|
1
|
Lee SM, Oh H. Association of PD-L1 positivity with Epstein Barr virus infection and microsatellite instability in gastric carcinomas with lymphoid stroma. Sci Rep 2024; 14:30932. [PMID: 39730741 DOI: 10.1038/s41598-024-81764-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Accepted: 11/28/2024] [Indexed: 12/29/2024] Open
Abstract
Gastric carcinoma with lymphoid stroma (GCLS) is characterized by dense intra-and peritumoral lymphocytic infiltration and a high rate of Epstein Barr Virus (EBV) infection, suggesting being a promising candidate for immunotherapy. We investigated correlations between PD-L1 expression and clinicopathologic factors, including EBV positivity and microsatellite instability (MSI) status in GCLSs. The study included resected 214 GCLSs and 300 gastric adenocarcinomas (GACs) for control. Epstein Barr Virus encoding region in situ hybridization (EBER ISH), immunohistochemistry for PD-L1 and HER2, dual-colored in situ hybridization for HER2, and MSI analysis were performed. EBV positivity was found in 181 (85%) of 214 GCLSs. MSI analysis demonstrated that 0.6% of EBV + GCLSs and 54.5% of EBV-GCLSs were MSI-high compared to 7% of EBV-GACs. Approximately 3% and 3.9% of HER2 amplifications were found in EBV- and EBV + GCLSs compared to 13% of EBV-GACs. PD-L1 expression with ≥ 1, ≥ 5, and ≥ 10 combined positive scores (CPS) were observed in 81.8%, 70.2%, and 55.3% of EBV + GCLSs. PD-L1 expression with ≥ 10 CPS was observed in 21.2% of EBV-GCLSs, predominantly in MSI-H tumors (85.7%). EBV positivity and MSI are associated with PD-L1 positivity rates in patients with GCLS who may respond better to PD-1/PD-L1 inhibitors but not anti-HER2 inhibitors.
Collapse
Affiliation(s)
- Sun Mi Lee
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 W. 11th street, Indianapolis, IN, 46202, USA.
- Department of Pathology, Jeju National University Hospital, Jeju-si, South Korea.
| | - Hyunjoo Oh
- Department of Internal Medicine, Jeju National University Hospital, Jeju-si, South Korea
| |
Collapse
|
|
2
|
Li Z, Zhao H, Hu H, Shang H, Ren Y, Qiu W, Su H, Lyu H, Chen X. Mechanisms of resistance to trastuzumab in HER2-positive gastric cancer. Chin J Cancer Res 2024; 36:306-321. [PMID: 38988489 PMCID: PMC11230884 DOI: 10.21147/j.issn.1000-9604.2024.03.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 04/30/2024] [Indexed: 07/12/2024] Open
Abstract
Gastric cancer is one of the most prevalent cancers worldwide, and human epidermal growth factor receptor 2 (HER2)-positive cases account for approximately 20% of the total cases. Currently, trastuzumab + chemotherapy is the recommended first-line treatment for patients with HER2-positive advanced gastric cancer, and the combination has exhibited definite efficacy in HER2-targeted therapy. However, the emergence of drug resistance during treatment considerably reduces its effectiveness; thus, it is imperative to investigate the potential mechanisms underlying resistance. In the present review article, we comprehensively introduce multiple mechanisms underlying resistance to trastuzumab in HER2-positive gastric cancer cases, aiming to provide insights for rectifying issues associated with resistance to trastuzumab and devising subsequent treatment strategies.
Collapse
Affiliation(s)
- Zhifei Li
- Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer, Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou 450008, China
| | - Huan Zhao
- Henan University of Traditional Chinese Medicine, Zhengzhou 450046, China
| | - Huihui Hu
- Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer, Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou 450008, China
| | - Haili Shang
- Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer, Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou 450008, China
| | - Yongjing Ren
- Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer, Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou 450008, China
| | - Wenhui Qiu
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China
| | - Hao Su
- The First Affiliated Hospital of Xinxiang Medical University, Xinxiang 453000, China
| | - Huifang Lyu
- Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China
| | - Xiaobing Chen
- Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Henan Engineering Research Center of Precision Therapy of Gastrointestinal Cancer, Zhengzhou Key Laboratory for Precision Therapy of Gastrointestinal Cancer, Zhengzhou 450008, China
| |
Collapse
|
|
3
|
Li LL, Yu AY, Zhu M, Ma LY, Cao MH, Liu WL, Qin XB, Gao C, Han ZX, Wang HM. Clinicopathological characteristics and prognosis of Epstein-Barr virus-associated gastric cancer. Arch Virol 2024; 169:114. [PMID: 38700535 DOI: 10.1007/s00705-024-06033-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 02/22/2024] [Indexed: 05/24/2024]
Abstract
OBJECTIVE Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a distinct molecular subtype of gastric cancer (GC). At present, the clinical characteristics and prognostic implications of EBV infection and the potential clinical benefits of immune checkpoint blockade in GC remain to be clarified. Hence, this study was designed to analyze the clinical and pathological characteristics of GC patients with varying EBV infection states and compare their overall survival (OS). METHODS A retrospective study was performed on 1031 consecutive GC patients who underwent gastrectomy at the Affiliated Hospital of Xuzhou Medical University from February 2018 to November 2022. EBV-encoded RNA (EBER) in situ hybridization (ISH) was used for EBV assessment, and immunohistochemical staining was used for evaluation of human epidermal growth factor receptor 2 (HER2), programmed death ligand 1 (PD-L1), and Ki67 expression. EBVaGC was defined as tumors with EBV positivity. In addition, EBV-negative GC (EBVnGC) patients were matched with EBVaGC patients based on seven clinicopathological parameters (age, gender, anatomic subsite, tumor size, Lauren classification, degree of differentiation, and tumor-node-metastasis [TNM] stage). The correlations of clinical features with HER2, PD-L1, and Ki67 expression were evaluated statistically. The survival of patients was assessed through medical records, telephone, or WeChat communication, and prognostic analysis was performed using the logrank test as well as univariable and multivariable regression analysis. RESULTS Out of 1031 GC patients tested, 35 (3.4%) were diagnosed with EBVaGC. Notably, the EBVaGC group exhibited a distinct predominance of males and younger patients, significantly higher Ki67 and PD-L1 expression levels, and a lower prevalence of pericancerous nerve invasion than the EBVnGC group (P < 0.01). In the 35 EBVaGC cases, Ki67 expression was negatively correlated with age (P < 0.05), suggesting that a younger onset age was associated with higher Ki67 expression. In addition, PD-L1 expression was correlated with the degree of differentiation, T-stage, and clinical stage of the patient. Furthermore, PD-L1 expression was elevated in tumors with lower differentiation or at later stages (P < 0.05). Using univariate analysis, Ki67, PD-L1, and clinical stage were identified as significant factors influencing the overall survival (OS) of EBVaGC patients (P < 0.05). Moreover, multivariate survival analysis revealed that clinical stage and Ki67 expression were independent risk factors for the OS of the patients (P < 0.05), and the three-year OS rate of EBVaGC patients was 64.2%. CONCLUSION EBV-ISH is a practical and valuable method to identify EBVaGC. Owing to its unique etiological, pathological, and clinical characteristics, patients with EBVaGC might benefit from immune checkpoint blockade therapy.
Collapse
Affiliation(s)
- Lin-Lin Li
- Department of Pathology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China
| | - Ao-Yang Yu
- Graduate School of Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Mei Zhu
- Department of Oncology, Xuzhou Cancer Hospital, Xuzhou, 221005, Jiangsu, China
| | - Lu-Yao Ma
- Graduate School of Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China
| | - Meng-Han Cao
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China
| | - Wen-Lou Liu
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China
| | - Xiao-Bing Qin
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China
| | - Chao Gao
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China
| | - Zheng-Xiang Han
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China.
| | - Hong-Mei Wang
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, Jiangsu, China.
| |
Collapse
|
|
4
|
Scheck MK, Hofheinz RD, Lorenzen S. HER2-Positive Gastric Cancer and Antibody Treatment: State of the Art and Future Developments. Cancers (Basel) 2024; 16:1336. [PMID: 38611014 PMCID: PMC11010911 DOI: 10.3390/cancers16071336] [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: 02/07/2024] [Revised: 03/22/2024] [Accepted: 03/25/2024] [Indexed: 04/14/2024] Open
Abstract
Despite a decreasing incidence in Western countries, gastric cancer is among the most common cancer subtypes globally and is associated with one of the highest tumor-related mortality rates. Biomarkers play an increasing role in the treatment against gastric cancer. HER2 was one of the first biomarkers that found its way into clinical practice. Since the ToGA trial, trastuzumab has been part of first-line palliative chemotherapy in metastatic or unresectable gastric cancer. HER2-targeting agents, such as the tyrosine kinase inhibitor lapatinib, the antibody drug conjugate (ADC) trastuzumab-emtansine or dual HER2 inhibition (pertuzumab and trastuzumab), have been investigated in the second-line setting but led to negative study results. More recently, the ADC trastuzumab-deruxtecan was authorized after the failure of trastuzumab-based treatment. However, further improvements in HER2-directed therapy are required as resistance mechanisms and HER2 heterogeneity limit the existing treatment options. This review aims to give an overview of the current standard-of-care HER2-directed therapy in gastric cancer, as well as its challenges and future developments.
Collapse
Affiliation(s)
- Magdalena K. Scheck
- Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar der TU München, 81675 Munich, Germany;
| | - Ralf D. Hofheinz
- Mannheim Cancer Center, Universitätsklinikum Mannheim, 68167 Mannheim, Germany;
| | - Sylvie Lorenzen
- Klinik und Poliklinik für Innere Medizin III, Klinikum rechts der Isar der TU München, 81675 Munich, Germany;
| |
Collapse
|
|
5
|
Kheraldine H, Gupta I, Cyprian FS, Vranic S, Al-Farsi HF, Merhi M, Dermime S, Al Moustafa AE. Targeting HER2-positive breast cancer cells by a combination of dasatinib and BMS-202: Insight into the molecular pathways. Cancer Cell Int 2024; 24:94. [PMID: 38431613 PMCID: PMC10909263 DOI: 10.1186/s12935-023-03195-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Accepted: 12/26/2023] [Indexed: 03/05/2024] Open
Abstract
BACKGROUND Recent investigations have reported the benefits of using a tyrosine kinase inhibitor, dasatinib (DA), as well as programmed death-ligand 1 (PD-L1) inhibitors in the management of several solid tumors, including breast cancer. Nevertheless, the outcome of the combination of these inhibitors on HER2-positive breast cancer is not explored yet. METHODS Herein, we investigated the impact of DA and PD-L1 inhibitor (BMS-202) combination on HER2-positive breast cancer cell lines, SKBR3 and ZR75. RESULTS Our data reveal that the combination significantly inhibits cell viability of both cancer cell lines as compared to monotreatment. Moreover, the combination inhibits epithelial-mesenchymal transition (EMT) progression and reduces cancer cell invasion by restoring E-cadherin and β-catenin expressions and loss of vimentin, major biomarkers of EMT. Additionally, the combination reduces the colony formation of both cell lines in comparison with their matched control. Also, the combination considerably inhibits the angiogenesis of the chorioallantoic membrane model compared with monotreatment. Molecular pathway analysis of treated cells shows that this combination blocks HER2, AKT, β-catenin, and JNK1/2/3 activities. CONCLUSION Our findings implicate that a combination of DA and BMS-202 could have a significant impact on the management of HER2-positive breast cancer.
Collapse
Affiliation(s)
- Hadeel Kheraldine
- College of Medicine, QU Health, Qatar University, P. O. Box 2713, Doha, Qatar
- Biomedical Research Centre, Qatar University, P. O. Box 2713, Doha, Qatar
| | - Ishita Gupta
- College of Medicine, QU Health, Qatar University, P. O. Box 2713, Doha, Qatar
- Sidra Medicine, Doha, Qatar
| | - Farhan Sachal Cyprian
- College of Medicine, QU Health, Qatar University, P. O. Box 2713, Doha, Qatar
- Biomedical Research Centre, Qatar University, P. O. Box 2713, Doha, Qatar
| | - Semir Vranic
- College of Medicine, QU Health, Qatar University, P. O. Box 2713, Doha, Qatar
| | - Halema F Al-Farsi
- College of Medicine, QU Health, Qatar University, P. O. Box 2713, Doha, Qatar
| | - Maysaloun Merhi
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
- Translational Cancer Research Facility, Interim Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Said Dermime
- National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar
- Translational Cancer Research Facility, Interim Translational Research Institute, Hamad Medical Corporation, Doha, Qatar
| | - Ala-Eddin Al Moustafa
- College of Medicine, QU Health, Qatar University, P. O. Box 2713, Doha, Qatar.
- Biomedical Research Centre, Qatar University, P. O. Box 2713, Doha, Qatar.
- Oncology Department, Faculty of Medicine, McGill University, Montreal, QC, Canada.
| |
Collapse
|
|
6
|
Ren X, Feng C, Wang Y, Chen P, Wang S, Wang J, Cao H, Li Y, Ji M, Hou P. SLC39A10 promotes malignant phenotypes of gastric cancer cells by activating the CK2-mediated MAPK/ERK and PI3K/AKT pathways. Exp Mol Med 2023; 55:1757-1769. [PMID: 37524874 PMCID: PMC10474099 DOI: 10.1038/s12276-023-01062-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 03/13/2023] [Accepted: 05/25/2023] [Indexed: 08/02/2023] Open
Abstract
Solute carrier family 39 member 10 (SLC39A10) belongs to a subfamily of zinc transporters and plays a key role in B-cell development. Previous studies have reported that its upregulation promotes breast cancer metastasis by enhancing the influx of zinc ions (Zn2+); however, its role in gastric cancer remains totally unclear. Here, we found that SLC39A10 expression was frequently increased in gastric adenocarcinomas and that SLC39A10 upregulation was strongly associated with poor patient outcomes; in addition, we identified SLC39A10 as a direct target of c-Myc. Functional studies showed that ectopic expression of SLC39A10 in gastric cancer cells dramatically enhanced the proliferation, colony formation, invasiveness abilities of these gastric cancer cells and tumorigenic potential in nude mice. Conversely, SLC39A10 knockdown inhibited gastric cancer cell proliferation and colony formation. Mechanistically, SLC39A10 exerted its carcinogenic effects by increasing Zn2+ availability and subsequently enhancing the enzyme activity of CK2 (casein kinase 2). As a result, the MAPK/ERK and PI3K/AKT pathways, two major downstream effectors of CK2, were activated, while c-Myc, a downstream target of these two pathways, formed a vicious feedback loop with SLC39A10 to drive the malignant progression of gastric cancer. Taken together, our data demonstrate that SLC39A10 is a functional oncogene in gastric cancer and suggest that targeting CK2 is an alternative therapeutic strategy for gastric cancer patients with high SLC39A10 expression.
