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McMiller TL, Besharati S, Yarchoan M, Zhu Q, Ünsal-Kaçmaz K, Xu K, Lee J, Bhaijee F, Engle LL, Taube JM, Berger AE, Anders RA, Topalian SL. Immune microenvironment of Epstein-Barr virus (EBV)-negative compared to EBV-associated gastric cancers: implications for immunotherapy. J Immunother Cancer 2024; 12:e010201. [PMID: 39572160 PMCID: PMC11580252 DOI: 10.1136/jitc-2024-010201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 10/29/2024] [Indexed: 11/24/2024] Open
Abstract
BACKGROUND Gastric carcinomas (GC) are aggressive malignancies, and only ~15% of patients respond to anti-programmed cell death (ligand) 1 (PD-(L)1) monotherapy. However, Epstein-Barr virus (EBV)-associated GCs (~5-10% of GCs) often harbor PD-L1 and PD-L2 chromosomal amplifications and robust CD8+ T cell infiltrates, and respond at a high rate to anti-PD-1. The current study compares the tumor immune microenvironments (TiMEs) of EBV+ versus EBV(-) GCs. METHODS Over 1000 cases of primary invasive GCs were screened to identify 25 treatment-naïve specimens for study (11 EBV+, 14 EBV(-)). Quantitative immunohistochemistry (IHC) was conducted for markers of immune cell subsets and co-regulatory molecules. Gene expression profiling (GEP) was performed on RNAs isolated from macrodissected areas of CD3+ T cell infiltrates abutting PD-L1+ stromal/tumor cells, using multiplex quantitative reverse transcriptase PCR for a panel of 122 candidate immune-related genes. RESULTS IHC revealed that 17/25 GCs contained PD-L1+ stromal cells, with no significant difference between EBV+/- specimens; however, only 3/25 specimens (all EBV+) contained PD-L1+ tumor cells. CD8+ T cell densities were higher in EBV+ versus EBV(-) tumors (p=0.044). With GEP normalized to the pan-leukocyte marker PTPRC/CD45, EBV+ GCs overexpressed ITGAE (CD103, marking intraepithelial T cells and a dendritic cell subset) and the interferon-inducible genes CXCL9 and IDO1. In contrast, EBV(-) tumors overexpressed several functionally-related gene groups associated with myeloid cells (CD163, IL1A, NOS2, RIGI), immunosuppressive cytokines/chemokines (CXCL2, CXCR4, IL10, IL32), coinhibitory molecules (HAVCR2/TIM-3 and VSIR/VISTA), and adenosine pathway components (ENTPD1/ CD39 and NT5E/CD73). Notably, compared with EBV+ GCs, EBV(-) GCs also overexpressed components of the cyclooxygenase 2 (COX-2)/prostaglandin E2 (PGE2) pathway associated with cancer-promoting inflammation, including PTGS2/COX-2 (most highly upregulated gene, 32-fold, p=0.005); prostaglandin receptors PTGER1 (EP1; up 21-fold, p=0.015) and PTGER4 (EP4; up twofold, p=0.022); and the major COX-2-inducing cytokine IL1B (up 11-fold, p=0.019). Consistent with these findings, COX-2 protein expression trended higher in EBV(-) versus EBV+ GCs (p=0.068). CONCLUSIONS While certain markers of immunosuppression are found in the GC TiME regardless of EBV status, EBV(-) GCs, which are much more common than EBV+ GCs, overexpress components of the COX-2/PGE2 pathway. These findings provide novel insights into the immune microenvironments of EBV+ and EBV(-) GC, and offer potential targets to overcome resistance to anti-PD-(L)1 therapies.
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Affiliation(s)
- Tracee L McMiller
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Sepideh Besharati
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Mark Yarchoan
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Qingfeng Zhu
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | | | - Ke Xu
- Bristol Myers Squibb Co, Princeton, New Jersey, USA
| | - Junghwa Lee
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Feriyl Bhaijee
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Logan L Engle
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Janis M Taube
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Alan E Berger
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Robert A Anders
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Suzanne L Topalian
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- Bloomberg-Kimmel Institute for Cancer Immunotherapy and Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Cho YJ, Hwang I, Park S, Lee S, Kang SY, Kim MJ, Ahn S, Kim KM. Prognostic Effect of Tertiary Lymphoid Structures in Epstein-Barr Virus-Associated Gastric Carcinomas Measured by Digital Image Analysis. J Transl Med 2024; 104:102071. [PMID: 38677591 DOI: 10.1016/j.labinv.2024.102071] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 02/25/2024] [Accepted: 04/18/2024] [Indexed: 04/29/2024] Open
Abstract
Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is characterized by prominent tumor-infiltrating lymphocytes (TILs) and has a favorable prognosis. Tertiary lymphoid structures (TLS), characterized by ectopic aggregated lymphocytes with high-endothelial venules (HEV), are associated with favorable outcomes in various solid tumors. We hypothesized that EBVaGC, characterized by intense TILs, may be closely associated with TLS or HEV. To test this hypothesis, we digitally analyzed the TLS, HEV, and TILs in 73 surgically resected advanced EBVaGCs. For HEV, dual MECA-79 and CD31 dual immunohistochemistry were performed, and the ectopic expression of MECA-79 in tumor cells was measured. In 73 patients with EBVaGC, a high-TLS ratio was found in 29 (39.7%) cases, high-tumor-associated HEV density in 44 (60.3%) cases, and high-CD8+ TIL density in 38 (52.1%) cases. Ectopic tumor expression of MECA-79 was observed in 36 patients (49.3%) cases. A low-TLS ratio and tumor-associated HEV density were significantly associated with lymph node metastasis (P = .005 and .042, respectively). Ectopic MECA-79 expression was significantly associated with lymph node metastasis (P = .003). Patients with a low-TLS ratio (P = .038), low-HEV density (P = .042), and ectopic tumor MECA-79 expression (P = .032) had significantly worse prognoses. In conclusion, TLS ratio and HEV density affect the survival of patients with EBVaGC and may be related to the immune response that interrupts lymph node metastasis.
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Affiliation(s)
- Yun Joo Cho
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Inwoo Hwang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Suho Park
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Somin Lee
- Center for Companion Diagnostics, Precision Medicine Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - So Young Kang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Min-Ji Kim
- Biomedical Statistics Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea
| | - Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; Center for Companion Diagnostics, Precision Medicine Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
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Shin J, Park YS. Unusual or Uncommon Histology of Gastric Cancer. J Gastric Cancer 2024; 24:69-88. [PMID: 38225767 PMCID: PMC10774758 DOI: 10.5230/jgc.2024.24.e7] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 12/06/2023] [Accepted: 12/07/2023] [Indexed: 01/17/2024] Open
Abstract
This review comprehensively examines the diverse spectrum of gastric cancers, focusing on unusual or uncommon histology that presents significant diagnostic and therapeutic challenges. While the predominant form, tubular adenocarcinoma, is well-characterized, this review focuses on lesser-known variants, including papillary adenocarcinoma, micropapillary carcinoma, adenosquamous carcinoma, squamous cell carcinoma (SCC), hepatoid adenocarcinoma, gastric choriocarcinoma, gastric carcinoma with lymphoid stroma, carcinosarcoma, gastroblastoma, parietal cell carcinoma, oncocytic adenocarcinoma, Paneth cell carcinoma, gastric adenocarcinoma of the fundic gland type, undifferentiated carcinoma, and extremely well-differentiated adenocarcinoma. Although these diseases have different nomenclatures characterized by distinct histopathological features, these phenotypes often overlap, making it difficult to draw clear boundaries. Furthermore, the number of cases was limited, and the unique histopathological nature and potential pathogenic mechanisms were not well defined. This review highlights the importance of understanding these rare variants for accurate diagnosis, effective treatment planning, and improving patient outcomes. This review emphasizes the need for ongoing research and case studies to enhance our knowledge of these uncommon forms of gastric cancer, which will ultimately contribute to more effective treatments and better prognostic assessments. This review aimed to broaden the pathological narrative by acknowledging and addressing the intricacies of all cancer types, regardless of their rarity, to advance patient care and improve prognosis.
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Affiliation(s)
- Jinho Shin
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young Soo Park
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Park JH, Cho HJ, Seo J, Park KB, Kwon YH, Bae HI, Seo AN, Kim M. Genetic landscape and PD-L1 expression in Epstein-Barr virus-associated gastric cancer according to the histological pattern. Sci Rep 2023; 13:19487. [PMID: 37945587 PMCID: PMC10636116 DOI: 10.1038/s41598-023-45930-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2023] [Accepted: 10/25/2023] [Indexed: 11/12/2023] Open
Abstract
Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a distinct molecular subtype of gastric cancer. This study aims to investigate genomic and clinicopathological characteristics of EBVaGC according to the histological pattern. We retrospectively collected 18 specimens of surgically resected EBVaGCs. Whole-exome sequencing was performed for all cases. Moreover, PD-L1 expression and tumor-infiltrating lymphocyte (TIL) percentage were investigated. Among 18 EBVaGCs, 10 cases were of intestinal histology, 3 were of poorly cohesive histology, and the remaining 5 were of gastric carcinoma with lymphoid stroma histology. Whole-exome sequencing revealed that EBVaGCs with intestinal histology harbored pathogenic mutations known to frequently occur in tubular or papillary adenocarcinoma, including TP53, KRAS, FBXW7, MUC6, ERBB2, CTNNB1, and ERBB2 amplifications. One patient with poorly cohesive carcinoma histology harbored a CDH1 mutation. Patients with EBVaGCs with intestinal or poorly cohesive carcinoma histology frequently harbored driver mutations other than PIK3CA, whereas those with EBVaGCs with gastric carcinoma with lymphoid stroma histology lacked other driver mutations. Moreover, the histological pattern of EBVaGCs was significantly associated with the levels of TILs (P = 0.005) and combined positive score (P = 0.027). In conclusion, patients with EBVaGCs with different histological patterns exhibited distinct genetic alteration, PD-L1 expression, and degree of TILs.
