalizing gastric cancer treatment. CHINESE JOURNAL OF CANCER 2016; 35:84. [PMID: 27581614 PMCID: PMC5006280 DOI: 10.1186/s40880-016-0149-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Accepted: 08/11/2016] [Indexed: 03/06/2023]
Abstract
Gastric cancer ranks the fourth most prevalent malignancy yet it is the second leading cause of cancer-related death. Every year, gastric cancer adds nearly 1 million new cancer cases, and 723,000 or 10% of cancer deaths to the global cancer burden. Approximately, 405,000 or 43% of the new cases and 325,000 or 45% of the deaths are in China, making gastric cancer a particularly challenging malignancy. This thematic series discusses the molecular classifications of gastric cancer by the Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) as well as the implications in personalized therapeutic choices; discusses the evolution of gastric surgery and presents perspectives on surgical techniques in treating gastric cancer; and reviews current and emerging targeted agents as well as immunotherapies in treating gastric cancer. With these advancements in molecular characterization, surgical intervention, and targeted and immunotherapies, gastric cancer will enter a personalized medicine era in the next 5 years.
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Affiliation(s)
- Li Yan
- US Chinese Anti-Cancer Association, Martinez, CA, 94553, USA. .,Beijing Cancer Hospital and Institute, Peking University School of Oncology, Beijing, 100142, P. R. China.
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Sun W, Yan L. Gastric cancer: current and evolving treatment landscape. CHINESE JOURNAL OF CANCER 2016; 35:83. [PMID: 27581465 PMCID: PMC5006607 DOI: 10.1186/s40880-016-0147-6] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 08/04/2016] [Indexed: 12/23/2022]
Abstract
Gastric (including gastroesophageal junction) cancer is the third leading cause of cancer-related death in the world. In China, an estimated 420,000 patients were diagnosed with gastric cancer in 2011, ranking this malignancy the second most prevalent cancer type and resulting in near 300,000 deaths. The treatment landscape of gastric cancer has evolved in recent years. Although systemic chemotherapy is still the mainstay treatment of metastatic disease, the introduction of agents targeting human epidermal growth factor receptor 2 and vascular endothelial growth factor/vascular endothelia growth factor receptor has brought this disease into the molecular and personalized medicine era. The preliminary yet encouraging clinical efficacy observed with immune checkpoint inhibitors, e.g., anti-programmed cell death protein 1/programmed death-ligand 1, will further shape the treatment landscape for gastric cancer. Molecular characterization of patients will play a critical role in developing new agents, as well as in implementing new treatment options for this disease.
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Affiliation(s)
- Weijing Sun
- University of Pittsburgh School of Medicine, Pittsburgh, PA, 15232, USA.
| | - Li Yan
- US Chinese Anti-Cancer Association, Martinez, CA, 94553, USA. .,Beijing Cancer Hospital and Institute, Peking University School of Oncology, Beijing, 100142, P. R. China.
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