Collapse
Affiliation(s)
- Xiaojuan Ren
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
| | - Chao Feng
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
| | - Yubo Wang
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
| | - Pu Chen
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
| | - Simeng Wang
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
| | - Jianling Wang
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
| | - Hongxin Cao
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China
| | - Yujun Li
- Department of Endocrinology, The Second Affiliated Hospital of Xi'an Jiaotong University, 710004, Xi'an, P. R. China.
| | - Meiju Ji
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China.
- Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China.
| | - Peng Hou
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China.
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, P. R. China.
| |
Collapse
|
|
7
|
Ji Z, Shen J, Lan Y, Yi Q, Liu H. Targeting signaling pathways in osteosarcoma: Mechanisms and clinical studies. MedComm (Beijing) 2023; 4:e308. [PMID: 37441462 PMCID: PMC10333890 DOI: 10.1002/mco2.308] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 05/17/2023] [Accepted: 05/19/2023] [Indexed: 07/15/2023] Open
Abstract
Osteosarcoma (OS) is a highly prevalent bone malignancy among adolescents, accounting for 40% of all primary malignant bone tumors. Neoadjuvant chemotherapy combined with limb-preserving surgery has effectively reduced patient disability and mortality, but pulmonary metastases and OS cells' resistance to chemotherapeutic agents are pressing challenges in the clinical management of OS. There has been an urgent need to identify new biomarkers for OS to develop specific targeted therapies. Recently, the continued advancements in genomic analysis have contributed to the identification of clinically significant molecular biomarkers for diagnosing OS, acting as therapeutic targets, and predicting prognosis. Additionally, the contemporary molecular classifications have revealed that the signaling pathways, including Wnt/β-catenin, PI3K/AKT/mTOR, JAK/STAT3, Hippo, Notch, PD-1/PD-L1, MAPK, and NF-κB, have an integral role in OS onset, progression, metastasis, and treatment response. These molecular classifications and biological markers have created new avenues for more accurate OS diagnosis and relevant treatment. We herein present a review of the recent findings for the modulatory role of signaling pathways as possible biological markers and treatment targets for OS. This review also discusses current OS therapeutic approaches, including signaling pathway-based therapies developed over the past decade. Additionally, the review covers the signaling targets involved in the curative effects of traditional Chinese medicines in the context of expression regulation of relevant genes and proteins through the signaling pathways to inhibit OS cell growth. These findings are expected to provide directions for integrating genomic, molecular, and clinical profiles to enhance OS diagnosis and treatment.
Collapse
Affiliation(s)
- Ziyu Ji
- School of Integrated Traditional Chinese and Western MedicineSouthwest Medical UniversityLuzhouSichuanChina
| | - Jianlin Shen
- Department of OrthopaedicsAffiliated Hospital of Putian UniversityPutianFujianChina
| | - Yujian Lan
- School of Integrated Traditional Chinese and Western MedicineSouthwest Medical UniversityLuzhouSichuanChina
| | - Qian Yi
- Department of PhysiologySchool of Basic Medical ScienceSouthwest Medical UniversityLuzhouSichuanChina
| | - Huan Liu
- Department of OrthopaedicsThe Affiliated Traditional Chinese Medicine Hospital of Southwest Medical UniversityLuzhouSichuanChina
| |
Collapse
|
|
8
|
Pyo JS, Kim NY, Kang DW. Prognostic Implication of EBV Infection in Gastric Carcinomas: A Systematic Review and Meta-Analysis. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:834. [PMID: 37241066 PMCID: PMC10221611 DOI: 10.3390/medicina59050834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 04/12/2023] [Accepted: 04/18/2023] [Indexed: 05/28/2023]
Abstract
Background and objectives: This study aims to elucidate the prognostic implications of Epstein-Barr virus (EBV) infection in gastric carcinomas (GCs) through a systematic review and meta-analysis. Materials and Methods: In total, 57 eligible studies and 22,943 patients were included in this meta-analysis. We compared the prognoses of EBV-infected and non-infected GC patients. The subgroup analysis was performed based on the study location, molecular classification, and Lauren's classification. This study was checked according to the PRISMA 2020. The meta-analysis was performed using the Comprehensive Meta-Analysis software package. Results: EBV infection was found in 10.4% (95% confidence interval (CI) 0.082-0.131) of GC patients. The EBV-infected GC patients had a better overall survival compared with the EBV-non-infected GC patients (hazard ratio (HR) 0.890, 95% CI 0.816-0.970). In the subgroup analysis based on molecular classification, no significant differences were found between EBV+ and microsatellite instability and microsatellite stable (MSS)/EBV- subgroups (HR 1.099, 95% CI 0.885-1.364 and HR 0.954, 95% CI 0.872-1.044, respectively). In the diffuse type of Lauren's classification, EBV-infected GCs have a better prognosis compared with the EBV-non-infected GCs (HR 0.400, 95% CI 0.300-0.534). The prognostic impact of EBV infection was found in the Asian and American subgroups but not in the European subgroup (HR 0.880, 95% CI 0.782-0.991, HR 0.840, 95% CI 0.750-0.941, and HR 0.915, 95% CI 0.814-1.028). Conclusions: EBV infection is a favorable survival factor for GCs. However, the prognostic implications of EBV infection in the new molecular classification are not clear.
Collapse
Affiliation(s)
- Jung-Soo Pyo
- Department of Pathology, Uijeongbu Eulji Medical Center, Eulji University School of Medicine, Uijeongbu-si 11759, Republic of Korea
| | - Nae-Yu Kim
- Department of Internal Medicine, Uijeongbu Eulji Medical Center, Eulji University School of Medicine, Uijeongbu-si 11759, Republic of Korea
| | - Dong-Wook Kang
- Department of Pathology, Chungnam National University Sejong Hospital, 20 Bodeum 7-ro, Sejong-si 30099, Republic of Korea
- Department of Pathology, Chungnam National University School of Medicine, 266 Munhwa Street, Daejeon 35015, Republic of Korea
| |
Collapse
|
|
9
|
Hirabayashi M, Georges D, Clifford GM, de Martel C. Estimating the Global Burden of Epstein-Barr Virus-Associated Gastric Cancer: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol 2023; 21:922-930.e21. [PMID: 35963539 DOI: 10.1016/j.cgh.2022.07.042] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Evidence suggests that a fraction of new gastric cancer cases may be etiologically associated with Epstein-Barr virus (EBV), a known carcinogenic agent. We aimed to systematically explore the proportion of EBV-positive gastric cancer. METHODS We did a systematic review (PROSPERO CRD42020164473) from January 1990 to August 2021. For each country and geographical region with available data, pooled prevalence and corresponding 95% confidence intervals (CIs) of EBV in gastric tumors were calculated for 3 subtypes of gastric adenocarcinoma (conventional adenocarcinoma, lymphoepithelioma-like gastric carcinoma, and remnant/stump carcinoma). For conventional adenocarcinoma, prevalence ratios (PRs) were presented for sex, Lauren's classification, gastric cancer stage, and anatomical location of the stomach. RESULTS In 220 eligible studies including over 68,000 cases of conventional gastric adenocarcinoma, EBV prevalence in tumor cells was 7.5% (95% CI, 6.9%-8.1%) and was higher in men compared with women (PR, 2.1; 95% CI, 1.9-2.4), in diffuse type compared with intestinal type (PR, 1.3; 95% CI, 1.1-1.5), and in the proximal region compared with the distal region (PR, 2.5; 95% CI, 2.0-3.1). There was no difference in EBV prevalence by gastric cancer stage. EBV prevalence was 75.9% (95% CI, 62.8%-85.5%) among lymphoepithelioma-like gastric carcinoma and 26.3% (95% CI, 22.2%-32.0%) among remnant or stump carcinoma. CONCLUSIONS Assuming a causal association between EBV and gastric cancer, our findings, when applied to the GLOBOCAN 2020 gastric cancer incidence, suggest that primary prevention such as the development of an effective EBV vaccine might prevent 81,000 EBV-associated gastric cancer cases worldwide annually.
Collapse
Affiliation(s)
- Mayo Hirabayashi
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France
| | - Damien Georges
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France
| | - Gary M Clifford
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France
| | - Catherine de Martel
- Early Detection, Prevention and Infections Branch, International Agency for Research on Cancer, Lyon, France.
| |
Collapse
|
|
10
|
Zeng Y, Jin RU. Molecular pathogenesis, targeted therapies, and future perspectives for gastric cancer. Semin Cancer Biol 2022; 86:566-582. [PMID: 34933124 DOI: 10.1016/j.semcancer.2021.12.004] [Citation(s) in RCA: 93] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 11/29/2021] [Accepted: 12/11/2021] [Indexed: 01/27/2023]
Abstract
Gastric cancer is a major source of global cancer mortality with limited treatment options and poor patient survival. As our molecular understanding of gastric cancer improves, we are now beginning to recognize that these cancers are a heterogeneous group of diseases with incredibly unique pathogeneses and active oncogenic pathways. It is this molecular diversity and oftentimes lack of common oncogenic driver mutations that bestow the poor treatment responses that oncologists often face when treating gastric cancer. In this review, we will examine the treatments for gastric cancer including up-to-date molecularly targeted therapies and immunotherapies. We will then review the molecular subtypes of gastric cancer to highlight the diversity seen in this disease. We will then shift our discussion to basic science and gastric cancer mouse models as tools to study gastric cancer molecular heterogeneity. Furthermore, we will elaborate on a molecular process termed paligenosis and the cyclical hit model as key events during gastric cancer initiation that impart nondividing mature differentiated cells the ability to re-enter the cell cycle and accumulate disparate genomic mutations during years of chronic inflammation and injury. As our basic science understanding of gastric cancer advances, so too must our translational and clinical efforts. We will end with a discussion regarding single-cell molecular analyses and cancer organoid technologies as future translational avenues to advance our understanding of gastric cancer heterogeneity and to design precision-based gastric cancer treatments. Elucidation of interpatient and intratumor heterogeneity is the only way to advance future cancer prevention, diagnoses and treatment.
Collapse
Affiliation(s)
- Yongji Zeng
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, USA
| | - Ramon U Jin
- Section of Hematology/Oncology, Department of Medicine, Baylor College of Medicine, Houston, USA.
| |
Collapse
|
|
11
|
Lei ZN, Teng QX, Tian Q, Chen W, Xie Y, Wu K, Zeng Q, Zeng L, Pan Y, Chen ZS, He Y. Signaling pathways and therapeutic interventions in gastric cancer. Signal Transduct Target Ther 2022; 7:358. [PMID: 36209270 PMCID: PMC9547882 DOI: 10.1038/s41392-022-01190-w] [Citation(s) in RCA: 121] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/14/2022] [Accepted: 09/07/2022] [Indexed: 11/23/2022] Open
Abstract
Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.
Collapse
Affiliation(s)
- Zi-Ning Lei
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qiu-Xu Teng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qin Tian
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Wei Chen
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Yuhao Xie
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA
| | - Kaiming Wu
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Qianlin Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Leli Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Yihang Pan
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA.
| | - Yulong He
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| |
Collapse
|
|
12
|
Romano C, Di Gregorio S, Pennisi MS, Tirrò E, Broggi G, Caltabiano R, Manzella L, Ruggieri M, Vigneri P, Di Cataldo A. Multiple primary malignances managed with surgical excision: a case report with next generation sequencing analysis. Mol Biol Rep 2022; 49:9059-9064. [PMID: 35715605 DOI: 10.1007/s11033-022-07630-8] [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: 03/04/2022] [Revised: 05/17/2022] [Accepted: 05/19/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Multiple primary malignancies (MPM) are defined as tumors originating in the same individual without any correlation between them. In addition to morphological and immunohistochemical analyses, sensitive DNA sequencing methods such as next generation sequencing (NGS) may help to discriminate the common or different genetic alterations driving each malignancy, to better diagnose these uncommon cases. METHODS AND RESULTS Here we report the case of a man who developed a poorly differentiated gastric adenocarcinoma invading the pancreas followed, two years later, by a colorectal cancer involving also the kidney and the diaphragm. Despite the advanced stage of both diseases, adjuvant chemotherapy was successful. While the second tumor was initially interpreted as a relapse of his stomach cancer, NGS-based mutation profiling of the two carcinomas revealed two distinct malignances, independently developing in different times and indicative of metachronous MPM. Indeed, sequencing of cancer-associated genes identified somatic mutations only in the first gastric cancer, besides germline variants on three different genes (PDGFRA, APC and TP53). However, analysis of both somatic and germline mutations with bio-informatics prediction tools failed to find a correlation between these variants and the unexpectedly good prognosis of both cancers. CONCLUSIONS In summary, NGS analysis contributed to defined different molecular profiles for two tumors developed in the span of two years, thus allowing diagnosing the case as MPN. However, NGS was unable to establish a direct correlation between the identified alterations and cancer development.