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Affiliation(s)
- Ji Hyun Park
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hee Jin Cho
- Department of Biomedical Convergence Science and Technology, Kyungpook National University, Daegu, Republic of Korea
- Cell and Matrix Research Institute, Kyungpook National University, Daegu, Republic of Korea
| | - Jeonghwa Seo
- Department of Statistics, Kyungpook National University Chilgok Hospital, Kyungpook National University, Daegu, Republic of Korea
| | - Ki Bum Park
- Department of Surgery, School of Medicine, Kyungpook National University Chilgok Hospital, Kyungpook National University, Daegu, Republic of Korea
| | - Yong Hwan Kwon
- Department of Internal Medicine, School of Medicine, Kyungpook National University Chilgok Hospital, Kyungpook National University, Daegu, Republic of Korea
| | - Han Ik Bae
- Department of Pathology, School of Medicine, Kyungpook National University Chilgok Hospital, Kyungpook National University, Daegu, 41405, Republic of Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University Chilgok Hospital, Kyungpook National University, Daegu, 41405, Republic of Korea.
| | - Moonsik Kim
- Department of Pathology, School of Medicine, Kyungpook National University Chilgok Hospital, Kyungpook National University, Daegu, 41405, Republic of Korea.
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Alberti A, Stocker G, Lordick F, Hacker UT, Kobitzsch B, Haffner I, Baiocchi GL, Zamparini M, Tiberio GAM, Baronchelli C, Caruso A, Bossi P, Berruti A. Plasma EBV DNA as a prognostic factor in EBV associated gastric cancer: a multicenter, prospective study (EBV PRESAGE study). Front Oncol 2023; 13:1276138. [PMID: 37941551 PMCID: PMC10629611 DOI: 10.3389/fonc.2023.1276138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Accepted: 10/05/2023] [Indexed: 11/10/2023] Open
Abstract
Purpose The Cancer Genome Atlas Research Network identified Epstein-Barr-Virus (EBV)-positive gastric cancer as a distinct molecular subtype. The prevalence is 8-9% and the histological examination shows pronounced lymphocytic infiltration, elevated levels of IFN-γ and consequently overexpression of PD-L1. The role of plasma EBV DNA load as a prognostic factor in patients with this cancer subtype is still to be defined. Methods and analysis The present multicenter prospective observational study "EBV PRESAGE", involving German and Italian cancer centers, aims to evaluate the prognostic role of plasma EBV DNA in EBV-related gastric cancer (GC). The objective is to study the association between plasma EBV DNA load at different consecutive time points and the patient's prognosis. Every patient with a new diagnosis of gastric cancer (including gastroesophageal junction adenocarcinoma) will be screened for Epstein-Barr encoded small Region (EBER) on tissue biopsies using in situ hybridization (ISH). If EBER ISH is positive, blood analysis for plasma EBV DNA will be conducted. The plasma EBV quantitative analysis will be centralized, and extraction, detection, and quantification of EBV DNA in plasma samples will be performed using real-time PCR. Discussion We hypothesized that plasma EBV DNA represents a non-invasive tool for monitoring EBV-related GC and might be valuable as a prognostic marker.
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Affiliation(s)
- Andrea Alberti
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia at the Azienda Socio Sanitaria Territoriale (ASST)-Spedali Civili, Brescia, Italy
| | - Gertraud Stocker
- Department of Medicine II (Oncology, Gastroenterology, Hepatology and Pulmonology), University Cancer Center Leipzig (UCCL), University of Leipzig Medical Center, Leipzig, Germany
| | - Florian Lordick
- Department of Medicine II (Oncology, Gastroenterology, Hepatology and Pulmonology), University Cancer Center Leipzig (UCCL), University of Leipzig Medical Center, Leipzig, Germany
| | - Ulrich T. Hacker
- Department of Medicine II (Oncology, Gastroenterology, Hepatology and Pulmonology), University Cancer Center Leipzig (UCCL), University of Leipzig Medical Center, Leipzig, Germany
| | - Benjamin Kobitzsch
- Department of Medicine II (Oncology, Gastroenterology, Hepatology and Pulmonology), University Cancer Center Leipzig (UCCL), University of Leipzig Medical Center, Leipzig, Germany
| | - Ivonne Haffner
- Department of Medicine II (Oncology, Gastroenterology, Hepatology and Pulmonology), University Cancer Center Leipzig (UCCL), University of Leipzig Medical Center, Leipzig, Germany
| | - Gian Luca Baiocchi
- Surgical Unit, Department of Clinical and Experimental Sciences, University of Brescia at the Azienda Socio Sanitaria Territoriale (ASST), Cremona, Italy
| | - Manuel Zamparini
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia at the Azienda Socio Sanitaria Territoriale (ASST)-Spedali Civili, Brescia, Italy
| | - Guido A. M. Tiberio
- Surgical Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia at the Azienda Socio Sanitaria Territoriale (ASST)-Spedali Civili, Brescia, Italy
| | - Carla Baronchelli
- Pathology Unit, Azienda Socio Sanitaria Territoriale (ASST)-Spedali Civili, Brescia, Italy
| | - Arnaldo Caruso
- Microbiology Unit, Department of Molecular and Translational Medicine, University of Brescia-Spedali Civili at the Azienda Socio Sanitaria Territoriale (ASST) – Spedali Civili, Brescia, Italy
| | - Paolo Bossi
- Medical Oncology and Hematology Unit, Humanitas University, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Alfredo Berruti
- Medical Oncology Unit, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia at the Azienda Socio Sanitaria Territoriale (ASST)-Spedali Civili, Brescia, Italy
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Park KB, Seo AN, Kim M. Gastric cancer with distinct Epstein-Barr virus-positive and -negative tumor components and their whole exome sequencing result: a case Report. Diagn Pathol 2023; 18:81. [PMID: 37434198 DOI: 10.1186/s13000-023-01363-3] [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: 03/23/2023] [Accepted: 06/12/2023] [Indexed: 07/13/2023] Open
Abstract
BACKGROUND Epstein-Barr virus (EBV)-associated gastric cancer exhibits distinct clinicopathologic characteristics, showing a good response to immune checkpoint inhibitors and a favorable prognosis. However, gastric cancer comprising distinct EBV-positive and -negative components in a single mass have been rarely reported, and their detailed genetic characteristics have not yet been investigated. Therefore, we reported the case of gastric cancer exhibiting distinct EBV-positive and -negative areas and further investigated its genetic characteristics. CASE PRESENTATIONS A 70-year-old man underwent distal gastrectomy for gastric cancer, which was detected during a routine health check-up. EBV-encoded RNA in situ hybridization revealed distinct EBV-positive and -negative components at each other's borders, morphologically consistent with collision tumor. We separately sequenced EBV-positive and -negative tumor areas through whole exome sequencing (WES) with matched normal tissue. Remarkably, both EBV-positive and -negative areas shared pathogenic mutations of ARID1A, KCNJ2, and RRAS2. Furthermore, they shared 92 somatic single nucleotide variants and small insertion or deletion mutations, of which 32.7% and 24.5% are EBV-positive and -negative tumor components, respectively. CONCLUSIONS WES results suggested that gastric cancer with distinct EBV-positive and -negative tumor components, formerly categorized as a collision tumor, can be clonally related. EBV-negative tumor component might be associated with loss of EBV during tumor progression.
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Affiliation(s)
- Ki Bum Park
- Department of Surgery, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, 807 Hogukno, Buk-gu, Daegu, 41404, Republic of Korea.
| | - Moonsik Kim
- Department of Pathology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, 807 Hogukno, Buk-gu, Daegu, 41404, Republic of Korea.
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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: 25] [Impact Index Per Article: 12.5] [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.
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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.
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Gomez K, Schiavoni G, Nam Y, Reynier JB, Khamnei C, Aitken M, Palmieri G, Cossu A, Levine A, van Noesel C, Falini B, Pasqualucci L, Tiacci E, Rabadan R. Genomic landscape of virus-associated cancers. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.02.14.23285775. [PMID: 36824731 PMCID: PMC9949223 DOI: 10.1101/2023.02.14.23285775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/18/2023]
Abstract
It has been estimated that 15%-20% of human cancers are attributable to infections, mostly by carcinogenic viruses. The incidence varies worldwide, with a majority affecting developing countries. Here, we present a comparative analysis of virus-positive and virus-negative tumors in nine cancers linked to five viruses. We find that virus-positive tumors occur more frequently in males and show geographical disparities in incidence. Genomic analysis of 1,658 tumors reveals virus-positive tumors exhibit distinct mutation signatures and driver gene mutations and possess a lower somatic mutation burden compared to virus-negative tumors of the same cancer type. For example, compared to the respective virus-negative counterparts, virus-positive cases across different cancer histologies had less often mutations of TP53 and deletions of 9p21.3/ CDKN2 A- CDKN1A ; Epstein-Barr virus-positive (EBV+) gastric cancer had more frequent mutations of EIF4A1 and ARID1A and less marked mismatch repair deficiency signatures; and EBV-positive cHL had fewer somatic genetic lesions of JAK-STAT, NF-κB, PI3K-AKT and HLA-I genes and a less pronounced activity of the aberrant somatic hypermutation signature. In cHL, we also identify germline homozygosity in HLA class I as a potential risk factor for the development of EBV-positive Hodgkin lymphoma. Finally, an analysis of clinical trials of PD-(L)1 inhibitors in four virus-associated cancers suggested an association of viral infection with higher response rate in patients receiving such treatments, which was particularly evident in gastric cancer and head and neck squamous cell carcinoma. These results illustrate the epidemiological, genetic, prognostic, and therapeutic trends across virus-associated malignancies.