Collapse
Affiliation(s)
- Chiara Romano
- Department of Clinical and Experimental Medicine, University of Catania, 95123, Catania, Italy. .,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico - San Marco", 95123, Catania, Italy.
| | - Sandra Di Gregorio
- Department of Clinical and Experimental Medicine, University of Catania, 95123, Catania, Italy.,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico - San Marco", 95123, Catania, Italy
| | - Maria Stella Pennisi
- Department of Clinical and Experimental Medicine, University of Catania, 95123, Catania, Italy.,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico - San Marco", 95123, Catania, Italy
| | - Elena Tirrò
- Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico - San Marco", 95123, Catania, Italy.,Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, 90127, Palermo, Italy
| | - Giuseppe Broggi
- Department of Medical, Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Section of Anatomic Pathology, University of Catania, 95123, Catania, Italy
| | - Rosario Caltabiano
- Department of Medical, Surgical Sciences and Advanced Technologies "G.F. Ingrassia", Section of Anatomic Pathology, University of Catania, 95123, Catania, Italy
| | - Livia Manzella
- Department of Clinical and Experimental Medicine, University of Catania, 95123, Catania, Italy.,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico - San Marco", 95123, Catania, Italy
| | - Martino Ruggieri
- Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, 95123, Catania, Italy
| | - Paolo Vigneri
- Department of Clinical and Experimental Medicine, University of Catania, 95123, Catania, Italy.,Center of Experimental Oncology and Hematology, A.O.U. Policlinico "G. Rodolico - San Marco", 95123, Catania, Italy
| | - Antonio Di Cataldo
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, 95123, Catania, Italy
| |
Collapse
|
|
13
|
Manuel Lopes de Sousa H, Patrícia Costa Ribeiro J, Basílio Timóteo M. Epstein-Barr Virus-Associated Gastric Cancer: Old Entity with New Relevance. Infect Dis (Lond) 2021. [DOI: 10.5772/intechopen.93649] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Gastric cancer (GC) represents a major public health issue worldwide, being the fifth most common cancer and one of the leading causes of death by cancer. In 2014, The Cancer Genome Atlas (TCGA) established that tumors positive for Epstein-Barr virus (EBV) are considered a specific subtype of GC (EBVaGC). Several meta-analyses have shown that EBVaGC represents almost 10% of all gastric cancer worldwide, with small differences in the geographic distribution. This tumor subtype has a high potential of being clinically relevant and studies have shown that it has specific features, a better prognosis, and increased overall survival. In this review, we summarize some of the most frequent aspects of EBVaGC, including the specific features of this GC subtype, data regarding the potential steps of EBVaGC carcinogenesis, and perspectives on treatment opportunities.
Collapse
|
|
14
|
Sahgal P, Huffman BM, Patil DT, Chatila WK, Yaeger R, Cleary JM, Sethi NS. Early TP53 Alterations Shape Gastric and Esophageal Cancer Development. Cancers (Basel) 2021; 13:5915. [PMID: 34885025 PMCID: PMC8657039 DOI: 10.3390/cancers13235915] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 12/14/2022] Open
Abstract
Gastric and esophageal (GE) adenocarcinomas are the third and sixth most common causes of cancer-related mortality worldwide, accounting for greater than 1.25 million annual deaths. Despite the advancements in the multi-disciplinary treatment approaches, the prognosis for patients with GE adenocarcinomas remains poor, with a 5-year survival of 32% and 19%, respectively, mainly due to the late-stage diagnosis and aggressive nature of these cancers. Premalignant lesions characterized by atypical glandular proliferation, with neoplastic cells confined to the basement membrane, often precede malignant disease. We now appreciate that premalignant lesions also carry cancer-associated mutations, enabling disease progression in the right environmental context. A better understanding of the premalignant-to-malignant transition can help us diagnose, prevent, and treat GE adenocarcinoma. Here, we discuss the evidence suggesting that alterations in TP53 occur early in GE adenocarcinoma evolution, are selected for under environmental stressors, are responsible for shaping the genomic mechanisms for pathway dysregulation in cancer progression, and lead to potential vulnerabilities that can be exploited by a specific class of targeted therapy.
Collapse
Affiliation(s)
- Pranshu Sahgal
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; (P.S.); (B.M.H.); (J.M.C.)
- Cancer Program, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA 02142, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215, USA
| | - Brandon M. Huffman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; (P.S.); (B.M.H.); (J.M.C.)
| | - Deepa T. Patil
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215, USA;
| | - Walid K. Chatila
- Tri-Institutional Program in Computational Biology and Medicine, Weill Cornell Medical College, New York, NY 10021, USA;
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
| | - James M. Cleary
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; (P.S.); (B.M.H.); (J.M.C.)
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Nilay S. Sethi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; (P.S.); (B.M.H.); (J.M.C.)
- Cancer Program, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA 02142, USA
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02215, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| |
Collapse
|
|
15
|
Olnes MJ, Martinson HA. Recent advances in immune therapies for gastric cancer. Cancer Gene Ther 2021; 28:924-934. [PMID: 33664460 PMCID: PMC8417143 DOI: 10.1038/s41417-021-00310-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/28/2021] [Accepted: 02/11/2021] [Indexed: 01/31/2023]
Abstract
Gastric cancer (GC) is an aggressive malignancy that is the third leading cause of cancer mortality worldwide. Localized GC can be cured with surgery, but most patients present with more advanced non-operable disease. Until recently, treatment options for relapsed and refractory advanced GC have been limited to combination chemotherapy regimens, HER-2 directed therapy, and radiation, which lead to few durable responses. Over the past decade, there have been significant advances in our understanding of the molecular and immune pathogenesis of GC. The infectious agents Epstein-Barr virus and Helicobacter pylori perturb the gastric mucosa immune equilibrium, which creates a microenvironment that favors GC tumorigenesis and evasion of immune surveillance. Insights into immune mechanisms of GC have translated into novel therapeutics, including immune checkpoint inhibitors, which have become a treatment option for select patients with GC. Furthermore, chimeric antigen receptor T-cell therapies have emerged as a breakthrough treatment for many cancers, with recent studies showing this to be a potential therapy for GC. In this review, we summarize the current state of knowledge on immune mechanisms of GC and the status of emerging immunotherapies to treat this aggressive cancer, as well as outline current challenges and directions for future research.
Collapse
Affiliation(s)
- Matthew J Olnes
- Hematology and Medical Oncology, Alaska Native Tribal Health Consortium, Anchorage, AK, USA.
- WWAMI School of Medical Education, University of Alaska Anchorage, Anchorage, AK, USA.
| | - Holly A Martinson
- WWAMI School of Medical Education, University of Alaska Anchorage, Anchorage, AK, USA
| |
Collapse
|
|
16
|
Carli D, Kalantari S, Manicone R, Coppo P, Francia di Celle P, La Selva R, Santoro F, Ranieri C, Cardaropoli S, Fagioli F, Ferrero GB, Resta N, Mussa A. Kaposiform hemangioendothelioma further broadens the phenotype of PIK3CA-related overgrowth spectrum. Clin Genet 2021; 100:624-627. [PMID: 34402524 DOI: 10.1111/cge.14047] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/25/2021] [Accepted: 08/13/2021] [Indexed: 12/12/2022]
Abstract
Kaposiform hemangioendothelioma (KHE) is a rare locally aggressive mixed vascular tumor, with typical onset in early childhood and characterized by progressive angio- and lymphangiogenesis. Its etiopathogenesis and molecular bases are still unclear. Here, we report the first case of congenital KHE harboring a PIK3CA mosaic pathogenic variant (c.323G > A, p.Arg108His) in a boy with very subtle PIK3CA-related overgrowth spectrum (PROS) features. This finding provides insights into the pathophysiology of KHE, offering targeted therapeutic options by inhibition of the PI3K/Akt/mTOR pathway. We propose the inclusion of this mixed lymphatic and vascular anomaly within the PROS.
Collapse
Affiliation(s)
- Diana Carli
- Pediatric Clinical Genetics Unit, Department of Public Health and Pediatric Sciences, Regina Margherita Children's Hospital, Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.,Pediatric Onco-Hematology, Regina Margherita Children's Hospital, Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy
| | - Silvia Kalantari
- Immunogenetics and Transplant Biology Service, Città della Salute e della Scienza University Hospital, Turin, Italy
| | - Rosaria Manicone
- Pediatric Onco-Hematology, Regina Margherita Children's Hospital, Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy
| | - Paola Coppo
- Pediatric Dermatology, Regina Margherita Children's Hospital, Città della Salute e della Scienza di Torino, Torino, Italy
| | - Paola Francia di Celle
- Molecular Pathology Laboratory, Pathology Division, Città della Salute e della Scienza University Hospital, Torino, Italy
| | - Roberta La Selva
- Pediatric Dermatology, Regina Margherita Children's Hospital, Città della Salute e della Scienza di Torino, Torino, Italy
| | - Federica Santoro
- Department of Medical Sciences, Pathology Unit, Città della Salute e della Scienza Hospital, University of Torino, Torino, Italy
| | - Carlotta Ranieri
- Department of Biomedical Sciences and Human Oncology (DIMO), Medical Genetics, University of Bari "Aldo Moro", Bari, Italy
| | - Simona Cardaropoli
- Pediatric Clinical Genetics Unit, Department of Public Health and Pediatric Sciences, Regina Margherita Children's Hospital, Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy
| | - Franca Fagioli
- Pediatric Onco-Hematology, Regina Margherita Children's Hospital, Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy
| | - Giovanni Battista Ferrero
- Pediatric Clinical Genetics Unit, Department of Public Health and Pediatric Sciences, Regina Margherita Children's Hospital, Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy.,Department of Clinical and Biological Sciences, University of Torino, Torino, Italy
| | - Nicoletta Resta
- Department of Biomedical Sciences and Human Oncology (DIMO), Medical Genetics, University of Bari "Aldo Moro", Bari, Italy
| | - Alessandro Mussa
- Pediatric Clinical Genetics Unit, Department of Public Health and Pediatric Sciences, Regina Margherita Children's Hospital, Città della Salute e della Scienza di Torino, University of Torino, Torino, Italy
| |
Collapse
|
|
17
|
Wang J, Shao X, Liu Y, Shi R, Yang B, Xiao J, Liu Y, Qu X, Li Z. Mutations of key driver genes in gastric cancer metastasis risk: a systematic review and meta-analysis. Expert Rev Mol Diagn 2021; 21:963-972. [PMID: 34196586 DOI: 10.1080/14737159.2021.1946394] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Objective: Associations between gene mutations and metastasis in gastric cancer (GC) remain contradictory, resulting in the inaccurate estimation of the magnitude of the risk associated with specific genotypes.Methods: In this study, we first screened out four key driver genes (TP53, PIK3CA, APC and ARID1A) by jointly analyzing the mutation levels and searching the literature for genes associated with GC metastasis. We then performed a meta-analysis to demonstrate the relationship between these key driver gene mutations and GC metastasis, including lymphatic and distance metastasis.Results: We found out four key driver genes (TP53, PIK3CA, APC and ARID1A), associated with risk of GC metastasis. The results showed that TP53 (OR 1.39, 95% CI 1.12-1.72) and APC mutations (OR 0.58, 95% CI 0.38-0.89) were associated with lymph node metastasis and distant metastasis in GC. And TP53 mutations (OR 1.65, 95% CI 1.25-2.18) were significantly related to GC metastasis in the Asian population. APC mutations (OR 0.54, 95% CI 0.29-1.00) were also related to GC metastasis in the European and American populations. There was no significant association with GC metastasis in PIK3CA or ARID1A mutations.Expert opinion:Mutations of TP53 and APC play important roles in lymph node metastasis and distant metastasis of GC and may be potential important biomarkers of progression and therapeutic targets. These observations should be further prospectively verified.
Collapse
Affiliation(s)
- Jin Wang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.,Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China
| | - Xinye Shao
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.,Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China
| | - Yang Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.,Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China
| | - Ruichuan Shi
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.,Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China
| | - Bowen Yang
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.,Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China
| | - Jiawen Xiao
- Department of Medical Oncology, Shenyang Fifth People Hospital, Shenyang, China
| | - Yunpeng Liu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.,Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China
| | - Xiujuan Qu
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.,Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China
| | - Zhi Li
- Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, Shenyang, China.,Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Hospital of China Medical University, Shenyang, China
| |
Collapse
|
|
18
|
Baghery Saghchy Khorasani A, Pourbagheri-Sigaroodi A, Pirsalehi A, Safaroghli-Azar A, Zali MR, Bashash D. The PI3K/Akt/mTOR signaling pathway in gastric cancer; from oncogenic variations to the possibilities for pharmacologic interventions. Eur J Pharmacol 2021; 898:173983. [PMID: 33647255 DOI: 10.1016/j.ejphar.2021.173983] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 02/13/2021] [Accepted: 02/23/2021] [Indexed: 12/24/2022]
Abstract
Genetic and epigenetic alterations have been under concentrated investigations for many years in order to unearth the molecules regulating human cancer pathogenesis. However, the identification of a wide range of dysregulated genes and their protein products has raised a question regarding how the results of this large collection of alterations could converge into a formation of one malignancy. The answer may be found in the signaling cascades that regulate the survival and metabolism of the cells. Aberrancies of each participant molecule of such cascades may well result in augmented viability and unlimited proliferation of cancer cells. Among various signaling pathways, the phosphatidylinositol-3-kinase (PI3K) axis has been shown to be activated in about one-third of human cancers. One of the malignancies that is mostly affected by this axis is gastric cancer (GC), one of the most fatal cancers worldwide. In the present review, we aimed to illustrate the significance of the PI3K/Akt/mTOR axis in the pathogenesis of GC and also provided a wide perspective about the application of the inhibitors of this axis in the therapeutic strategies of this malignancy.