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9
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Epstein-Barr Virus-Positive Lymphoepithelioma-Like Carcinoma in Celiac Disease. ACG Case Rep J 2023; 10:e00970. [PMID: 36777463 PMCID: PMC9911188 DOI: 10.14309/crj.0000000000000970] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 12/27/2022] [Indexed: 02/14/2023] Open
Abstract
Lymphoepithelioma-like carcinoma (LELC) is a rare lymphoproliferative malignancy that has been described in many organs over the years. LELC in the duodenum has rarely been described in literature. This article aims to present a rare cause of melena in a young man and the diagnostic challenge that ensued to throw more light on this rare disease. In this article, we describe a 43-year-old man who presented with melena and weight loss and was subsequently diagnosed with LELC after multiple endoscopic biopsies. The patient was also found to have celiac disease in association with his LELC.
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10
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Cheng R, Xu Y, Yue B. Short-term outcomes of three rare cases of intramucosal Epstein-Barr virus-associated gastric cancer treated with endoscopic submucosal dissection. J Int Med Res 2022; 50:3000605221115162. [PMID: 35915584 PMCID: PMC9350515 DOI: 10.1177/03000605221115162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Epstein-Barr virus-associated gastric cancer (EBVaGC) is a subtype of gastric cancer morphologically characterized by massive lymphocyte infiltration. We herein report the short-term outcomes of three rare cases of intramucosal EBVaGC treated with endoscopic submucosal dissection (ESD). Histologically, the lesions exhibited poorly to moderately differentiated tubular adenocarcinoma without lymphovascular invasion, and in situ hybridization revealed EBV-encoded small RNA. Helicobacter pylori infection was not found in any of the lesions. During the 3 to 12 months of follow-up following ESD, none of the ESD-treated patients showed evidence of local recurrence or distant metastases. Essential characteristics of intramucosal EBVaGC may include lymphocyte infiltration into the mucosal stroma or cancer nests as well as the presence of a lace pattern. We believe that ESD might be a safe and suitable treatment method for intramucosal EBVaGC that avoids needless surgery, particularly in patients with severe comorbidities or a high operational risk.
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Affiliation(s)
- Rui Cheng
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yao Xu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Bing Yue
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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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.
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12
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Ho WJ, Danilova L, Lim SJ, Verma R, Xavier S, Leatherman JM, Sztein MB, Fertig EJ, Wang H, Jaffee E, Yarchoan M. Viral status, immune microenvironment and immunological response to checkpoint inhibitors in hepatocellular carcinoma. J Immunother Cancer 2021; 8:jitc-2019-000394. [PMID: 32303615 PMCID: PMC7204805 DOI: 10.1136/jitc-2019-000394] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2020] [Indexed: 12/12/2022] Open
Abstract
Background and aims Immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have clinical activity in hepatocellular carcinoma (HCC), but only a subset of patients respond to these therapies, highlighting a need for novel biomarkers to improve clinical benefit. HCC usually occurs in the setting of liver cirrhosis from chronic hepatitis B or C viral infection, but the effects of viral status on the tumor immune microenvironment and clinical responses to ICIs in HCC remains unclear. Methods We conducted a meta-analysis to estimate the objective response rates for PD-1/PD-L1 inhibitors in virally-infected and uninfected patients, and examined the effects of viral etiology on the tumor microenvironment using data from The Cancer Genome Atlas, as well as peripheral blood responses using an independent cohort of patients studied by mass cytometry (cytometry by time-of-flight (CyTOF)). Results Meta-analysis comparing objective response rates (ORR) between virally-infected and uninfected patients showed no clinically meaningful difference (absolute difference of ORR in virally-infected vs uninfected=−1.4%, 95% CI: −13.5% to 10.6%). There was no relationship between viral etiology on features of the tumor immune microenvironment that are known to modulate responses to PD-1/PD-L1 inhibitors, and the tumor mutational burden was similar between virally-infected and uninfected HCC. RNA sequencing of tissue-resident T cell and B cell repertoires similarly showed no effect of viral status on their diversity. CyTOF analysis of peripheral blood specimens further demonstrated similar expression of immune-related markers in response to PD-1 inhibitor therapy in virally-infected and uninfected HCC. Conclusion There is no significant effect of viral etiology on the tumor immune microenvironment in HCC, and viral status should not be used as a criterion to select patients for PD-1/PD-L1 therapy.
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Affiliation(s)
- Won Jin Ho
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Ludmila Danilova
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Division of Biostatistics and Bioinformatics, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
| | - Su Jin Lim
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Rohan Verma
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Stephanie Xavier
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - James M Leatherman
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Marcelo B Sztein
- Center for Vaccine Development, University of Maryland, Baltimore, Maryland, USA.,Molecular Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Elana J Fertig
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Division of Biostatistics and Bioinformatics, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA.,Institute for Computational Medicine, Mathematical Institute for Data Science, Johns Hopkins University, Baltimore, MD, United States
| | - Hao Wang
- Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Division of Biostatistics and Bioinformatics, Johns Hopkins Medicine Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland, USA
| | - Elizabeth Jaffee
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Pancreatic Cancer Precision Medicine Program, Skip Viragh Center for Pancreatic Cancer, Johns Hopkins University School of Medicine, Baltimore, MD, United States
| | - Mark Yarchoan
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA .,Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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13
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Clinicopathological Features and Prognostic Implication of Gastric Carcinoma with Lymphoid Stroma. Gastroenterol Res Pract 2020; 2020:6628412. [PMID: 33343655 PMCID: PMC7728477 DOI: 10.1155/2020/6628412] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/04/2020] [Accepted: 11/15/2020] [Indexed: 12/14/2022] Open
Abstract
Methods This study included 34 eligible studies and 1757 GCLSs. The clinicopathologic characteristics of GCLS were investigated from eligible studies, and the meta-analysis was performed. In addition, we compared the survival rates between GCLS and non-GCLS. Results The estimated rate of GCLS was 0.062 (95% confidence interval (CI) 0.040-0.097). GCLS was significantly correlated with the diffuse type of Lauren's classification, proximal tumor location, less-frequent lymphatic invasion, and lower pTNM stage. However, there was no significant difference in age, sex, tumor differentiation, vascular invasion, perineural invasion, pT stage, lymph node metastasis, and distant metastasis between GCLS and non-GCLS patients. EBV positive rates in GCLS and non-GCLS patients were 0.723 (95% CI 0.643-0.791) and 0.064 (95% CI 0.039-0.103), respectively. HER2 expression in GCLS was significantly lower than that in non-GCLS. GCLS patients had a more favorable prognosis than that of non-GCLS patients (hazard ratio 0.500, 95% CI 0.305-0.821). Conclusion GCLS comprised 6.2% of overall GC and more frequent in the proximal portion of the stomach. Since GCLS was associated with better prognosis, the histologic finding can be useful for predicting the patient's prognosis.
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14
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Sadato D, Ogawa M, Hirama C, Hishima T, Horiguchi S, Harada Y, Shimoyama T, Itokawa M, Ohashi K, Oboki K. Potential prognostic impact of EBV RNA-seq reads in gastric cancer: a reanalysis of The Cancer Genome Atlas cohort. FEBS Open Bio 2020; 10:455-467. [PMID: 31991047 PMCID: PMC7050242 DOI: 10.1002/2211-5463.12803] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 01/21/2020] [Accepted: 01/24/2020] [Indexed: 01/18/2023] Open
Abstract
Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC), whose prognosis remains controversial, is diagnosed by in situ hybridization of EBV-derived EBER1/2 small RNAs. In The Cancer Genome Atlas (TCGA) Stomach Adenocarcinoma (STAD) project, the EBV molecular subtype was determined through a combination of multiple next-generation sequencing methods, but not by the gold standard in situ hybridization method. This leaves unanswered questions regarding the discordance of EBV positivity detected by different approaches and the threshold of sequencing reads. Therefore, we reanalyzed the TCGA-STAD RNA sequencing (RNA-seq) dataset including 375 tumor and 32 normal samples, using our analysis pipeline. We defined a reliable threshold for EBV-derived next-generation sequencing reads by mapping them to the EBV genome with three different random arbitrary alignments. We analyzed the prognostic impact of EBV status on the histopathological subtypes of gastric cancer. EBV-positive cases identified by reanalysis comprised nearly half of the cases (49.6%) independent from infiltrating lymphocyte signatures, and showed significantly longer overall survival for adenocarcinomas of the 'not-otherwise-specified' type [P = 0.016 (log-rank test); hazard ratios (HR): 0.476; 95% CI: 0.260-0.870, P = 0.016 (Cox univariate analysis)], but shorter overall survival for the tubular adenocarcinoma type [P = 0.005 (log-rank test); HR: 3.329; 95% CI: 1.406-7.885, P = 0.006 (Cox univariate analysis)]. These results demonstrate that the EBV positivity rates were higher when determined by RNA-seq than when determined by EBER1/2 in situ hybridization. The RNA-seq-based EBV positivity demonstrated distinct results for gastric cancer prognosis depending on the histopathological subtype, suggesting its potential to be used in clinical prognoses.