Collapse
Affiliation(s)
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Pirsalehi
- Department of Internal Medicine, School of Medicine, Ayatollah Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ava Safaroghli-Azar
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| |
Collapse
|
|
19
|
Tabibzadeh A, Tameshkel FS, Moradi Y, Soltani S, Moradi-Lakeh M, Ashrafi GH, Motamed N, Zamani F, Motevalian SA, Panahi M, Esghaei M, Ajdarkosh H, Mousavi-Jarrahi A, Niya MHK. Signal transduction pathway mutations in gastrointestinal (GI) cancers: a systematic review and meta-analysis. Sci Rep 2020; 10:18713. [PMID: 33127962 PMCID: PMC7599243 DOI: 10.1038/s41598-020-73770-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 09/02/2020] [Indexed: 02/07/2023] Open
Abstract
The present study was conducted to evaluate the prevalence of the signaling pathways mutation rate in the Gastrointestinal (GI) tract cancers in a systematic review and meta-analysis study. The study was performed based on the PRISMA criteria. Random models by confidence interval (CI: 95%) were used to calculate the pooled estimate of prevalence via Metaprop command. The pooled prevalence indices of signal transduction pathway mutations in gastric cancer, liver cancer, colorectal cancer, and pancreatic cancer were 5% (95% CI: 3-8%), 12% (95% CI: 8-18%), 17% (95% CI: 14-20%), and 20% (95% CI: 5-41%), respectively. Also, the mutation rates for Wnt pathway and MAPK pathway were calculated to be 23% (95% CI, 14-33%) and 20% (95% CI, 17-24%), respectively. Moreover, the most popular genes were APC (in Wnt pathway), KRAS (in MAPK pathway) and PIK3CA (in PI3K pathway) in the colorectal cancer, pancreatic cancer, and gastric cancer while they were beta-catenin and CTNNB1 in liver cancer. The most altered pathway was Wnt pathway followed by the MAPK pathway. In addition, pancreatic cancer was found to be higher under the pressure of mutation compared with others based on pooled prevalence analysis. Finally, APC mutations in colorectal cancer, KRAS in gastric cancer, and pancreatic cancer were mostly associated gene alterations.
Collapse
Affiliation(s)
- Alireza Tabibzadeh
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fahimeh Safarnezhad Tameshkel
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Yousef Moradi
- Social Determinants of Health Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Saber Soltani
- Department of Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Maziar Moradi-Lakeh
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
- Preventive Medicine and Public Health Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - G Hossein Ashrafi
- Cancer Theme SEC Faculty, Kingston University, Penrhyn Road, London, KT1 2EE, UK
| | - Nima Motamed
- Department of Social Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Farhad Zamani
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed Abbas Motevalian
- Department of Epidemiology, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Mahshid Panahi
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Maryam Esghaei
- Department of Virology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Ajdarkosh
- Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | | |
Collapse
|
|
20
|
Li QH, Wang YZ, Tu J, Liu CW, Yuan YJ, Lin R, He WL, Cai SR, He YL, Ye JN. Anti-EGFR therapy in metastatic colorectal cancer: mechanisms and potential regimens of drug resistance. Gastroenterol Rep (Oxf) 2020; 8:179-191. [PMID: 32665850 PMCID: PMC7333932 DOI: 10.1093/gastro/goaa026] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/27/2020] [Accepted: 04/09/2020] [Indexed: 12/24/2022] Open
Abstract
Cetuximab and panitumumab, as the highly effective antibodies targeting epidermal growth factor receptor (EGFR), have clinical activity in the patients with metastatic colorectal cancer (mCRC). These agents have good curative efficacy, but drug resistance also exists at the same time. The effects of KRAS, NRAS, and BRAF mutations and HER2 amplification on the treatment of refractory mCRC have been elucidated and the corresponding countermeasures have been put forward. However, the changes in EGFR and its ligands, the mutations or amplifications of PIK3CA, PTEN, TP53, MET, HER3, IRS2, FGFR1, and MAP2K1, the overexpression of insulin growth factor-1, the low expression of Bcl-2-interacting mediator of cell death, mismatch repair-deficient, and epigenetic instability may also lead to drug resistance in mCRC. Although the emergence of drug resistance has genetic or epigenetic heterogeneity, most of these molecular changes relating to it are focused on the key signaling pathways, such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway. Accordingly, numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out. Herein, we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice.
Collapse
Affiliation(s)
- Qing-Hai Li
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Ying-Zhao Wang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Jian Tu
- Department of Musculoskeletal Oncology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Chu-Wei Liu
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yu-Jie Yuan
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Run Lin
- Department of Radiology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Wei-Ling He
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Shi-Rong Cai
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yu-Long He
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Jin-Ning Ye
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| |
Collapse
|
|
21
|
Moore A, Hikri E, Goshen-Lago T, Barkan T, Morgenstern S, Brook E, Maderer A, Roth W, Gordon N, Kashtan H, Brenner B, Moehler M, Aharon IB. Young-onset gastric cancer and Epstein-Barr Virus (EBV) - a major player in the pathogenesis? BMC Cancer 2020; 20:34. [PMID: 31937281 PMCID: PMC6961297 DOI: 10.1186/s12885-020-6517-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Accepted: 01/06/2020] [Indexed: 12/30/2022] Open
Abstract
Objective Gastric cancer (GC) is a leading cause of cancer death, occurs predominantly in older age, with increasing incidence in young patients. The Cancer Genome Atlas indicates four subtypes for GC among which Epstein-Barr virus (EBV) subtype is estimated at 8.7%. We aim to determine the prevalence of EBV subtype in young GC patients (≤45 years) compared with an average-onset cohort (≥55 years) and characterize the clinicopathologic pattern of young-onset GC. Methods Gastric cancer samples of patients of both cohorts were screened for EBV by qPCR. Additional staining was done for Human epidermal growth factor receptor 2 (HER2), microsatellite instability (MSI) status and Programmed death-ligand 1 (PD-L1). Demographics and clinical data were retrieved from the medical records. Results Thirty-nine young-onset and 35 average-onset GC patients were reviewed. There was no apparent difference in tumor location, family history, histology and HER2 status between the cohorts. More young-onset patients were diagnosed with metastatic disease (27% vs 9%, p = 0.0498). EBV was significantly more prevalent in the young-onset cohort (33% vs 11%, p = 0.025). 15/17 EBV positive patients were under the median age of diagnosis for GC in the US (68 years). MSI-H was found only in the average-onset cohort [0% vs 27%, p = 0.001). PD-L1 positivity was higher in the young-onset cohort (31% vs 3%, p = 0.002). Conclusion Our study indicates that EBV subtype is more prevalent in young-onset GC and may play a key role in the pathogenesis. Higher rate of PD-L1 positivity in young-onset GC could change treatment strategies. We are currently evaluating these findings in a prospective trial.
Collapse
Affiliation(s)
- Assaf Moore
- Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel. .,Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel.
| | - Elad Hikri
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel
| | - Tal Goshen-Lago
- Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel
| | - Tamar Barkan
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel
| | - Sara Morgenstern
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel.,Department of Pathology, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel
| | - Elena Brook
- Department of Pathology, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel
| | - Annett Maderer
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Wilfried Roth
- Tissue Bank and Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Noa Gordon
- Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel
| | - Hanoch Kashtan
- Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel.,Department of surgery B, Beilinson campus, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel
| | - Baruch Brenner
- Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel
| | - Markus Moehler
- Department of Internal Medicine I, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Irit Ben Aharon
- Institute of Oncology, Davidoff Cancer Center, Rabin Medical Center, Ze'ev Jabotinsky Rd 39, 4941492, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 6997801, Tel Aviv, Israel
| |
Collapse
|
|
22
|
Pellino A, Riello E, Nappo F, Brignola S, Murgioni S, Djaballah SA, Lonardi S, Zagonel V, Rugge M, Loupakis F, Fassan M. Targeted therapies in metastatic gastric cancer: Current knowledge and future perspectives. World J Gastroenterol 2019; 25:5773-5788. [PMID: 31636471 PMCID: PMC6801189 DOI: 10.3748/wjg.v25.i38.5773] [Citation(s) in RCA: 82] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Revised: 08/26/2019] [Accepted: 09/27/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) represents a leading cause of cancer related morbidity and mortality worldwide accounting for more than 1 million of newly diagnosed cases and thousands of deaths every year. In the last decade, the development of targeted therapies and the optimization of already available chemotherapeutic drugs has expanded the available treatment options for advanced GC and granted better survival expectations to the patients. At the same time, global efforts have been undertaken to investigate in detail the genomic and epigenomic heterogeneity of this disease, resulting in the identification of new specific and sensitive predictive and prognostic biomarkers and in innovative molecular classifications based on gene expression profiling. Nonetheless, several randomized studies aimed at exploring new innovative agents, such as immune checkpoint inhibitors, failed to demonstrate clinically meaningful survival advantages. Therefore, it is essential to further improve the molecular characterization of GC subgroups in order to provide researchers and medical oncologists with new tools for patients' selection and stratification in future clinical development programs and subsequent trials. The aim of the present manuscript is to provide a global overview of the recent molecular classifications from The Cancer Genome Atlas and the Asian Cancer Research Group and to present key promising developments in the field of immunotherapy and targeted therapies in metastatic GC.
Collapse
Affiliation(s)
- Antonio Pellino
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua 35100, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua 35100, Italy
| | - Erika Riello
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua 35100, Italy
- Surgical Pathology & Cytopathology Unit, Department of Medicine, University of Padua, Padua 35100, Italy
| | - Floriana Nappo
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua 35100, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua 35100, Italy
| | - Stefano Brignola
- Surgical Pathology & Cytopathology Unit, Department of Medicine, University of Padua, Padua 35100, Italy
| | - Sabina Murgioni
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua 35100, Italy
| | | | - Sara Lonardi
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua 35100, Italy
| | - Vittorina Zagonel
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua 35100, Italy
| | - Massimo Rugge
- Surgical Pathology & Cytopathology Unit, Department of Medicine, University of Padua, Padua 35100, Italy
- Veneto Cancer Registry, Padua 35100, Italy
| | - Fotios Loupakis
- Department of Oncology, Veneto Institute of Oncology IOV-IRCCS, Padua 35100, Italy
| | - Matteo Fassan
- Surgical Pathology & Cytopathology Unit, Department of Medicine, University of Padua, Padua 35100, Italy
| |
Collapse
|
|
23
|
Zhang YW, He D, Tan C, Dong M, Zhou L, Shao CK. Differential expression of HER2 and downstream proteins in prediction of advanced tumor phenotypes and overall survival of patients with Epstein-Barr virus-positive vs. negative gastric cancers. Pathol Res Pract 2019; 215:152675. [PMID: 31594682 DOI: 10.1016/j.prp.2019.152675] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 09/17/2019] [Accepted: 09/27/2019] [Indexed: 02/07/2023]
Abstract
This study evaluated the associations of HER2 protein, HER2 gene amplification, and positivity for p-AKT, p-ERK, and p-PLCγ proteins with clinicopathological status and overall survival (OS) of patients who had Epstein-Barr virus-associated gastric cancer (EBVaGC; n = 58) or EBV-negative GC (EBVnGC; n = 329). Tissue samples were subjected to immunohistochemistry and fluorescence in situ hybridization (FISH). Results showed that EBVaGC less expressed HER2 and amplified HER2 gene. p-AKT (p = 0.035) and p-ERK (p = 0.001) were inhibited in EBVaGC than in EBVnGC, while p-PLCγ (p = 0.034) was upregulated. Among EBVaGC patients, p-ERK positivity was associated with Lauren classification (p = 0.023), and p-PLCγ positivity was inversely associated with TNM stage (p = 0.041) and lymph node metastasis (p = 0.041). In contrast, among EBVnGC patients, HER2 expression was associated with distant metastasis (p = 0.043) and p-AKT positivity was associated with intestinal subtype (p < 0.004), lymph node metastasis (p = 0.031), distant metastasis (p < 0.001), and elder age (>60y, p < 0.004). Overall analysis showed that EBVaGC patients presented better OS than EBVnGC patients (p = 0.044). Among EBVaGC patients, p-AKT positivity (p = 0.008) was associated with worse OS; as well as, HER2 high expression (p < 0.001), p-AKT positivity (p = 0.010), and p-PLCγ (p < 0.001) were associated with worse OS in EBVnGC patients. Multivariate analysis showed that distant metastasis (95% CI: 1.559 to 4.028, p < 0.001), HER2 high expression (95% CI: 1.058 to 2.454, p = 0.026), and p-PLCγ positivity (95% CI: 1.056 to 2.435, p = 0.027) were independent prognostic predictors of OS in EBVnGC patients. Our results indicated that p-AKT positive patients presented worse OS than p-AKT negative ones in EBVaGC, as well as, HER2, p-AKT, and p-PLCγ are prognostic biomarkers for OS in EBVnGC patients.