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Affiliation(s)
- Daichi Sadato
- Division of HematologyTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalBunkyo‐kuJapan
- Center for Medical Research CooperationTokyo Metropolitan Institute of Medical ScienceSetagaya‐kuJapan
- Divisions of Clinical Research SupportTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalBunkyo-kuJapan
| | - Mina Ogawa
- Center for Medical Research CooperationTokyo Metropolitan Institute of Medical ScienceSetagaya‐kuJapan
- Divisions of Clinical Research SupportTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalBunkyo-kuJapan
- Department of Medical OncologyTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalBunkyo‐kuJapan
| | - Chizuko Hirama
- Division of HematologyTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalBunkyo‐kuJapan
- Center for Medical Research CooperationTokyo Metropolitan Institute of Medical ScienceSetagaya‐kuJapan
- Divisions of Clinical Research SupportTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalBunkyo-kuJapan
| | - Tsunekazu Hishima
- Department of PathologyTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalBunkyo‐kuJapan
| | - Shin‐Ichiro Horiguchi
- Department of PathologyTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalBunkyo‐kuJapan
| | - Yuka Harada
- Divisions of Clinical Research SupportTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalBunkyo-kuJapan
| | - Tatsu Shimoyama
- Department of Medical OncologyTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalBunkyo‐kuJapan
| | - Masanari Itokawa
- Center for Medical Research CooperationTokyo Metropolitan Institute of Medical ScienceSetagaya‐kuJapan
| | - Kazuteru Ohashi
- Division of HematologyTokyo Metropolitan Cancer and Infectious Diseases Center Komagome HospitalBunkyo‐kuJapan
| | - Keisuke Oboki
- Center for Medical Research CooperationTokyo Metropolitan Institute of Medical ScienceSetagaya‐kuJapan
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15
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Kim HS, Shin SJ, Beom SH, Jung M, Choi YY, Son T, Kim HI, Cheong JH, Hyung WJ, Noh SH, Chung H, Park JC, Shin SK, Lee SK, Lee YC, Koom WS, Lim JS, Chung HC, Rha SY, Kim H. Comprehensive expression profiles of gastric cancer molecular subtypes by immunohistochemistry: implications for individualized therapy. Oncotarget 2018; 7:44608-44620. [PMID: 27331626 PMCID: PMC5190122 DOI: 10.18632/oncotarget.10115] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Accepted: 05/29/2016] [Indexed: 12/20/2022] Open
Abstract
Gastric cancer (GC) is a leading cause of death. We aim to establish a clinically relevant assay that encompasses recent molecular classifications and provides useful clinical information in a large cohort of GC patients. A consecutive series of 438 GC patients that underwent palliative chemotherapy between 2014 and 2015 were assessed using 10 GC panels: EBER in-situ hybridization, immunohistochemistry for mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6), receptor tyrosine kinases (RTKs; HER2, EGFR, and MET), PTEN, and p53 protein. With a median of one aberration, 3.3 % of samples analyzed were Epstein-Barr virus (EBV)-positive; 4.8%, MMR-deficient. RTKs were overexpressed in 218 patients; EGFR was most commonly overexpressed (39.9%), followed by HER2 (13.5%) and MET (12.1%). Furthermore, 2.5 % and 10.7 % of cases had simultaneous overexpression of three and two RTKs, respectively. p53 overexpression/null tumors were identified in 259 patients (59.1%), and PTEN loss was identified in 89 patients (20.3%). EBV-positivity was mutually exclusive with MMR-deficiency, predominantly identified in male patients, and these tumors were undifferentiated with proximal location. p53 mutant type was significantly found predominantly in the EBV-negative (60.6% vs 14.3%, P=0.001) and HER2-positive (78.0% vs 56.2%, P=0.002) groups. We described a molecular spectrum of distinct GC subtypes using clinically applicable assay. This assay will provide a convenient screening tool and facilitate the development of targeted agents in clinical trials.
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Affiliation(s)
- Hyo Song Kim
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Su-Jin Shin
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seung-Hoon Beom
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Minkyu Jung
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yoon Young Choi
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Taeil Son
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyoung-Il Kim
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jae-Ho Cheong
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Woo Jin Hyung
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung Hoon Noh
- Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyunsoo Chung
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jun Chul Park
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung Kwan Shin
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sang Kil Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yong Chan Lee
- Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Woong Sub Koom
- Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Joon Seok Lim
- Department of Radiology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyun Cheol Chung
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sun Young Rha
- Division of Medical Oncology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, Seoul, Republic of Korea
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16
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Wang W, Wang K, Chen Z, Chen L, Guo W, Liao P, Rotroff D, Knepper TC, Liu Z, Zhang W, Mcleod HL, He Y. Immunoclassification characterized by CD8 and PD-L1 expression is associated with the clinical outcome of gastric cancer patients. Oncotarget 2018; 9:12164-12173. [PMID: 29552300 PMCID: PMC5844736 DOI: 10.18632/oncotarget.24037] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2017] [Accepted: 11/15/2017] [Indexed: 12/13/2022] Open
Abstract
Background Gastric cancer (GC) is a major cause of cancer deaths, especially in Eastern Asia. Current classification systems, including the WHO, Lauren, and TCGA, have clarified the pathological and molecular profiles of GC. However, these classifications lack an association with clinical outcome and guidance for medication selection. Objective We aimed to identify a new immunoclassification for GC to better predict patient prognosis and aid in patient selection for immunotherapy. Results For all samples, 35 were EBV positive (+) and 112 were EBV negative (-). EBV infection was associated with the number of CD3+ T cells (OR = 2.91 95% CI 1.27-6.68, p = 0.012) and PD-L1 expression in TME (OR = 2.57, 95% CI 1.13–5.82, p = 0.024). EBV+ patients showed a poor overall survival (OS) compared with EBV- patients (HR = 2.37; 95% CI, 1.03–5.41; p = 0.011). Importantly, WIR patients lived significantly shorter than SIR patients with high CD8+ T cells and low PD-L1 expression (HR = 3.37; 95% CI, 1.63–6.97; p = 0.015). Materials and Methods 147 formalin-fixed and paraffin-embedded (FFPE) samples of GC were obtained. Epstein-Barr virus (EBV) infection was measured. Immune markers including CD3, CD8 and PD-L1 were detected by immunohistochemistry (IHC) at tumor infiltration area (TI) and invasive margin area (IM) in tumor microenvironment (TME). PD-L1 expression was assessed by immunoreactive score (IRS) system. For immunoclassification, patients were classified into two subgroups: strong immunoreaction (SIR) and weak immunoreaction (WIR) defined by the number of CD8+ T cells and PD-L1 expression in TI. Conclusions In this study, we suggest a new immunoclassification for gastric cancer which is associated with patient outcome and may provide a way to guide immunotherapy in the future.
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Affiliation(s)
- Weili Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China
| | - Kuansong Wang
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zihua Chen
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ling Chen
- Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wei Guo
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Ping Liao
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China
| | - Daniel Rotroff
- Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA
| | - Todd C Knepper
- Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA
| | - Zhaoqian Liu
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China
| | - Wei Zhang
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China
| | - Howard L Mcleod
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China.,Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA
| | - Yijing He
- Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, China.,Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA
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17
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Kim Y, Kim HS, Park JS, Kim CJ, Kim WH. Identification of Epstein-Barr Virus in the Human Placenta and Its Pathologic Characteristics. J Korean Med Sci 2017; 32:1959-1966. [PMID: 29115077 PMCID: PMC5680494 DOI: 10.3346/jkms.2017.32.12.1959] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 09/03/2017] [Indexed: 12/27/2022] Open
Abstract
Epstein-Barr virus (EBV), a common pathogen in humans, is suspected as the cause of multiple pregnancy-related pathologies including depression, preeclampsia, and stillbirth. Moreover, transmission of EBV through the placenta has been reported. However, the focus of EBV infection within the placenta has remained unknown to date. In this study, we proved the expression of latent EBV genes in the endometrial glandular epithelial cells of the placenta and investigated the cytological characteristics of these cells. Sixty-eight placentas were obtained from pregnant women. Tissue microarray was constructed. EBV latent genes including EBV-encoding RNA-1 (EBER1), Epstein-Barr virus nuclear antigen 1 (EBNA1), late membrane antigen (LMP1), and RPMS1 were detected with silver in situ hybridization and/or mRNA in situ hybridization. Nuclear features of EBV-positive cells in EBV-infected placenta were compared with those of EBV-negative cells via image analysis. Sixteen placentas (23.5%) showed positive expression of all 4 EBV latent genes; only the glandular epithelial cells of the decidua showed EBV gene expression. EBV infection status was not significantly correlated with maternal, fetal, or placental factors. The nuclei of EBV-positive cells were significantly larger, longer, and round-shaped than those of EBV-negative cells regardless of EBV-infection status of the placenta. For the first time, evidence of EBV gene expression has been shown in placental tissues. Furthermore, we have characterized its cytological features, allowing screening of EBV infection through microscopic examination.
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Affiliation(s)
- Younghoon Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University, Seoul, Korea
| | - Hye Sung Kim
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
| | - Joong Shin Park
- Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul, Korea
| | - Chong Jai Kim
- Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
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18
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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.
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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
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Shen H, Zhong M, Wang W, Liao P, Yin X, Rotroff D, Knepper TC, Mcleod HL, Zhou C, Xie S, Li W, Xu B, He Y. EBV infection and MSI status significantly influence the clinical outcomes of gastric cancer patients. Clin Chim Acta 2017; 471:216-221. [PMID: 28601671 DOI: 10.1016/j.cca.2017.06.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 06/02/2017] [Accepted: 06/06/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Epstein-Barr virus (EBV) and microsatellite instability (MSI) are associated with the carcinogenesis of many kinds of tumors, including gastric cancer (GC). However, the impact of EBV and MSI status on the prognosis of stage II and III GC is still unclear. The aim of this study was to find out the prognostic value of EBV and MSI status in a population of GC patients from Southern China. METHODS Patients were genotyped for EBV infection based on the detection of EBV DNA from the formalin-fixed paraffin-embedded (FFPE) specimens. Sequentially, MSI status was measured by direct sequencing. Clinical characteristics and overall survival (OS) were analyzed in 202 GC patients. Additionally, the association of EBV and MSI status with chemotherapy-based toxicity was analyzed in 324 GC patients. RESULTS The survival analysis revealed EBV+ patients had a poorer OS than EBV- patients (HR=1.75, 95% CI: 1.08-2.82, FDR p=0.04). This survival advantage for EBV- patients was also found in patients <60y (FDR p=0.04) and patient with stage III disease (FDR p=0.04). CONCLUSIONS EBV infection and MSI status are associated with overall survival of gastric cancer patients. However, traditional chemotherapy showed no difference on outcome of patients in EBV and MSI subgroups.