Collapse
Affiliation(s)
- Yi-Wang Zhang
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China
| | - Dan He
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China
| | - Cui Tan
- Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, No. 107 Yangtze River Road, Guangzhou 510120, Guangdong Province, China
| | - Min Dong
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China
| | - Lu Zhou
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China
| | - Chun-Kui Shao
- Department of Pathology, The Third Affiliated Hospital, Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou 510630, Guangdong Province, China.
| |
Collapse
|
|
24
|
Yang Y, Liu YQ, Wang XH, Ji K, Li ZW, Bai J, Yang AR, Hu Y, Han HB, Li ZY, Bu ZD, Wu XJ, Zhang LH, Ji JF. [Clinicopathological and molecular characteristics of Epstein-Barr virus associated gastric cancer: a single center large sample case investigation]. JOURNAL OF PEKING UNIVERSITY. HEALTH SCIENCES 2019; 51:451-458. [PMID: 31209416 DOI: 10.19723/j.issn.1671-167x.2019.03.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Epstein-Barr virus associated gastric cancer (EBVaGC) is different from the traditional gastric cancer (Epstein-Barr virus non-associated gastric cancer, EBVnGC), and has unique clinicopathological features. This study investigated the largest single center cancer series so as to establish the clinicopathological and molecular characteristics of EBVaGC in China. METHODS A retrospective analysis was conducted on EBVaGC and EBVnGC patients diagnosed at Peking University Cancer Hospital from 2003 to 2018 by comparing their clinicopathological features and prognosis. The gastric cancer (GC) dataset of public database was analyzed to obtain differentially expressed genes. The expression of important genes and their association with prognosis of GC were verified in GC tissues from our hospital. RESULTS In this study, 3 241 GC patients were included, and a total of 163 EBVaGC (5.0%) patients were identified. Compared with EBVnGC, EBVaGC was higher in male and younger patients, and positively associated with remnant GC, poorly differentiated adenocarcinoma, and mixed type GC. EBVaGC was inversely related to lymph node metastasis. The 5-year survival rate of EBVnGC and EBVaGC was 59.6% and 63.2% respectively (P<0.05). In order to explore molecular features of EBVaGC, the Cancer Genome Atlas (TCGA) dataset was analyzed (n=240), and 7 404 significant differentially expressed genes were obtained, involving cell proliferation, apoptosis, invasion and metastasis. The down-regulated invasion/metastasis gene SALL4 and the up-regulated immune checkpoint gene PD-L1 were important molecular features of EBVaGC. Validation of these two genes in large GC series showed that the majority of the EBVaGC was SALL4 negative (1/92, 1.1%, lower than EBVnGC, 303/1 727, 17.5%), and that PD-L1 was mostly positive in EBVaGC (81/110, 73.6%, higher than EBVnGC, 649/2 350, 27.6%). GC patients with SALL4 negative and PD-L1 positive were often associated with better prognosis. CONCLUSION EBVaGC is a unique subtype of GC with less metastasis and a good prognosis. It also has a distinct molecular background. The down-regulation of invasion/metastasis gene SALL4 and up-regulation of immune checkpoint gene PD-L1 are important molecular features.
Collapse
Affiliation(s)
- Y Yang
- Department of Gastrointestinal Cancer Center, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education; Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Y Q Liu
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education; Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - X H Wang
- Department of Biobank, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education; Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - K Ji
- Department of Gastrointestinal Cancer Center, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education; Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Z W Li
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education; Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - J Bai
- Berry Oncology Corporation, Beijing 102206, China
| | - A R Yang
- Berry Oncology Corporation, Beijing 102206, China
| | - Y Hu
- Department of Biobank, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education; Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - H B Han
- Department of Biobank, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education; Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Z Y Li
- Department of Gastrointestinal Cancer Center, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education; Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Z D Bu
- Department of Gastrointestinal Cancer Center, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education; Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - X J Wu
- Department of Gastrointestinal Cancer Center, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education; Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - L H Zhang
- Department of Gastrointestinal Cancer Center, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education; Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - J F Ji
- Department of Gastrointestinal Cancer Center, Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education; Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing 100142, China
| |
Collapse
|
|
25
|
Shen X, Zhao Y, Chen X, Sun H, Liu M, Zhang W, Jiang F, Li P. Associations of PIK3CA mutations with clinical features and prognosis in gastric cancer. Future Oncol 2019; 15:1873-1894. [DOI: 10.2217/fon-2018-0335] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Aim: The clinical implications of PIK3CA mutations in gastric cancer (GC) are not conclusive. Materials & methods: A systematic searching of the previous publications and related studies in The Cancer Genome Atlas (TCGA) database were performed to investigate the clinical implications of PIK3CA mutations in GC. Results: Twenty-six independent cohort studies including six studies with original data were identified. Meta-analysis suggested PIK3CA mutations were associated with high T stage, poor differentiation and microsatellite instability, but not with prognosis in overall. However, PIK3CA mutation was found to be associated with favorable overall survival in subgroup of patients with low PIK3CA mutation prevalence. Conclusion: PIK3CA mutations might be involved in GC development and might be used as favorable prognostic factor in GC population with low PIK3CA mutations prevalence.
Collapse
Affiliation(s)
- Xiaobing Shen
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, No. 87, Dingjiaqiao Road, Nanjing, 210009, PR China
| | - Ying Zhao
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, No. 87, Dingjiaqiao Road, Nanjing, 210009, PR China
| | - Xiaowei Chen
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, No. 87, Dingjiaqiao Road, Nanjing, 210009, PR China
| | - Haixiang Sun
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, No. 87, Dingjiaqiao Road, Nanjing, 210009, PR China
| | - Mengqi Liu
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, No. 87, Dingjiaqiao Road, Nanjing, 210009, PR China
| | - Wenwen Zhang
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, No. 87, Dingjiaqiao Road, Nanjing, 210009, PR China
| | | | - Pengfei Li
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, No. 87, Dingjiaqiao Road, Nanjing, 210009, PR China
| |
Collapse
|
|
26
|
Wang Y, Lv Y, Liu TS, Yan WD, Chen LY, Li ZH, Piao YS, An RB, Lin ZH, Ren XS. Cordycepin suppresses cell proliferation and migration by targeting CLEC2 in human gastric cancer cells via Akt signaling pathway. Life Sci 2019; 223:110-119. [DOI: 10.1016/j.lfs.2019.03.025] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 03/03/2019] [Accepted: 03/10/2019] [Indexed: 11/28/2022]
|
|
27
|
Iranpour M, Nourian M, Saffari S, Samizadeh E, Mirghafori M, Iravani S, Ghafouri-Fard S. PIK3CA Mutation Analysis in Iranian Patients with Gastric Cancer. IRANIAN BIOMEDICAL JOURNAL 2019; 23. [PMID: 29704890 PMCID: PMC6305827 DOI: 10.29252/.23.1.87] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background: Aberrant activation of phosphatidylinositol-3 kinases (PI3K)/AKT/mTOR (mammalian target of rapamycin) pathway is a critical event during gastric cancer progression. Selective function of AKT inhibitor AZD5363 in PI3KCA mutant gastric cancer necessitates the assessment of PI3KCA mutations in these patients. Methods: The study included 100 patients with gastric cancer who underwent surgical resection at Imam Reza Hospital, Tehran, Iran, between January 2009 and December 2016. Mutations in codon 1047 of PIK3CA were evaluated by tetra-primer ARMS-PCR and direct sequencing methods. Results: We detected p.H1047R and p.H1047L in eight and three samples, respectively. Also, a significant association was found between PIK3CA mutations and lymphatic invasion. Kaplan-Meier analysis demonstrated no significant differences in overall survival between patients with and without mutations. Conclusion: Our study detected gain-of-function mutations in exon 20 of PI3KCA gene in 11% of gastric cancer patients. Future studies are needed to assess the mutation rate in other regions of this gene to find eligible patients for targeted therapies.
Collapse
Affiliation(s)
- Mostafa Iranpour
- AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran
| | - Mahyar Nourian
- AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran
| | - Sana Saffari
- Department of Biology, Tehran North Branch, Islamic Azad University, Tehran, Iran
| | - Esmaeil Samizadeh
- Department of Pathology, AJA University of Medical Sciences, Tehran, Iran
| | - Mahdieh Mirghafori
- Department of Biology and Anatomical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahrokh Iravani
- AJA Cancer Epidemiology Research and Treatment Center (AJA-CERTC), AJA University of Medical Sciences, Tehran, Iran,Corresponding Authors: Shahrokh Iravani and Soudeh Ghafouri-Fard AJA Cancer Epidemiology Research and Treatment Center (AJA- CERTC), AJA University of Medical Sciences, Tehran, Iran; Tel. & Fax: (+98-21) 43825064; E-mail:
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran,
Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Tel. & Fax: (+98-21) 23872572; E-mail:
| |
Collapse
|
|
28
|
Baek DW, Kang BW, Kim JG. The Predictive Value of Epstein-Barr Virus-Positivity in Patients Undergoing Gastrectomy Followed by Adjuvant Chemotherapy. Chonnam Med J 2018; 54:173-177. [PMID: 30288373 PMCID: PMC6165919 DOI: 10.4068/cmj.2018.54.3.173] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 07/26/2018] [Accepted: 07/27/2018] [Indexed: 12/13/2022] Open
Abstract
The present study evaluated the survival impact of standard adjuvant chemotherapy and prognostic differences between Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) and EBV-negative gastric cancer (EBVnGC). A total of 276 patients were enrolled according to the following criteria: 1) pathologically diagnosed with primary gastric adenocarcinoma, 2) test results from EBV-encoded RNA in situ hybridization, 3) stage II/III according to the 7th edition of UICC/AJCC staging system for gastric cancer, and 4) postoperative adjuvant chemotherapy. Fifty-nine (21.4%) and 217 (78.6%) patients exhibited EBVaGC and EBVnGC, respectively, while 129 (46.7%) patients were classified as stage II and 147 (53.3%) as stage III. As for adjuvant chemotherapy, 87 (31.5%) patients received capecitabine and oxaliplatin, while 189 (68.5%) received S-1 monotherapy. With a median follow-up duration of 21.3 (6.4-89.0) months, the estimated 3-year disease-free survival (DFS) and overall survival (OS) rates were 74.8% and 83.0%, respectively. In univariate analysis and multivariate analysis using a Cox proportional hazard model including age, gender, stage, Lauren classification, and the type of chemotherapy, EBV-positivity was not significantly associated with DFS (p-value= 0.630) regardless of the type of chemotherapy. Therefore, no association was found between EBV positivity and the survival outcomes in patients with curatively resected gastric cancer who received standard adjuvant chemotherapy.
Collapse
Affiliation(s)
- Dong Won Baek
- Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Kyungpook National University Cancer Research Institute, Daegu, Korea
| | - Byung Woog Kang
- Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Kyungpook National University Cancer Research Institute, Daegu, Korea
| | - Jong Gwang Kim
- Department of Oncology/Hematology, Kyungpook National University Chilgok Hospital, School of Medicine, Kyungpook National University, Kyungpook National University Cancer Research Institute, Daegu, Korea
| |
Collapse
|
|
29
|
Peng X, Liu Y, Peng X, Wang Z, Zhang Z, Qiu Y, Jin M, Wang R, Kong D. Clinical features and the molecular biomarkers of olfactory neuroblastoma. Pathol Res Pract 2018; 214:1123-1129. [PMID: 29921494 DOI: 10.1016/j.prp.2018.06.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Revised: 06/06/2018] [Accepted: 06/06/2018] [Indexed: 01/07/2023]
Abstract
Olfactory neuroblastoma (ONB) is a kind of rare and complex head and neck tumor. The reports on this field are very scarce due to the low morbidity. Here, we summarized the clinical features and prognosis of ONB through analysis of 10 cases, and determined the phosphorylation status of some molecules known to be involved in carcinogesis such as Akt, Erk, Stat3 and Stat5 in ONB tissue. Ten ONB patients were recruited in this study, 6 male and 4 female, ranging from 26 to 66 years old. In the 10 cases, 6 were diagnosed as late T stage (T3/T4), 6 were at late Kadish stage (C/D) and 3 were at high Hyams grade (Ⅲ), which indicated a poorer prognosis. Patient characteristics-gender and tumor features were evaluated with respect to the overall survival (OS) through univariate analysis. The result indicated that the OS of male is obviously higher than that of female after a series of combined treatment. The OS of ONB patients in the late stage or high grade is lower than those in early stages or low grade. Moreover, p-Akt, p-Erk, p-Stat3 and p-Stat5 was detected in 5 (50%), 9 (90%), 7 (70%) and 0 patients (0%), respectively, suggesting the former 3 molecules might be potential biomarkers for diagnosis of ONB.
Collapse
Affiliation(s)
- Xiaolin Peng
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; Department of Otorhinolaryngology Head and Neck Surgery, Tianjin first central hospital, Tianjin 300192, China
| | - Yao Liu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Xin Peng
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Zhengming Wang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Zhe Zhang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Yuling Qiu
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Meihua Jin
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
| | - Ran Wang
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China.
| | - Dexin Kong
- Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China; Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
| |
Collapse
|
|
30
|
Liu X, Wu J, Zhang D, Wang K, Duan X, Meng Z, Zhang X. Network Pharmacology-Based Approach to Investigate the Mechanisms of Hedyotis diffusa Willd. in the Treatment of Gastric Cancer. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2018; 2018:7802639. [PMID: 29853970 PMCID: PMC5954954 DOI: 10.1155/2018/7802639] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2018] [Revised: 03/27/2018] [Accepted: 04/01/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Hedyotis diffusa Willd. (HDW) is one of the renowned herbs often used in the treatment of gastric cancer (GC). However, its curative mechanism has not been fully elucidated. OBJECTIVE To systematically investigate the mechanisms of HDW in GC. METHODS A network pharmacology approach mainly comprising target prediction, network construction, and module analysis was adopted in this study. RESULTS A total of 353 targets of the 32 bioactive compounds in HDW were obtained. The network analysis showed that CA isoenzymes, p53, PIK3CA, CDK2, P27Kip1, cyclin D1, cyclin B1, cyclin A2, AKT1, BCL2, MAPK1, and VEGFA were identified as key targets of HDW in the treatment of GC. The functional enrichment analysis indicated that HDW probably produced the therapeutic effects against GC by synergistically regulating many biological pathways, such as nucleotide excision repair, apoptosis, cell cycle, PI3K/AKT/mTOR signaling pathway, VEGF signaling pathway, and Ras signaling pathway. CONCLUSIONS This study holistically illuminates the fact that the pharmacological mechanisms of HDW in GC might be strongly associated with its synergic modulation of apoptosis, cell cycle, differentiation, proliferation, migration, invasion, and angiogenesis.