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Affiliation(s)
- Hua Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China; Gastroenterology and Urology Department, Hunan Cancer hospital, Xiangya School of Medicine, Central South University, Changsha, China
| | - Meizuo Zhong
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Weili Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China
| | - Ping Liao
- Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China
| | - Xianli Yin
- Gastroenterology and Urology Department, Hunan Cancer hospital, Xiangya School of Medicine, Central South University, Changsha, China
| | - Daniel Rotroff
- Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA
| | - Todd C Knepper
- Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA
| | - Howard L Mcleod
- Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China; Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA
| | - Chengfang Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China
| | - Shangchen Xie
- Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China
| | - Wei Li
- Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China
| | - Biaobo Xu
- Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China.
| | - Yijing He
- Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China; Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA.
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朱 晓, 李 夏, 李 素, 于 红. EBV相关性胃癌研究进展. Shijie Huaren Xiaohua Zazhi 2017; 25:1375-1381. [DOI: 10.11569/wcjd.v25.i15.1375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
胃癌细胞中存在Epstein-Barr病毒(Epstein-Barr virus, EBV)者被称为EBV相关性胃癌(Epstein-Barr virus-associated gastric carcinoma, EBVaGC). 近年来EBVaGC作为一种独特的分子亚型疾病逐渐被人们所认知, 全球胃癌患者中平均有10%者为EBVaGC. 本文对EBVaGC近年来在流行病学、临床病理特征、发病机制、治疗及预后等方面的研究进展作一综述. 但目前对EBVaGC的研究尚不明确, 且尚无临床诊疗规范与共识, 也带来了新的挑战和机遇.
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Kim DH, Chang MS, Yoon CJ, Middeldorp JM, Martinez OM, Byeon SJ, Rha SY, Kim SH, Kim YS, Woo JH. Epstein-Barr virus BARF1-induced NFκB/miR-146a/SMAD4 alterations in stomach cancer cells. Oncotarget 2016; 7:82213-82227. [PMID: 27438138 PMCID: PMC5347686 DOI: 10.18632/oncotarget.10511] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Accepted: 05/12/2016] [Indexed: 12/21/2022] Open
Abstract
Epstein-Barr virus (EBV)-encoded BamHI-A rightward frame 1 (BARF1) is a putative viral oncogene in EBV-infected stomach cancer. The aim of the present study was to investigate BARF1-induced cellular protein and microRNA alterations. In this study, BARF1-expressing stomach cancer cells showed a high rate of proliferation, high levels of NFκB, and miR-146a upregulation, which was reversed by NFκB knockdown. During BARF1-induced NFκB upregulation, hCSF1 receptor level was unchanged. Knockdown of BARF1 in the naturally EBV-infected YCCEL1 stomach cancer cells suppressed cell proliferation, and downregulated NFκB and miR-146a. SMAD4 was identified as a miR-146a target and was downregulated in BARF1-expressing cells, whereas SMAD4 expression was restored by anti-miR-146a. Knockdown of BARF1 in YCCEL1 cells upregulated SMAD4, and this effect was reversed by miR-146a overexpression. Transfection of BARF1-expressing cells with pCEP4-SMAD4 abolished the cell proliferating effect of BARF1. In stomach cancer tissues, miR-146a was expressed at higher levels, and more frequent NFκB nuclear positivity immunohistochemically, but not of SMAD4 nuclear loss was found in the EBV-positive group compared with the EBV-negative group. In conclusion, EBV-encoded BARF1 promotes cell proliferation in stomach cancer by upregulating NFκB and miR-146a and downregulating SMAD4, thereby contributing to EBV-induced stomach cancer progression.
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Affiliation(s)
- Dong Ha Kim
- Asan Institute for Life Sciences, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Mee Soo Chang
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Chan Jin Yoon
- Asan Institute for Life Sciences, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jaap M. Middeldorp
- Department of Pathology, VU University Medical Center, Amsterdam, the Netherlands
| | - Olivia M. Martinez
- Department of Surgery/Division of Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA, USA
| | - Sun-ju Byeon
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Sun Young Rha
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Sung Han Kim
- Asan Institute for Life Sciences, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yang Soo Kim
- Asan Institute for Life Sciences, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jun Hee Woo
- Asan Institute for Life Sciences, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Liu Y, Yang W, Pan Y, Ji J, Lu Z, Ke Y. Genome-wide analysis of Epstein-Barr virus (EBV) isolated from EBV-associated gastric carcinoma (EBVaGC). Oncotarget 2016; 7:4903-14. [PMID: 26716899 PMCID: PMC4826252 DOI: 10.18632/oncotarget.6751] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Accepted: 11/26/2015] [Indexed: 12/29/2022] Open
Abstract
Epstein-Barr virus (EBV) is linked to the development of a variety of malignancies, including EBV-associated gastric carcinoma (EBVaGC). In this study, EBVaGC was detected in 15 (7.3%) of 206 GC cases. To identify the EBV genomic variation, EBV genomic sequences isolated from 9 EBVaGC biopsy specimens were successfully retrieved, designated EBVaGC1 to EBVaGC9. By comparative analysis of these strains with another 6 completely sequenced EBV strains, EBV-wild type, B95–8, AG876, GD1, GD2, and HKNPC1, it was demonstrated that EBVaGC1 to 9 were most closely related to the GD1 strain. Phylogenetic analysis of the GC biopsy specimen-derived EBV (GC-EBV) genomes was subsequently performed to assess their genomic diversity and it exhibited the greatest divergence from the type 2 strain, AG876. Compared with the reference EBV strain GD1, they harbored 961 variations in total, including 919 substitutions, 23 insertions, and 19 deletions. Single nucleotide polymorphism (SNP) density varied substantially across all known open reading frames and was highest in latency-associated genes. Moreover, we identified 2 interstrain recombinants at the EBNA1 locus, which provided a further mechanism for the generation of diversity. Some T-cell epitope sequences in EBNA1 and LMP2A genes showed extensive variation across strains, which implied their importance in the development of vaccines and T-cell therapy. In conclusion, we reported the first genome-wide view of sequence variation of EBV isolated from primary EBVaGC biopsy specimens, which might serve as an effective method for further understanding the genomic variations contribute to EBVaGC carcinogenesis and treatment.
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Affiliation(s)
- Ying Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Genetics, Peking University Cancer Hospital and Institute, Haidian, Beijing, China
| | - Wenjun Yang
- Key Laboratory of Reproduction and Heredity of Ningxia Region, Medical Oncology Department of General Hospital, Ningxia Medical University, Yinchuan, Ningxia, China
| | - Yaqi Pan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Genetics, Peking University Cancer Hospital and Institute, Haidian, Beijing, China
| | - Jiafu Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Haidian, Beijing, China
| | - Zheming Lu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Genetics, Peking University Cancer Hospital and Institute, Haidian, Beijing, China
| | - Yang Ke
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Laboratory of Genetics, Peking University Cancer Hospital and Institute, Haidian, Beijing, China
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23
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A protein and mRNA expression-based classification of gastric cancer. Mod Pathol 2016; 29:772-84. [PMID: 27032689 DOI: 10.1038/modpathol.2016.55] [Citation(s) in RCA: 105] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 02/09/2016] [Accepted: 02/10/2016] [Indexed: 12/14/2022]
Abstract
The overall survival of gastric carcinoma patients remains poor despite improved control over known risk factors and surveillance. This highlights the need for new classifications, driven towards identification of potential therapeutic targets. Using sophisticated molecular technologies and analysis, three groups recently provided genetic and epigenetic molecular classifications of gastric cancer (The Cancer Genome Atlas, 'Singapore-Duke' study, and Asian Cancer Research Group). Suggested by these classifications, here, we examined the expression of 14 biomarkers in a cohort of 146 gastric adenocarcinomas and performed unsupervised hierarchical clustering analysis using less expensive and widely available immunohistochemistry and in situ hybridization. Ultimately, we identified five groups of gastric cancers based on Epstein-Barr virus (EBV) positivity, microsatellite instability, aberrant E-cadherin, and p53 expression; the remaining cases constituted a group characterized by normal p53 expression. In addition, the five categories correspond to the reported molecular subgroups by virtue of clinicopathologic features. Furthermore, evaluation between these clusters and survival using the Cox proportional hazards model showed a trend for superior survival in the EBV and microsatellite-instable related adenocarcinomas. In conclusion, we offer as a proposal a simplified algorithm that is able to reproduce the recently proposed molecular subgroups of gastric adenocarcinoma, using immunohistochemical and in situ hybridization techniques.
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Epstein-Barr virus infection serves as an independent predictor of survival in patients with lymphoepithelioma-like gastric carcinoma. Gastric Cancer 2016; 19:852-9. [PMID: 26265391 DOI: 10.1007/s10120-015-0524-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 07/22/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND The pathogenesis and clinicopathologic characteristics of Epstein-Barr virus (EBV)-negative lymphoepithelioma-like gastric carcinoma (LELC) are still unclear. In addition, it remains controversial whether EBV infection itself affects the prognosis of LELC. METHODS Between 1995 and 2011, 145 LELC patients (124 patients with EBV infection and 21 patients without EBV infection) underwent radical gastrectomy with D2 lymph node dissection. The clinicopathologic features and prognosis of EBV-negative LELC cases were compared with those of EBV-positive LELC cases. The median duration of follow-up after surgery was 55 months. Microsatellite instability (MSI) analysis was performed on 20 EBV-negative LELC cases. RESULTS EBV-negative LELC accounted for 14.5 % of the total LELC cases. EBV-negative LELC was significantly associated with older age, female sex, advanced T stage, and advanced American Joint Committee on Cancer (AJCC) tumor stage compared with EBV-positive LELC. In univariate analysis, patients with EBV-negative LELC had significantly shorter overall, disease-specific, and recurrence-free survival than those with EBV-positive LELC. The 5-year overall survival rates were 81.0 % for patients with EBV-negative LELC and 96.2 % for patients with EBV-positive LELC. In a Cox proportional hazards model, EBV infection, age, and AJCC tumor stage were identified as independent predictors of overall survival. MSI-high, MSI-low, and microsatellite-stable tumors accounted for 25, 10, and 65 % of EBV-negative LELC cases, respectively. MSI status did not affect the prognosis of EBV-negative LELC cases. CONCLUSIONS EBV infection serves as an independent predictor of survival in patients with LELC. EBV-negative LELC exhibited clinicopathologic features and prognosis distinct from those of EBV-positive LELC.
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25
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Cho J, Kang MS, Kim KM. Epstein-Barr Virus-Associated Gastric Carcinoma and Specific Features of the Accompanying Immune Response. J Gastric Cancer 2016; 16:1-7. [PMID: 27104020 PMCID: PMC4834615 DOI: 10.5230/jgc.2016.16.1.1] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 03/14/2016] [Indexed: 12/13/2022] Open
Abstract
Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is one of the four subtypes of gastric carcinoma (GC), as defined by the novel classification recently proposed by The Cancer Genome Atlas. EBVaGC has several clinicopathological features such as longer survival and higher frequency of lymphoepithelioma-like carcinoma (LELC) and carcinoma with Crohn's disease-like lymphoid reaction that distinguish it from EBV-negative GC. The intensity and pattern of host cellular immune response in GC have been found to significantly correlate with the prognosis of patients with GC, suggesting that immune reaction and tumor microenvironment have critical roles in the progression of GC, and in particular, EBVaGC. Here, we reviewed the cellular and molecular mechanisms underlying prominent immune reactions in patients with EBVaGC. In EBVaGC, deregulation of the expression of immune response-related genes promotes marked intra- or peritumoral immune cell infiltration. The expression of programmed death receptor-ligand 1 is known to be increased in EBVaGC, and therefore, it has been proposed as a favorable prognostic factor for patients with EBVaGC, albeit some data supporting this claim are controversial. Overall, the underlying mechanisms and clinical significance of the host cellular immune response in patients with EBVaGC have not been thoroughly elucidated. Therefore, further research is necessary to better understand the role of tumor microenvironment in EBVaGC.
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Affiliation(s)
- Junhun Cho
- Department of Pathology & Translational Genomics, Samsung Medical Center, Seoul, Korea
| | - Myung-Soo Kang
- Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyoung-Mee Kim
- Department of Pathology & Translational Genomics, Samsung Medical Center, Seoul, Korea
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26
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Rymbai ML, Ramalingam VV, Samarasan I, Chandran BS, Mathew G, Jerobin J, Abraham AM, Sachithanandham J, Kannangai R. Frequency of Epstein--Barr virus infection as detected by messenger RNA for EBNA 1 in histologically proven gastric adenocarcinoma in patients presenting to a tertiary care center in South India. Indian J Med Microbiol 2016; 33:369-73. [PMID: 26068337 DOI: 10.4103/0255-0857.158556] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Epstein-Barr virus (EBV)-associated gastric carcinoma is a relatively uncommon entity detected in approximately 10% of gastric adenocarcinoma. OBJECTIVE The purpose of this study is to estimate the frequency of EBV-associated gastric carcinoma and also to assess the nature of presentation, any significant difference between this subgroup and EBV-negative gastric adenocarcinomas with respect to age and sex predilection, lymph nodal status, site of presentation. MATERIALS AND METHODS We prospectively analyzed 100 cases of gastric adenocarcinoma who underwent either a partial or total gastrectomy during the period from March 2010 to August 2011. The tumour and the corresponding normal gastric tissue from the same patient were analyzed for the presence of Epstein-Barr nuclear antigen 1 (EBNA1) messenger ribonucleic acid (mRNA) by real-time polymerase chain reaction (PCR). RESULT EBV was detected in 6% cases of gastric adenocarcinoma. All the positive patients were males. The majority of cases involved the proximal stomach and there was variable lymph nodal involvement. CONCLUSION Our study endorses that there is an association between EBV infection and gastric adenocarcinoma in the Indian population. There was no significant difference between this subgroup and EBV-negative gastric adenocarcinomas with respect to age and sex predilection, lymph nodal status and site of presentation. Short-term follow-up of this subgroup of patients seems to indicate a good overall prognosis after appropriate treatment. However, a larger study with long-term follow-up is needed to further establish the role of EBV in gastric adenocarcinoma in this study population.
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Affiliation(s)
| | | | | | | | | | | | | | | | - R Kannangai
- Department of Clinical Virology, Christian Medical College, Vellore, Tamil Nadu, India
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Choi E, Byeon SJ, Kim SH, Lee HJ, Kwon HJ, Ahn H, Kim DH, Chang MS. Implication of Leptin-Signaling Proteins and Epstein-Barr Virus in Gastric Carcinomas. PLoS One 2015; 10:e0130839. [PMID: 26147886 PMCID: PMC4493019 DOI: 10.1371/journal.pone.0130839] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2015] [Accepted: 05/26/2015] [Indexed: 02/07/2023] Open
Abstract
We investigated the clinicopathological implications of leptin-signaling proteins and Epstein-Barr virus (EBV)-infection status in gastric carcinomas. Immunohistochemistry for leptin signalling-related proteins (leptin, leptin-receptor, pSTAT3, ERK, pAkt, mTOR and HIF-1 alpha), and in situ hybridization for EBV-encoded small RNAs was performed in 343 cases of gastric carcinomas. The siRNA against leptin-receptor was transfected into three stomach cancer cell lines, and western blot for caspase 3 was performed. The TNM stage was a prognostic factor in all 343 patients, and was negatively correlated with expression of leptin, pSTAT3, ERK, pAkt, mTOR and HIF-1 alpha (P < 0.05). Leptin-receptor expression was correlated with poor survival in 207 patients of the advanced gastric cancer (AGC) subgroup, 139 of the Lauren diffuse group, and in 160 patients with lymph node metastasis (P < 0.05, respectively). Additionally, in stomach cancer cells, cleaved caspase 3 level increased by leptin-receptor inhibition, that is, apoptosis increased. Interestingly, EBV-positive AGC (n = 29) tended to show better survival of patients than EBV-negative AGC (n = 178) (P = 0.06). pAkt expression was related with a good survival of 32 patients (9%) in the EBV-positive subgroup, but was not an independent prognostic factor. Among, leptin signaling-related proteins, expressions of leptin-receptor and mTOR were different between EBV-positive subgroup and EBV-negative subgroup (P < 0.05, respectively). In conclusion, leptin-signaling proteins and EBV status show different significance on patient survival, according to subsets of gastric carcinomas. The leptin-receptor may predict poor patient prognosis in the AGC, Lauren diffuse and lymph node metastasis subgroups, while EBV-positive status can show a good prognosis in the AGC. Each leptin signaling-related protein may be differently involved in carcinogenesis of EBV-negative and EBV-positive subsets.
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Affiliation(s)
- Euno Choi
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Sun-ju Byeon
- Department of Surgery, Seoul National University Boramae Hospital, Seoul, Korea
| | - Soo Hee Kim
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Ju Lee
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hyeong Ju Kwon
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - HyeSeong Ahn
- Department of Surgery, Seoul National University Boramae Hospital, Seoul, Korea
| | - Dong Ha Kim
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Mee Soo Chang
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
- * E-mail:
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28
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Huang SC, Ng KF, Chen KH, Hsu JT, Liu KH, Yeh TS, Chen TC. Prognostic factors in Epstein-Barr virus-associated stage I-III gastric carcinoma: implications for a unique type of carcinogenesis. Oncol Rep 2014; 32:530-8. [PMID: 24899228 DOI: 10.3892/or.2014.3234] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2014] [Accepted: 05/09/2014] [Indexed: 11/06/2022] Open
Abstract
Epstein-Barr virus-associated gastric carcinoma (EBVaGC) has distinct clinicopathological features. However, the prognostic factors remain unclear, particularly in UICC/AJCC stage I-III cancer. We retrospectively enrolled 1,020 patients with stage I-III gastric cancer that received radical gastrectomy with lymphadenectomy. Formalin-fixed, paraffin‑embedded surgical specimens were retrieved to construct tissue microarrays. EBV positivity was identified by in situ hybridization with EBV-encoded small RNA, and the histological classification was reviewed. Fifty-two cases of EBVaGC were identified, exhibiting a male predominance (p=0.003), a higher prevalence in stump cancer (p<0.001), and poorly differentiated carcinoma (p=0.010) compared with the controls. The survival analysis revealed no difference in survival between the EBVaGC cases and the EBV-negative cases (p=0.977). The multivariate analysis showed that EBVaGC cases with a tumor size >5 cm, non-lymphoepithelioma-like carcinoma (LELC), or a lymph node ratio >0.15 had a worse overall survival (hazard ratio 2.884, 12.178 and 19.352; p=0.027, 0.005 and <0.0001, respectively). The depth of tumor invasion and the number of lymph node metastases did not reach statistical significance (p=0.834 and 0.833, respectively). These prognostic factors, tumor size, LELC classification and lymph node ratio, may reflect a unique type of carcinogenesis of EBVaGC and may be considered when selecting high-risk patients for adjuvant treatment.