Collapse
Affiliation(s)
- Xinkui Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Dan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Kaihuan Wang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Xiaojiao Duan
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Ziqi Meng
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| | - Xiaomeng Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100102, China
| |
Collapse
|
|
31
|
Na SJ, Park HL, O JH, Lee SY, Song KY, Kim SH. Correlation Between Infection Status of Epstein-Barr Virus and 18F-Fluorodeoxyglucose Uptake in Patients with Advanced Gastric Cancer. ACTA ACUST UNITED AC 2018; 31:749-753. [PMID: 28652452 DOI: 10.21873/invivo.11126] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 05/18/2017] [Accepted: 05/27/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND Epstein-Barr virus-associated gastric cancer (EBVaGC) is one of the four molecular subtypes of gastric cancer, as defined by the classification recently proposed by The Cancer Genome Atlas. We evaluated the correlation between EBV positivity and 18F-fluorodeoxyglucose (18F-FDG) uptake by positron emission tomography/computed tomography (PET/CT) in patients with gastric cancer. MATERIALS AND METHODS We retrospectively enrolled patients with gastric cancer who underwent pretreatment 18F-FDG PET/CT and subsequent surgical resection, and then were diagnosed with advanced gastric cancer (pathologic stage ≥T2 with any N stage). Maximum standardized uptake values (SUVmax) of gastric cancer were measured by pretreatment 18F-FDG PET/CT. EBV sequences were detected by in situ hybridization (ISH) techniques. We analyzed the correlation between EBV positivity, clinicopathologic features and metabolic activity of the primary tumor. RESULTS A total of 205 patients were included and 15 (7.3%) patients were identified as having EBV-positive gastric cancer. Age, gender, tumor location, and histological type showed no significant differences between EBV-positive and negative groups. EBV-positive cancer is significantly more frequent in the higher-metabolic-tumor group than in the lower one (p=0.032). The mean SUVmax of gastric cancers showed significant differences between EBV-positive and negative groups (9.9±4.2 vs. 7.0±4.8, p=0.026). CONCLUSION The infection status of EBV was significantly related to the 18F-FDG uptake of primary tumors in patients with advanced gastric cancer.
Collapse
Affiliation(s)
- Sae Jung Na
- Department of Radiology, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hye Lim Park
- Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Joo Hyun O
- Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung Yong Lee
- Department of Radiology, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Kyo Young Song
- Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sung Hoon Kim
- Department of Radiology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| |
Collapse
|
|
32
|
Kang W, Zheng X, Wang P, Guo S. Deguelin exerts anticancer activity of human gastric cancer MGC-803 and MKN-45 cells in vitro. Int J Mol Med 2018; 41:3157-3166. [PMID: 29512685 PMCID: PMC5881843 DOI: 10.3892/ijmm.2018.3532] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Accepted: 02/05/2018] [Indexed: 01/22/2023] Open
Abstract
During the pathogenesis of gastric cancer, Akt signaling is considered as a pivotal inducer of gastric cancer development. Here we report the identification of anticancer activities of deguelin, a natural agent that inhibits Akt signaling. When applied to MGC-803 and MKN-45 cells, deguelin suppressed the proliferation and arrested cell cycle by p21-mediated inhibition of cyclin E. We further present in vitro evidence that deguelin promoted apoptosis of cancer cells by decreasing the phospho-Akt signaling and affecting expression of the apoptosis-associated genes Bax and Bcl-2. Additionally, deguelin was found to suppress the migration and invasion of gastric cancer cells. Taken together, these results indicated that deguelin exerted anticancer activity of human gastric cancer MGC-803 and MKN-45 cells in vitro.
Collapse
Affiliation(s)
- Wen Kang
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, P.R. China
| | - Xiao Zheng
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, P.R. China
| | - Ping Wang
- Department of Pathology, College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, P.R. China
| | - Shanyu Guo
- Department of General Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200011, P.R. China
| |
Collapse
|
|
33
|
Verma R, Sharma PC. Next generation sequencing-based emerging trends in molecular biology of gastric cancer. Am J Cancer Res 2018; 8:207-225. [PMID: 29511593 PMCID: PMC5835690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 11/29/2017] [Indexed: 06/08/2023] Open
Abstract
Gastric cancer (GC) is one of the leading causes of cancer related mortality in the world. Being asymptomatic in nature till advanced stage, diagnosis of gastric cancer becomes difficult in early stages of the disease. The onset and progression of gastric cancer has been attributed to multiple factors including genetic alterations, epigenetic modifications, Helicobacter pylori and Epstein-Barr Virus (EBV) infection, and dietary habits. Next Generation Sequencing (NGS) based approaches viz. Whole Genome Sequencing (WGS), Whole Exome Sequencing (WES), RNA-Seq, and targeted sequencing have expanded the knowledge base of molecular pathogenesis of gastric cancer. In this review, we highlight recent NGS-based advances covering various genetic alterations (Microsatellite Instability, Single Nucleotide Variations, and Copy Number Variations), epigenetic changes (DNA methylation, histone modification, microRNAs) and differential gene expression during gastric tumorigenesis. We also briefly discuss the current and future potential biomarkers, drugs and therapeutic approaches available for the management of gastric cancer.
Collapse
Affiliation(s)
- Renu Verma
- University School of Biotechnology, Guru Gobind Singh Indraprastha UniversityNew Delhi 110078, India
| | - Prakash C Sharma
- University School of Biotechnology, Guru Gobind Singh Indraprastha UniversityNew Delhi 110078, India
| |
Collapse
|
|
34
|
Li H, Chen S, Li H, Cui J, Gao Y, Wu D, Luan S, Qin Y, Zhai T, Liu D, Huo Z. Association between PIK3CA alteration and prognosis of gastric cancer patients: a meta-analysis. Oncotarget 2018; 9:7651-7659. [PMID: 29484141 PMCID: PMC5800933 DOI: 10.18632/oncotarget.23871] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 12/26/2017] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Increasing evidence suggests that dysregulation of phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) plays an important role in carcinogenesis. However, the relationship between PIK3CA expression and gastric cancer (GC) prognosis remains controversial. METHODS We searchedPubMed, Embase, Web of Science, and the Cochrane Library databases for relevant studies up to June 30, 2017. Primary outcomes were hazard ratio (HR), odds ratio (OR), and 95% confidence intervals (CI) for association with overall survival and clinicopathological features. RESULTS Eleven studies comprising 2481 GC patients were analyzed. Pooled analysis showed that PIK3CA upregulation was significantly associated with worse overall survival (HR = 1.79, 95% CI 1.42-2.27, p< 0.001) at the protein (HR = 1.94, 95% CI 1.52-2.47, p< 0.001) but not the gene (HR = 1.57, 95% CI 0.92-2.69, p= 0.097) level. PIK3CA gene mutation did not correlate with overall survival (HR = 1.05, 95% CI 0.83-1.34, p= 0.666) but was significantly associated with poor tumor differentiation (OR = 0.37, 95% CI 0.17-0.76, p= 0.011). CONCLUSION High PIK3CA protein expression predicted poor prognosis in GC, whereas PIK3CA gene amplification or mutation did not. Moreover, PIK3CA mutation was an indicator of poorly differentiated tumors.
Collapse
Affiliation(s)
- Hua Li
- Department of Surgical Oncology, Affiliated Xing Tai People Hospital of Hebei Medial University, Xingtai 054001, China
| | - Shubo Chen
- Department of Surgical Urology, Affiliated Xing Tai People Hospital of Hebei Medial University, Xingtai 054001, China
| | - Hui Li
- Department of General Surgery, Affiliated Xing Tai People Hospital of Hebei Medial University, Xingtai 054001, China
| | - Jianxin Cui
- Department of General Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Yunhe Gao
- Department of General Surgery, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
| | - Dianchao Wu
- Department of Surgical Oncology, Affiliated Xing Tai People Hospital of Hebei Medial University, Xingtai 054001, China
| | - Shangfeng Luan
- Department of Surgical Oncology, Affiliated Xing Tai People Hospital of Hebei Medial University, Xingtai 054001, China
| | - Yan Qin
- Department of Surgical Oncology, Affiliated Xing Tai People Hospital of Hebei Medial University, Xingtai 054001, China
| | - Tongshan Zhai
- Department of Surgical Oncology, Affiliated Xing Tai People Hospital of Hebei Medial University, Xingtai 054001, China
| | - Dengxiang Liu
- Institute of Cancer Control, Affiliated Xing Tai People Hospital of Hebei Medial University, Xingtai 054001, China
| | - Zhibin Huo
- Department of Surgical Oncology, Affiliated Xing Tai People Hospital of Hebei Medial University, Xingtai 054001, China
| |
Collapse
|
|
35
|
Ribeiro J, Oliveira A, Malta M, Oliveira C, Silva F, Galaghar A, Afonso LP, Neves MC, Medeiros R, Pimentel-Nunes P, Sousa H. Clinical and pathological characterization of Epstein-Barr virus-associated gastric carcinomas in Portugal. World J Gastroenterol 2017; 23:7292-7302. [PMID: 29142476 PMCID: PMC5677199 DOI: 10.3748/wjg.v23.i40.7292] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 07/27/2017] [Accepted: 08/15/2017] [Indexed: 02/07/2023] Open
Abstract
AIM To determine the prevalence of Epstein-Barr virus (EBV)-associated gastric carcinomas in the North Region of Portugal and to study its clinicopathological characteristics.
METHODS We have performed a retrospective study including a total of 179 consecutive patients with gastric cancer (GC) submitted to gastrectomy during 2011 at the Portuguese Oncology Institute of Porto. Clinical and pathological data was collected from individual clinical records and inserted on a database with unique codification. Tumour tissues were collected from the institutional tumour bank. EBV was detected by in situ hybridization for the detection of EBV-encoded small RNAs (EBERs) and EBV latent proteins (LMP1 and LMP2A) were detected by immunohistochemistry.
RESULTS The analysis showed that EBV-associated gastric carcinomas (EBVaGC) represents 8.4% (15/179) of all GC cases, with a significant differential distribution among histological types (P < 0.001): 100% (3/3) of medullary carcinomas, 100% (1/1) of adenosquamous carcinoma, 8.7% (8/92) of tubular adenocarcinomas, 8.0% (2/25) of mixed carcinomas and 2% (1/51) in poorly cohesive carcinomas. The analysis revealed a higher predominance of EBVaGC in the upper third and middle (cardia, fundus and body) of the stomach (P = 0.041), a significant lower number of regional lymph nodes invasion (P = 0.025) and a tendency for better prognosis (P = 0.222). EBV latent protein expression revealed that all EBVaGC cases were LMP1-negative, nevertheless 6 cases (40%) expressed LPM2A, which reveals that these cases show a distinct EBV-Latency profile (latency II-like).
CONCLUSION EBVaGC represents 8.4% of all GC in the North Region of Portugal. The EBV-infected patients have specific clinic-pathological features that should be further explored to develop new strategies of management and treatment.
Collapse
Affiliation(s)
- Joana Ribeiro
- Molecular Oncology and Viral Pathology Group, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal
- Faculty of Medicine of Porto University, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal
| | - Andreia Oliveira
- Molecular Oncology and Viral Pathology Group, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal
| | - Mariana Malta
- Molecular Oncology and Viral Pathology Group, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal
| | - Claudia Oliveira
- Molecular Oncology and Viral Pathology Group, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal
| | - Fernanda Silva
- Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal
| | - Ana Galaghar
- Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal
| | - Luís Pedro Afonso
- Department of Pathology, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal
| | - Maria Cassiano Neves
- Medical Oncology Department, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal
- Instituto CUF de Oncologia, Rua Mário Botas, 1998-018 Lisbon, Portugal
| | - Rui Medeiros
- Molecular Oncology and Viral Pathology Group, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal
- Virology Service, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal
- Research Department - Portuguese League Against Cancer (Liga Portuguesa Contra o Cancro - Núcleo Regional do Norte), Estrada Interior da Circunvalação nº 6657, 4200- 172 Porto, Portugal
| | - Pedro Pimentel-Nunes
- Gastroenterology Service, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal
- CINTESIS - Center for Health Technology and Services Research (Centro de Investigação Médica, Faculdade de Medicina da Universidade do Porto), Rua Dr. Plácido da Costa, 4200-450 Porto, Portugal
| | - Hugo Sousa
- Molecular Oncology and Viral Pathology Group, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal
- Virology Service, Portuguese Oncology Institute of Porto, Rua Dr. António Bernardino Almeida, 4200-072 Porto, Portugal
| |
Collapse
|
|
36
|
Xia LJ, Wu YL, Zhang FC. Combination of cecropinXJ and LY294002 induces synergistic cytotoxicity, and apoptosis in human gastric cancer cells via inhibition of the PI3K/Akt signaling pathway. Oncol Lett 2017; 14:7522-7528. [PMID: 29344198 DOI: 10.3892/ol.2017.7112] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2015] [Accepted: 05/16/2017] [Indexed: 12/16/2022] Open
Abstract
The aim of the present study was to investigate the cytotoxic and apoptotic effects of cecropinXJ against human gastric cancer BGC823 cells, either alone, or in combination with a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002. Cell viability and the apoptosis rate were measured using flow cytometry with Annexin-V staining. Additionally, the expression levels of several RAC-α serine/threonine kinase (Akt) phosphorylation-associated proteins and apoptosis-regulating proteins were evaluated by western blot analysis. It was observed that the combination of cecropinXJ and LY294002 resulted in significant synergistic cytotoxic and apoptosis effects, as compared with any single agent alone, in a dose-dependent manner. Corresponding to enhanced apoptosis, the expression levels of certain apoptosis-regulating proteins were changed, the most notable being the upregulation of caspase-3, B-cell lymphoma-2 (Bcl-2)-associated death promotor, Bcl-2 homologous antagonist killer, Bcl-2 interacting killer, Bcl-2-like protein 11, Bcl-2-like protein 4 and cytochrome c, and the downregulation of phosphorylated-Bad and Bcl-2 proteins. The present study provided a novel therapeutic regimen for the use of the cecropinXJ in combination with LY294002 for the treatment of gastric cancer.