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Affiliation(s)
- Shih-Chiang Huang
- Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Guishan, Taoyuan 333, Taiwan, R.O.C
| | - Kwai-Fong Ng
- Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Guishan, Taoyuan 333, Taiwan, R.O.C
| | - Kuang-Hua Chen
- Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Guishan, Taoyuan 333, Taiwan, R.O.C
| | - Jun-Te Hsu
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Guishan, Taoyuan 333, Taiwan, R.O.C
| | - Keng-Hao Liu
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Guishan, Taoyuan 333, Taiwan, R.O.C
| | - Ta-Sen Yeh
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Guishan, Taoyuan 333, Taiwan, R.O.C
| | - Tse-Ching Chen
- Department of Pathology, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Guishan, Taoyuan 333, Taiwan, R.O.C
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Camargo MC, Kim WH, Chiaravalli AM, Kim KM, Corvalan AH, Matsuo K, Yu J, Sung JJY, Herrera-Goepfert R, Meneses-Gonzalez F, Kijima Y, Natsugoe S, Liao LM, Lissowska J, Kim S, Hu N, Gonzalez CA, Yatabe Y, Koriyama C, Hewitt SM, Akiba S, Gulley ML, Taylor PR, Rabkin CS. Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: an international pooled analysis. Gut 2014; 63:236-43. [PMID: 23580779 PMCID: PMC4384434 DOI: 10.1136/gutjnl-2013-304531] [Citation(s) in RCA: 280] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND OBJECTIVE About 9% of gastric carcinomas have Epstein-Barr virus (EBV) in the tumour cells, but it is unclear whether viral presence influences clinical progression. We therefore examined a large multicentre case series for the association of tumour EBV status with survival after gastric cancer diagnosis, accounting for surgical stage and other prognostic factors. METHODS We combined individual-level data on 4599 gastric cancer patients diagnosed between 1976 and 2010 from 13 studies in Asia (n=8), Europe (n=3), and Latin America (n=2). EBV positivity of tumours was assessed by in situ hybridisation. Mortality HRs for EBV positivity were estimated by Cox regression models stratified by study, adjusted for distributions of sex (71% male), age (mean 58 years), stage (52% tumour-node-metastasis stages III or IV), tumour histology (49% poorly differentiated, 57% Lauren intestinal-type), anatomic subsite (70% non-cardia) and year of diagnosis. Variations by study and continent were assessed using study-specific HRs for EBV positivity. RESULTS During median 3.0 years follow-up, 49% of patients died. Stage was strongly predictive of mortality, with unadjusted HRs (vs stage I) of 3.1 for stage II, 8.1 for stage III and 13.2 for stage IV. Tumour EBV positivity was 8.2% overall and inversely associated with stage (adjusted OR: 0.79 per unit change). Adjusted for stage and other confounders, EBV positivity was associated with lower mortality (HR, 0.72; 95% CI 0.61 to 0.86), with low heterogeneity among the study populations (p=0.2). The association did not significantly vary across patient or tumour characteristics. There was no significant variation among the three continent-specific HRs (p=0.4). CONCLUSIONS Our findings suggest that tumour EBV positivity is an additional prognostic indicator in gastric cancer. Further studies are warranted to identify the mechanisms underlying this protective association.
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Affiliation(s)
- M Constanza Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
| | - Woo-Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
| | | | - Kyoung-Mee Kim
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Alejandro H Corvalan
- Department of Hematology and Oncology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Keitaro Matsuo
- Division of Molecular Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Jun Yu
- Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Joseph J Y Sung
- Department of Medicine and Therapeutics, Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | | | - Fernando Meneses-Gonzalez
- Programa de Residencia en Epidemiología, Dirección General Adjunta de Epidemiología, Secretaría de Salud, México City, México
| | - Yuko Kijima
- Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Shoji Natsugoe
- Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Linda M Liao
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
| | - Jolanta Lissowska
- Division of Cancer Epidemiology and Prevention, M Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | - Sung Kim
- Division of Cancer Epidemiology and Prevention, M Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland
| | - Nan Hu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
| | - Carlos A Gonzalez
- Unit of Nutrition, Environment and Cancer, Epidemiology Research Program, Catalan Institute of Oncology, Barcelona, Spain; on behalf of the Euro-gast EPIC study
| | - Yashushi Yatabe
- Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Chihaya Koriyama
- Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Stephen M Hewitt
- Tissue Array Research Program and Applied Molecular Pathology Laboratory, Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland, USA
| | - Suminori Akiba
- Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Margaret L Gulley
- Department of Pathology and Laboratory Medicine, The Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Philip R Taylor
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
| | - Charles S Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA
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Bittar Z, Fend F, Quintanilla-Martinez L. Lymphoepithelioma-like carcinoma of the stomach: a case report and review of the literature. Diagn Pathol 2013; 8:184. [PMID: 24188515 PMCID: PMC4228252 DOI: 10.1186/1746-1596-8-184] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Accepted: 10/26/2013] [Indexed: 12/29/2022] Open
Abstract
A lymphoepithelioma-like carcinoma (LLC), characterized by a carcinoma with stromal heavy lymphocyte infiltration, is one of the histological patterns observed in patients with Epstein-Barr virus (EBV)-associated gastric carcinoma. Although this entity is hard to be recognized in the biopsy specimens, pathologists and clinicians should acknowledge this subset of gastric cancer because it generally has a better prognosis than other forms of EBV-associated gastric carcinomas and conventional gastric carcinomas. This might be due to the fact that the patient's inflammatory response may prevent the spread of tumor through the gastric wall and to the lymph nodes or remote organs. We report a case of EBV-positive, microsatellite stable LLC as a rare morphologic variant of gastric carcinoma.
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Affiliation(s)
- Zeid Bittar
- Institute of Pathology, University Hospital Tuebingen, Eberhard-Karls-University, Liebermeisterstrasse 8, Tuebingen 72076, Germany.
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Epstein-Barr virus-encoded BARF1 promotes proliferation of gastric carcinoma cells through regulation of NF-κB. J Virol 2013; 87:10515-23. [PMID: 23824821 DOI: 10.1128/jvi.00955-13] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
In Epstein-Barr virus (EBV)-infected gastric carcinoma, EBV-encoded BARF1 has been hypothesized to function as an oncogene. To evaluate cellular changes induced by BARF1, we isolated the full-length BARF1 gene from gastric carcinoma cells that were naturally infected with EBV and transfected BARF1 into EBV-negative gastric carcinoma cells. BARF1 protein was primarily secreted into culture supernatant and only marginally detectable within cells. Compared with gastric carcinoma cells containing empty vector, BARF1-expressing gastric carcinoma cells exhibited increased cell proliferation (P < 0.05). There were no significant differences in apoptosis, invasion, or migration between BARF1-expressing gastric carcinoma cells and empty vector-transfected cells. BARF1-expressing gastric carcinoma cells demonstrated increased nuclear expression of nuclear factor kappa B (NF-κB) RelA protein and increased NF-κB-dependent cyclin D1. The expression of p21(WAF1) was diminished by BARF1 transfection and increased by NF-κB inhibition. Proliferation of naturally EBV-infected gastric carcinoma cells was suppressed by BARF1 small interfering RNA (siRNA) (P < 0.05). Immunohistochemical analysis of 120 human gastric carcinoma tissues demonstrated increased expression of cyclin D1 and reduced expression of p21(WAF1) in EBV-positive samples versus EBV-negative gastric carcinomas (P < 0.05). In conclusion, the secreted BARF1 may stimulate proliferation of EBV-infected gastric carcinoma cells via upregulation of NF-κB/cyclin D1 and reduction of the cell cycle inhibitor p21(WAF1), thereby facilitating EBV-induced cancer progression.
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Methylation and Expression of Retinoblastoma and Transforming Growth Factor-β1 Genes in Epstein-Barr Virus-Associated and -Negative Gastric Carcinomas. Gastroenterol Res Pract 2012; 2012:906017. [PMID: 23008701 PMCID: PMC3447358 DOI: 10.1155/2012/906017] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2012] [Revised: 08/08/2012] [Accepted: 08/13/2012] [Indexed: 12/26/2022] Open
Abstract
Background. Retinoblastoma (RB) and transforming growth factor-β1 (TGF-β1) are important tumor-related factors. Methods. A series of 30 EBV-associated gastric carcinoma (EBVaGC) and 38 matched EBV-negative gastric carcinoma (EBVnGC) tissues were examined for the promoter methylation of RB by methylation-specific PCR (MSP) method. The expression of RB and TGF-β1 in gastric carcinoma tissues was detected by immunohistochemistry. Results. The methylation rate of RB gene in EBVaGC and EBVnGC was 80.0% (24/30) and 50.0% (19/38), respectively. The difference of RB methylation rate between EBVaGC and EBVnGC was significant (χ2 = 6.490, P = 0.011). There was no significant difference for RB expression between EBVaGC (43.3%, 13/30) and EBVnGC (63.2%, 24/38), and also for TGF-β1 between EBVaGC (56.7%, 17/30) and EBVnGC (63.2%, 24/38). RB methylation was not reversely correlated with RB expression in gastric carcinoma tissues (χ2 = 2.943, P = 0.086, r = 0.208). RB methylation, loss expression of RB, and TGF-β1 expression were significantly associated with tumor invasion and lymph node metastasis (P < 0.05), but was not associated with sex, age, histological subtype (differentiation status) and tumor location. Conclusions. Methylation of RB is a common event in gastric carcinomas and EBV induces methylation of RB in EBVaGC, which may contribute to the development of gastric carcinomas. EBV has no significant effect on induction of TGF-β1 expression. Detection of RB methylation, RB expression, and TGF-β1 expression may be helpful to judge the status of tumor invasion and lymph node metastasis in gastric carcinomas.