Collapse
Affiliation(s)
- Li-Jie Xia
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang 830046, P.R. China
| | - Yan-Ling Wu
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang 830046, P.R. China
| | - Fu-Chun Zhang
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi, Xinjiang 830046, P.R. China
| |
Collapse
|
|
37
|
High-throughput Protein and mRNA Expression-based Classification of Gastric Cancers Can Identify Clinically Distinct Subtypes, Concordant With Recent Molecular Classifications. Am J Surg Pathol 2017; 41:106-115. [PMID: 27819872 DOI: 10.1097/pas.0000000000000756] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Gastric cancers have recently been classified into several types on the basis of molecular characterization, and the new taxonomy has shown to have clinical relevance. However, the technology required for thorough molecular classification is complicated and expensive, currently preventing widespread use. We aimed to reproduce the results of molecular classification using only simple techniques, that is, immunohistochemical analysis and in situ hybridization. We classified a cohort of 349 successive gastric adenocarcinomas into 5 subtypes, on the basis of protein or mRNA expression of MLH1, E-cadherin, p53, and Epstein-Barr virus. We observed that the subtypes presented distinct clinicopathologic characteristics and corresponded to the molecular classifications previously reported. Epstein-Barr virus -positive tumors were more common in male individuals and in the body of the stomach. Microsatellite-unstable (MSI) tumors, which showed aberrant MLH1 expression, were correlated with increased age and intestinal histology. Both types showed better overall survival than the other types. Gastric cancers with reduced expression of E-cadherin, corresponding to the epithelial to mesenchymal transition or genome stable subtypes, showed the poorest overall survival, with a high prevalence of poorly cohesive carcinoma (ie, diffuse type, of the Lauren classification system). In conclusion, we were able to reproduce a previously reported molecular classification of gastric cancers using immunohistochemical analysis and in situ hybridization. We verified the effectiveness and applicability of this method, which shows promise for use in a clinical setting in the foreseeable future.
Collapse
|
|
38
|
Chen EG, Zhang JS, Xu S, Zhu XJ, Hu HH. Long non-coding RNA DGCR5 is involved in the regulation of proliferation, migration and invasion of lung cancer by targeting miR-1180. Am J Cancer Res 2017; 7:1463-1475. [PMID: 28744397 PMCID: PMC5523028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 05/23/2017] [Indexed: 06/07/2023] Open
Abstract
Accumulating studies have demonstrated that non-coding RNAs (ncRNAs), including small non-coding RNAs (small ncRNAs) and long non-coding RNAs (lncRNAs), are involved in tumor growth in lung cancer (LC). However, the specific role of DGCR5 in LC progression is not yet clear. In the present study, we found that DGCR5 was downregulated and miR-1180 was upregulated in the sera and tissues of LC patients and was correlated with poor prognosis. We also found that DGCR5 suppressed proliferation, migration and invasion of LC cell lines H520 and H1299. In addition, a luciferase reporter gene assay was used to investigate the regulatory relationship between DGCR5 and miR-1180. Furthermore, we suggested that DGCR5 inhibited the expression of AKT, GSK-3β, and β-catenin by targeting miR-1180. Based on these findings, DGCR5 might serve as a potential target for the development of effective anti-neoplastic therapies in lung cancer.
Collapse
Affiliation(s)
- En-Guo Chen
- Department of Pulmonary Medicine, Sir Run Run Shaw Hospital of Zhejiang UniversityHangzhou 310016, Zhejiang Province, China
| | - Ji-Song Zhang
- Department of Pulmonary Medicine, Sir Run Run Shaw Hospital of Zhejiang UniversityHangzhou 310016, Zhejiang Province, China
| | - Shan Xu
- Department of Pulmonary Medicine, Sir Run Run Shaw Hospital of Zhejiang UniversityHangzhou 310016, Zhejiang Province, China
| | - Xiao-Jing Zhu
- Department of Pulmonary Medicine, Sir Run Run Shaw Hospital of Zhejiang UniversityHangzhou 310016, Zhejiang Province, China
| | - Hui-Hui Hu
- Department of Pulmonary Medicine, Sir Run Run Shaw Hospital of Zhejiang UniversityHangzhou 310016, Zhejiang Province, China
| |
Collapse
|
|
39
|
Kim JW, Lee HS, Nam KH, Ahn S, Kim JW, Ahn SH, Park DJ, Kim HH, Lee KW. PIK3CA mutations are associated with increased tumor aggressiveness and Akt activation in gastric cancer. Oncotarget 2017; 8:90948-90958. [PMID: 29207615 PMCID: PMC5710896 DOI: 10.18632/oncotarget.18770] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 06/10/2017] [Indexed: 12/19/2022] Open
Abstract
PIK3CA mutations are frequent in gastric cancer. However, their pathological and clinical implications are still unclear. We analyzed the clinicopathological characteristics according to the PIK3CA mutation status of patients with stage IB–IV disease who underwent gastrectomy between May 2003 and Dec. 2005 (cohort 1; n = 302) and of those with stage IV disease who received gastrectomy between Jul. 2006 and Dec. 2012 (cohort 2; n = 120). PIK3CA mutations were detected in 40 patients (13.2%) in cohort 1. In these patients, PIK3CA-mutant tumors were more frequently located in the upper third of the stomach (p = 0.021) and significantly showed poorly differentiated histology (p = 0.018) and increased lymphatic (p = 0.015), vascular (p = 0.005), and perineural invasion (p = 0.026). In addition, these tumors showed significantly increased lymphocyte and neutrophil infiltration in cancer stroma (p < 0.001), Epstein–Barr virus positivity (p < 0.001), and microsatellite instability (p = 0.015). Cytoplasmic Akt expression was significantly increased in these tumors (p = 0.001). In cohort 2, PIK3CA mutations were identified in 15 patients (12.5%). PIK3CA-mutant tumors showed significantly increased vascular invasion (p = 0.019) and microsatellite instability (p = 0.041). In addition, cytoplasmic Akt expression was also significantly increased (p = 0.018). However, in both cohorts, PIK3CA mutations were not associated with the prognosis of patients. In conclusion, PIK3CA mutations were associated with increased tumor aggressiveness, especially in locoregional disease, and Akt activation in gastric cancer. Our data suggest that PIK3CA-mutated gastric cancer is a distinct disease entity, which might need a different therapeutic approach.
Collapse
Affiliation(s)
- Ji-Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| | - Kyung Han Nam
- Department of Pathology, Haeundae Paik Hospital, Inje University College of Medicine, Busan 48108, Korea
| | - Soyeon Ahn
- Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| | - Jin Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| | - Sang-Hoon Ahn
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| | - Do Joong Park
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| | - Hyung-Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| | - Keun-Wook Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| |
Collapse
|
|
40
|
Park J, Yoo HM, Jang W, Shin S, Kim M, Kim Y, Lee SW, Kim JG. Distribution of somatic mutations of cancer-related genes according to microsatellite instability status in Korean gastric cancer. Medicine (Baltimore) 2017; 96:e7224. [PMID: 28640116 PMCID: PMC5484224 DOI: 10.1097/md.0000000000007224] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2017] [Revised: 05/23/2017] [Accepted: 05/30/2017] [Indexed: 02/05/2023] Open
Abstract
In studies of the molecular basis of gastric cancer (GC), microsatellite instability (MSI) is one of the key factors. Somatic mutations found in GC are expected to contribute to MSI-high (H) tumorigenesis. We estimated somatic mutation distribution according to MSI status in 52 matched pair GC samples using the Ion Torrent Ion S5 XL with the AmpliSeq Cancer Hotspot panel.Seventy-five (9.8%) somatic variants consisting of 34 hotspot mutations and 41 other likely pathogenic variants were identified in 34 GC samples. The TP53 mutations was most common (35%, 26/75), followed by EGFR (8%, 6/75), HNF1A (8%, 6/75), PIK3CA (8%, 6/75), and ERBB2 (5%, 4/75). To determine MSI status, 52 matched pair samples were estimated using 15 MSI markers. Thirty-nine MS stable (S), 5 MSI-low (L), and 8 MSI-H were classified. GCs with MSI-H tended to have more variants significantly compared with GCs with MS stable (MSS) and MSI-L (standardized J-T statistic = 3.161 for number of variants; P = .002). The mean number of all variants and hotspot mutations per tumor samples only in GCs with MSI-H were 3.9 (range, 1-6) and 1.1 (range, 0-3), respectively. Whereas, the mean number of all variants and hotspot mutations per tumor samples only in GCs with MSS/MSI-L were 1 (0-5)/0.8 (0-1) and 0.5 (0-3)/0.8 (0-1), respectively.In conclusion, GC with MSI-H harbored more mutations in genes that act as a tumor suppressor or oncogene compared to GC with MSS/MSI-L. This finding suggests that the accumulation of MSIs contributes to the genetic diversity and complexities of GC. In addition, targeted NGS approach allows for detection of common and also rare clinically actionable mutations and profiles of comutations in multiple patients simultaneously. Because GC shows distinctive patterns related to ethnics, further studies pertaining to different racial/ethnic groups or cancer types may reinforce our investigations.
Collapse
Affiliation(s)
| | - Han Mo Yoo
- Division of Gastrointestinal Surgery, Department of Surgery
| | | | | | | | | | - Seung-Woo Lee
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jeong Goo Kim
- Division of Gastrointestinal Surgery, Department of Surgery
| |
Collapse
|
|
41
|
Baek DW, Kang BW, Hwang S, Kim JG, Seo AN, Bae HI, Kwon OK, Lee SS, Chung HY, Yu W. Clinical Significance of p53 Protein Expression, Beta-catenin Expression and HER2 Expression for Epstein-Barr Virus-associated Gastric Cancer. Chonnam Med J 2017; 53:140-146. [PMID: 28584793 PMCID: PMC5457949 DOI: 10.4068/cmj.2017.53.2.140] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Revised: 03/10/2017] [Accepted: 03/16/2017] [Indexed: 12/13/2022] Open
Abstract
This study assessed the expression of the p53 protein, beta-catenin, and HER2 and their prognostic implications in patients with EBV-associated gastric cancer (EBVaGC). After reviewing 1318 consecutive cases of surgically resected or endoscopic submucosal dissected gastric cancers, 117 patients were identified as EBV-positive using EBV-encoded RNA in-situ hybridization. The immunohistochemistry results were interpreted as follows: strong p53 nuclear expression in at least 50% of tumor nuclei was interpreted as a positive result, strong beta-catenin expression in at least 10% of cytoplasmic nuclei was interpreted as a positive result, and moderate or strong complete or basolateral membrane staining in 10% of tumor cells was interpreted as a positive result for HER2. Immunohistochemical staining for p53 was performed on tumor tissue from 105 patients, among whom 25 (23.8%) tested positive. Meanwhile, beta-catenin expression was positive in 10 patients (17.5%) and HER2 expression was positive in 8 patients (6.8%). The positive expression of p53 was significantly associated with a high T stage (p=0.006). More patients with lymph node metastasis were p53-positive (p=0.013). In the univariate analysis, the p53-positive patients showed significantly decreased disease-free survival (DFS) when compared with the p53-negative patients (p=0.022), although the p53 status was only marginally associated with overall survival (OS) (p=0.080). However, p53 expression showed no prognostic significance on DFS in the multivariate analysis. Moreover, beta-catenin and HER2 showed no association with DFS and OS in the survival analysis. The current study found a significant correlation between p53 expression and tumor progression and lymph node metastases in patients with EBVaGC.
Collapse
Affiliation(s)
- Dong Won Baek
- Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University Cancer Research Institute, Kyungpook National University School of Medicine, Daegu, Korea
| | - Byung Woog Kang
- Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University Cancer Research Institute, Kyungpook National University School of Medicine, Daegu, Korea
| | - Soyoon Hwang
- Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University Cancer Research Institute, Kyungpook National University School of Medicine, Daegu, Korea
| | - Jong Gwang Kim
- Department of Oncology/Hematology, Kyungpook National University Medical Center, Kyungpook National University Cancer Research Institute, Kyungpook National University School of Medicine, Daegu, Korea
| | - An Na Seo
- Department of Pathology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Han Ik Bae
- Department of Pathology, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Oh Kyoung Kwon
- Department of Surgery, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Seung Soo Lee
- Department of Surgery, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Ho Young Chung
- Department of Surgery, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| | - Wansik Yu
- Department of Surgery, Kyungpook National University Hospital, Kyungpook National University School of Medicine, Daegu, Korea
| |
Collapse
|
|
42
|
Cao F, Zhang C, Han W, Gao XJ, Ma J, Hu YW, Gu X, Ding HZ, Zhu LX, Liu Q. p-Akt as a potential poor prognostic factor for gastric cancer: a systematic review and meta-analysis. Oncotarget 2017; 8:59878-59888. [PMID: 28938690 PMCID: PMC5601786 DOI: 10.18632/oncotarget.17001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2017] [Accepted: 03/17/2017] [Indexed: 12/18/2022] Open
Abstract
To understand the relationship between p-Akt expression and the prognosis of patients with gastric cancer, we searched six databases, Pubmed, EMBASE, Cochrane Library, CNKI, Wanfang and CBM for relevant articles in order to conduct this metaanalysis. The pooled hazard ratios and corresponding 95%CI of overall survival were calculated to evaluate the prognostic value of p-Akt expression in patients with gastric cancer. With 2261 patients combined from 13 available studies, the pooled HR showed a poor prognosis in patients with gastric cancer in the univariate analysis (HR=1.88, 95%CI:1.45-2.43, P<0.00001), and the group "univariate analysis+estimate" (HR=1.41, 95%CI: 1.01-1.97, P=0.04), but not in multivariate analysis (HR=0.66, 95%CI: 0.29-1.52, P=0.33) and estimate (HR=1.13, 95%CI: 0.65-1.95, P=0.67). In conclusion, our results indicated that p-Akt was likely to be an indicator of poor prognosis in patients with gastric cancer.
Collapse
Affiliation(s)
- Fang Cao
- Department of General Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China
| | - Cong Zhang
- Department of Pharmacy, Kunshan Hospital of TCM, Kunshan, Jiangsu 215300, P.R. China
| | - Wei Han
- Department of General Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China
| | - Xiao-Jiao Gao
- Department of Pathology, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China
| | - Jun Ma
- Department of Urological Surgery, Kunshan Hospital of TCM, Kunshan, Jiangsu 215300, P.R. China
| | - Yong-Wei Hu
- Department of General Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China
| | - Xing Gu
- Department of Gynaecology and Obstetrics, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China
| | - Hou-Zhong Ding
- Department of General Surgery, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China
| | - Li-Xia Zhu
- Department of Gynaecology and Obstetrics, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China
| | - Qin Liu
- Department of Gynaecology and Obstetrics, Kunshan First People's Hospital Affiliated to Jiangsu University, Kunshan, Jiangsu 215300, P.R. China
| |
Collapse
|
|
43
|
Choi Y, Ko YS, Park J, Choi Y, Kim Y, Pyo JS, Jang BG, Hwang DH, Kim WH, Lee BL. HER2-induced metastasis is mediated by AKT/JNK/EMT signaling pathway in gastric cancer. World J Gastroenterol 2016; 22:9141-9153. [PMID: 27895401 PMCID: PMC5107595 DOI: 10.3748/wjg.v22.i41.9141] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 08/12/2016] [Accepted: 09/12/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigated the relationships between HER2, c-Jun N-terminal kinase (JNK) and protein kinase B (AKT) with respect to metastatic potential of HER2-positive gastric cancer (GC) cells.
METHODS Immunohistochemistry was performed on tissue array slides containing 423 human GC specimens. Using HER2-positve GC cell lines SNU-216 and NCI-N87, HER2 expression was silenced by RNA interference, and the activations of JNK and AKT were suppressed by SP600125 and LY294002, respectively. Transwell assay, Western blot, semi-quantitative reverse transcription-polymerase chain reaction and immunofluorescence staining were used in cell culture experiments.
RESULTS In GC specimens, HER2, JNK, and AKT activations were positively correlated with each other. In vitro analysis revealed a positive regulatory feedback loop between HER2 and JNK in GC cell lines and the role of JNK as a downstream effector of AKT in the HER2/AKT signaling pathway. JNK inhibition suppressed migratory capacity through reversing EMT and dual inhibition of JNK and AKT induced a more profound effect on cancer cell motility.
CONCLUSION HER2, JNK and AKT in human GC specimens are positively associated with each other. JNK and AKT, downstream effectors of HER2, co-operatively contribute to the metastatic potential of HER2-positive GC cells. Thus, targeting of these two molecules in combination with HER2 downregulation may be a good approach to combat HER2-positive GC.
Collapse
|
|
44
|
Shi WJ, Gao JB. Molecular mechanisms of chemoresistance in gastric cancer. World J Gastrointest Oncol 2016; 8:673-681. [PMID: 27672425 PMCID: PMC5027022 DOI: 10.4251/wjgo.v8.i9.673] [Citation(s) in RCA: 118] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2016] [Revised: 06/07/2016] [Accepted: 06/29/2016] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer is the fourth most common cancer and the second leading cause of cancer deaths worldwide. Chemotherapy is one of the major treatments for gastric cancer, but drug resistance limits the effectiveness of chemotherapy, which results in treatment failure. Resistance to chemotherapy can be present intrinsically before the administration of chemotherapy or it can develop during chemotherapy. The mechanisms of chemotherapy resistance in gastric cancer are complex and multifactorial. A variety of factors have been demonstrated to be involved in chemoresistance, including the reduced intracellular concentrations of drugs, alterations in drug targets, the dysregulation of cell survival and death signaling pathways, and interactions between cancer cells and the tumor microenvironment. This review focuses on the molecular mechanisms of chemoresistance in gastric cancer and on recent studies that have sought to overcome the underlying mechanisms of chemoresistance.
Collapse
|
|
45
|
Baniak N, Senger JL, Ahmed S, Kanthan SC, Kanthan R. Gastric biomarkers: a global review. World J Surg Oncol 2016; 14:212. [PMID: 27514667 PMCID: PMC4982433 DOI: 10.1186/s12957-016-0969-3] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Accepted: 08/02/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Gastric cancer is an aggressive disease with a poor 5-year survival and large global burden of disease. The disease is biologically and genetically heterogeneous with a poorly understood carcinogenesis at the molecular level. Despite the many prognostic, predictive, and therapeutic biomarkers investigated to date, gastric cancer continues to be detected at an advanced stage with resultant poor clinical outcomes. MAIN BODY This is a global review of gastric biomarkers with an emphasis on HER2, E-cadherin, fibroblast growth factor receptor, mammalian target of rapamycin, and hepatocyte growth factor receptor as well as sections on microRNAs, long noncoding RNAs, matrix metalloproteinases, PD-L1, TP53, and microsatellite instability. CONCLUSION A deeper understanding of the pathogenesis and biological features of gastric cancer, including the identification and characterization of diagnostic, prognostic, predictive, and therapeutic biomarkers, hopefully will provide improved clinical outcomes.
Collapse
Affiliation(s)
- Nick Baniak
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - Jenna-Lynn Senger
- Department of Surgery, University of Alberta, 116 St & 85 Ave, Edmonton, T6G 2R3, T6G 2B7 AB Canada
| | - Shahid Ahmed
- Division of Medical Oncology, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - S. C. Kanthan
- Department of General Surgery, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| | - Rani Kanthan
- Department of General Surgery, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK S7N 0W8 Canada
| |
Collapse
|
|
46
|
Harada K, Baba Y, Shigaki H, Ishimoto T, Miyake K, Kosumi K, Tokunaga R, Izumi D, Ohuchi M, Nakamura K, Kiyozumi Y, Kurashige J, Iwatsuki M, Miyamoto Y, Sakamoto Y, Yoshida N, Watanabe M, Baba H. Prognostic and clinical impact of PIK3CA mutation in gastric cancer: pyrosequencing technology and literature review. BMC Cancer 2016; 16:400. [PMID: 27388016 PMCID: PMC4936296 DOI: 10.1186/s12885-016-2422-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2015] [Accepted: 06/15/2016] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations that activate the PI3K/AKT signaling pathway have been observed in several types of carcinoma and have been associated with patient prognosis. However, the significance of PIK3CA mutations in gastric cancer remains unclear. This retrospective study investigated the relationship between PIK3CA mutations and clinical outcomes in patients with gastric cancer. Additionally, we reviewed the rate of PIK3CA mutations in gastric cancer and the association between PIK3CA mutations and prognosis in human cancers. METHODS The study included 208 patients with gastric cancer who underwent surgical resection at Kumamoto University Hospital, Japan, between January 2001 and August 2010. Mutations in PIK3CA exons 9 and 20 were quantified by pyrosequencing assays. RESULTS PIK3CA mutations were detected in 25 (12 %) of the 208 patients. Ten patients had c.1634A > G (p.E545G), 10 had c.1624G > A (p.E542K), 13 had c.1633G > A (p.E545K), nine had c.3139C > T (p.H1047R), and 1 had c.3140A > G (p.H1047Y) mutations. PIK3CA mutations were not significantly associated with any clinical, epidemiologic, or pathologic characteristic. Kaplan-Meier analysis showed no significant differences in disease-free survival (log rank P = 0.84) and overall survival (log rank P = 0.74) between patients with and without PIK3CA mutations. CONCLUSIONS Mutations in PIK3CA did not correlate with prognosis in patients with gastric cancer, providing additional evidence for the lack of relationship between the two.
Collapse
Affiliation(s)
- Kazuto Harada
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Yoshifumi Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Hironobu Shigaki
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Takatsugu Ishimoto
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Keisuke Miyake
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Keisuke Kosumi
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Ryuma Tokunaga
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Daisuke Izumi
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Mayuko Ohuchi
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Kenichi Nakamura
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Yuki Kiyozumi
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Junji Kurashige
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Masaaki Iwatsuki
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Yuji Miyamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Yasuo Sakamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Naoya Yoshida
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan
| | - Masayuki Watanabe
- Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
| |
Collapse
|
|
47
|
MicroRNA-224 aggrevates tumor growth and progression by targeting mTOR in gastric cancer. Int J Oncol 2016; 49:1068-80. [PMID: 27315344 DOI: 10.3892/ijo.2016.3581] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 05/20/2016] [Indexed: 11/05/2022] Open
Abstract
Growing evidence suggests that microRNA plays an essential role in the development and metastasis of many tumors, including gastric cancer. Aberrant miR-224 expression has been indicated in tumor growth, the mechanism of miR-224 promoting the proliferation and metastatic ability for gastric cancer remains unclear. Accumulating evidence reports that mTOR signal pathway plays an important role in the cellular process, such as apoptosis, cell growth and proliferation. The goal of the present study was to identify whether miR-224 could inhibit the growth, migration, invasion, proliferation and metastasis of gastric cancer through targeting mTOR expression. Real-time PCR (RT-PCR) was used to quantify miR-224 expression in vitro and in vivo experiments. Luciferase reporter assays were performed to confirm the activity of mTOR pathway, and immunofluorescence staining assay was conducted to observe apoptosis and cell proliferation ability. Bioinformatics as well as cell luciferase function studies distinguished the direct modulation of miR-224 on the 3'-UTR of the mTOR, which leads to the inactivation of apoptosis signaling and the activation of cell proliferation. In addition, inhibition of miR-224 significantly reduced the expression of mTOR and improved caspase-9/3 expression while decreased cyclin D1/2 levels, attenuating gastric cancer cell proliferation. Therefore, the present study revealed the mechanistic links between miR-224 and mTOR in the pathogenesis of gastric cancer through modulation of caspase-9/3 and cyclin D1/2. In addition, targeting miR-224 could serve as a novel strategy for future gastric cancer therapy.
Collapse
|
|
48
|
Zhang Z, Dou M, Yao X, Tang H, Li Z, Zhao X. Potential Biomarkers in Diagnosis of Human Gastric Cancer. Cancer Invest 2016; 34:115-22. [PMID: 26934336 DOI: 10.3109/07357907.2015.1114122] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The high incidence of gastric cancer (GC) and its consequent mortality rate severely threaten human's health. It is not frequently diagnosed until a relatively advanced stage. Surgery is the only potentially curative treatment. Thus, early screening and diagnosis are critical for patients with GC. The tumor marker assays used currently for detecting GC are simple and rapid, but the usage is limited by its low sensitivity and specificity. Here, we provide a brief description of some new potential markers and new biotechnological methods for the diagnosis of GC, hoping to find out more effective approaches for early detection of GC.
Collapse
Affiliation(s)
- Zhihao Zhang
- a College of Pharmaceutical Sciences, Southwest University , Chongqing , China
| | - Mengmeng Dou
- a College of Pharmaceutical Sciences, Southwest University , Chongqing , China
| | - Xiaofang Yao
- a College of Pharmaceutical Sciences, Southwest University , Chongqing , China
| | - Hao Tang
- a College of Pharmaceutical Sciences, Southwest University , Chongqing , China
| | - Zhubo Li
- a College of Pharmaceutical Sciences, Southwest University , Chongqing , China
| | - Xiaoyan Zhao
- a College of Pharmaceutical Sciences, Southwest University , Chongqing , China
| |
Collapse
|
|
49
|
Skierucha M, Milne ANA, Offerhaus GJA, Polkowski WP, Maciejewski R, Sitarz R. Molecular alterations in gastric cancer with special reference to the early-onset subtype. World J Gastroenterol 2016; 22:2460-2474. [PMID: 26937134 PMCID: PMC4768192 DOI: 10.3748/wjg.v22.i8.2460] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 11/06/2015] [Accepted: 12/30/2015] [Indexed: 02/06/2023] Open
Abstract
Currently, gastric cancer (GC) is one of the most frequently diagnosed neoplasms, with a global burden of 723000 deaths in 2012. It is the third leading cause of cancer-related death worldwide. There are numerous possible factors that stimulate the pro-carcinogenic activity of important genes. These factors include genetic susceptibility expressed in a single-nucleotide polymorphism, various acquired mutations (chromosomal instability, microsatellite instability, somatic gene mutations, epigenetic alterations) and environmental circumstances (e.g., Helicobcter pylori infection, EBV infection, diet, and smoking). Most of the aforementioned pathways overlap, and authors agree that a clear-cut pathway for GC may not exist. Thus, the categorization of carcinogenic events is complicated. Lately, it has been claimed that research on early-onset gastric carcinoma (EOGC) and hereditary GC may contribute towards unravelling some part of the mystery of the GC molecular pattern because young patients are less exposed to environmental carcinogens and because carcinogenesis in this setting may be more dependent on genetic factors. The comparison of various aspects that differ and coexist in EOGCs and conventional GCs might enable scientists to: distinguish which features in the pathway of gastric carcinogenesis are modifiable, discover specific GC markers and identify a specific target. This review provides a summary of the data published thus far concerning the molecular characteristics of GC and highlights the outstanding features of EOGC.
Collapse
|
|
50
|
Role of Viral miRNAs and Epigenetic Modifications in Epstein-Barr Virus-Associated Gastric Carcinogenesis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:6021934. [PMID: 26977250 PMCID: PMC4764750 DOI: 10.1155/2016/6021934] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 01/12/2016] [Accepted: 01/14/2016] [Indexed: 01/26/2023]
Abstract
MicroRNAs are short (21–23 nucleotides), noncoding RNAs that typically silence posttranscriptional gene expression through interaction with target messenger RNAs. Currently, miRNAs have been identified in almost all studied multicellular eukaryotes in the plant and animal kingdoms. Additionally, recent studies reported that miRNAs can also be encoded by certain single-cell eukaryotes and by viruses. The vast majority of viral miRNAs are encoded by the herpesviruses family. These DNA viruses including Epstein-Barr virus encode their own miRNAs and/or manipulate the expression of cellular miRNAs to facilitate respective infection cycles. Modulation of the control pathways of miRNAs expression is often involved in the promotion of tumorigenesis through a specific cascade of transduction signals. Notably, latent infection with Epstein-Barr virus is considered liable of causing several types of malignancies, including the majority of gastric carcinoma cases detected worldwide. In this review, we describe the role of the Epstein-Barr virus in gastric carcinogenesis, summarizing the functions of the Epstein-Barr virus-encoded viral proteins and related epigenetic alterations as well as the roles of Epstein-Barr virus-encoded and virally modulated cellular miRNAs.
Collapse
|