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Abstract
Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a recently recognized entity, which is defined by the presence of EBV in the gastric carcinoma cells. EBVaGC represents about 10% of gastric carcinoma worldwide, and >80,000 patients are estimated to develop EBVaGC annually. EBVaGC shows some distinct clinicopathologic characteristics, such as male predominance, predisposition to the proximal stomach, and a high proportion in diffuse-type gastric carcinomas. Besides, EBVaGC also shows characteristic molecular abnormality, that is, global and nonrandom CpG-island methylation of the promoter region of many cancer-related genes, which causes downregulation of their expression. Moreover, EBVaGC has a relative favorable prognosis. The uniform presence of EBV-encoded small RNA in tumor cells but not in the surrounding normal epithelial cells, and the detection of monoclonal EBV episomes in EBVaGC, strongly suggests that EBV play an etiological role in gastric carcinogenesis. Therefore, EBVaGC should be regarded as a distinct entity of gastric carcinoma, although it only accounts for a relatively small fraction of total gastric carcinomas. In this review, the epidemiological and clinicopathologic features of EBVaGC and the genetic abnormalities of EBVaGC cell including chromosomal and epigenetic abnormalities are described. The roles of EBV in gastric carcinogenesis are discussed. We make an emphasis on the EBV latency pattern and genome polymorphisms as well as local immunity in EBVaGC. In addition, the treatment of EBVaGC is also briefly discussed. Taken together, this review aims to give the reader a full understanding of a newly defined entity of gastric carcinoma, EBVaGC.
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Characteristics of epstein barr virus variants associated with gastric carcinoma in Southern Tunisia. Virol J 2011; 8:500. [PMID: 22047541 PMCID: PMC3216291 DOI: 10.1186/1743-422x-8-500] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2011] [Accepted: 11/03/2011] [Indexed: 12/26/2022] Open
Abstract
Backgroud EBV-associated Gastric Carcinoma (EBVaGC) has a distinct clinical features and its prevalence is variable worldwide. Results To determine the prevalence of EBVaGC in Tunisia, EBV-encoded small RNA (EBER) expression was assessed in 81 gastric carcinoma (GC) specimens. The nuclear EBER expression was detected in 12 out of 81 GC cases (14.81%) and concordance between the score range of EBER staining and the number of EBV DNA copies as estimate by QPCR is observed. On the other hand, we found that EBVaGC strongly correlated with age at diagnosis, and weakly with tumor differentiation and venous invasion. Furthermore, the EBVaGC specimens were subjected to determine the EBV DNA polymorphisms. Our results show a unique genetic profile of the EBV strains regarding the A and D types, the F prototype, the retention of XhoI restriction site and the 30 bp del-LMP1 variant. According to our previous studies on nasopharyngeal carcinoma (NPC), we suggested that EBV strains associated to GC and NPC shared some similarities in Tunisian patients. Conclusion The prevalence of EBVaGC is of 14.81% in the southern Tunisia and that common EBV strain are associated with both NPC and GC which are likely to differ from Asian strains. Our findings support therefore a certain geographical distribution of EBV strains which is not restricted to EBV-associated malignancies.
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Fukayama M, Ushiku T. Epstein-Barr virus-associated gastric carcinoma. Pathol Res Pract 2011; 207:529-37. [PMID: 21944426 DOI: 10.1016/j.prp.2011.07.004] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2010] [Accepted: 07/29/2011] [Indexed: 12/13/2022]
Abstract
Epstein-Barr virus (EBV) has been accepted as an infective agent causing gastric carcinoma (GC). EBV-associated GC, comprising nearly 10% of all cases of GC, is the monoclonal growth of EBV-infected epithelial cells, which express only several EBV-latent genes (Latency I program). Histopathologically, there are two subtypes, lymphoepithelioma-like carcinoma and the ordinary type of GC. Other features include the lace pattern of carcinoma cells in the intramucosal stage and the dense infiltration of lymphocytes and macrophages at the invasive site of the submucosa. The primary molecular abnormality in EBV-associated GC is global and non-random CpG island methylation in the promoter region of many cancer-related genes. Experimental studies have demonstrated that viral latent membrane protein 2A (LMP2A) is responsible for the promotion of DNA methylation. LMP2A up-regulates cellular DNMT1 through the phosphorylation of STAT3, resulting in the repression of tumor suppressor genes, such as PTEN, through promoter methylation. DNA methylation in EBV-infected stomach cells may be due to overdrive of the cellular defense against foreign DNA. Further studies on the mechanisms of epigenetic abnormalities will clarify the strategies for prevention and treatment of this particular type of GC with EBV infection.
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Affiliation(s)
- Masashi Fukayama
- Department of Pathology and Diagnostic Pathology, Graduate School of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.
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Song HJ, Kim KM. Pathology of epstein-barr virus-associated gastric carcinoma and its relationship to prognosis. Gut Liver 2011; 5:143-8. [PMID: 21814592 PMCID: PMC3140657 DOI: 10.5009/gnl.2011.5.2.143] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2010] [Accepted: 12/25/2010] [Indexed: 12/13/2022] Open
Abstract
Among Epstein-Barr virus (EBV)-associated neoplasms, EBV-associated gastric carcinoma (EBVaGC) is the most common tumor worldwide. In contrast to the predominant site of occurrence of EBV-negative gastric carcinoma in the antrum, EBVaGC occurs most frequently in the proximal stomach, including the cardia, fundus and body. Microscopically, EBVaGC can be subclassified into three histological subtypes according to the host cellular immune responses: lymphoepithelioma-like carcinoma, carcinoma with Crohn's disease-like lymphoid reaction, and conventional-type adenocarcinoma. Recent studies have shown that patients with the lymphoepithelioma-like carcinoma subtype of EBVaGC have the best overall and disease-free survival, followed by Crohn's disease-like reactions, which in turn have better survival than patients with conventional-type adenocarcinoma. Histologic subclassifications of EBVaGCs are based on the differing degree and pattern of infl ammatory response and the extent of desmoplasia. Because these subclassifications appear to be a powerful prognostic parameter, further research into the underlying mechanisms of the cellular immune reaction in these pathologic subtypes of EBVaGCs may play a key role in understanding the innate immune response of patients with this highly aggressive carcinoma.
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Affiliation(s)
- Hye-Jong Song
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Song HJ, Srivastava A, Lee J, Kim YS, Kim KM, Ki Kang W, Kim M, Kim S, Park CK, Kim S. Host inflammatory response predicts survival of patients with Epstein-Barr virus-associated gastric carcinoma. Gastroenterology 2010; 139:84-92.e2. [PMID: 20398662 DOI: 10.1053/j.gastro.2010.04.002] [Citation(s) in RCA: 148] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2009] [Revised: 03/24/2010] [Accepted: 03/22/2010] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Lymphoepithelioma-like carcinoma (LELC) is a rare subtype of gastric carcinoma (GC) with a better survival rate than other GCs; most cases of LELC are associated with Epstein-Barr virus (EBV) infection. We investigated whether the survival advantage of LELC is related to the EBV infection itself or to associated inflammatory immune responses. METHODS From 1994 to 2008, 123 EBV-associated GCs were identified and compared with 405 EBV-negative GCs. EBV-associated GCs were subclassified, based on the pattern of host inflammatory immune responses, into 3 histologic subtypes: typical LELC (n = 53, 43.1%), Crohn's disease-like lymphocytic reaction (CLR) (n = 52, 42.3%), and conventional adenocarcinoma (n = 18, 14.6%). Patients with curatively resected EBV-negative GC were controls. Univariate and multivariate analyses were used, with Bonferroni correction. RESULTS Patients with EBV-associated GC had tumors of proximal location, lower N stage (P < .0001), and lower T stage (P = .02) and were older than controls (P = .0003). Upon univariate analysis, patients with EBV-associated GC had longer survival times than controls (P < .004); this difference was not significant in a multivariate analysis with Cox proportional hazards. Stratification of EBV-associated GCs by host cellular immune responses showed that patients with LELC and LELC+CLR have significantly longer overall survival time (hazard ratio, 0.09 and 0.42, respectively) and disease-free survival (hazard ratio, 0.05 and 0.46, respectively; P < .02). CONCLUSIONS Prognosis of EBV-associated GCs depends on the patient's inflammatory response. The definition of LELC should be expanded to include EBV-associated GCs with CLR because these have a prognosis similar to LELC.
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Affiliation(s)
- Hye-Jong Song
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul, Korea
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Chen JN, Ding YG, Feng ZY, Li HG, He D, Du H, Wu B, Shao CK. Association of distinctive Epstein-Barr virus variants with gastric carcinoma in Guangzhou, southern China. J Med Virol 2010; 82:658-67. [PMID: 20166192 DOI: 10.1002/jmv.21731] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
To investigate the clinicopathologic features, Epstein-Barr virus (EBV) latency pattern and genome polymorphism of EBV-associated gastric carcinoma (EBVaGC) in Guangzhou, an endemic area of nasopharyngeal carcinoma (NPC), an in situ hybridization assay of EBV-encoded small RNA-1 (EBER-1) was used to identify the presence of EBV in 676 consecutive gastric carcinoma cases. EBV-encoded proteins EBNA1, EBNA2, LMP1, and ZEBRA were detected by immunohistochemistry. EBV genome polymorphism was also analyzed by PCR and DNA sequencing. Of the 676 cases, 45 EBV-positive cases (6.7%) were identified, including 37 (8.5%) male and 8 (3.3%) female cases. EBNA1 was detected in 42 cases (93.3%), while EBNA2, LMP1, and ZEBRA were all negative. In the EBV genome polymorphism analysis, type A strain, prototype F, type I, XhoI-, and del-LMP1 variants were predominant among EBVaGC patients, accounting for 44 (97.8%), 37 (82.2%), 45 (100%), 34 (75.6%), and 42 (93.3%) cases, respectively. Moreover, a new hotspot mutation in the BamHI-W1/I1 boundary region (148,972 T --> C) was found in 39 (86.7%) of the 45 cases. The predominant EBV variants in EBVaGC in Guangzhou are prototype F, type I, and XhoI-, which are different from those in NPC in this area (predominant variant-type "f") and in EBVaGC in Latin American countries (predominant type "i" and XhoI+), suggesting that the EBV variants are not only geographically distributed but also disease restricted, and the pathogenic role of EBV in different EBV associated epithelial malignancies in different areas may be distinct.
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Affiliation(s)
- Jian-Ning Chen
- Department of Pathology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
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Jeong JY, Woo JH, Kim YS, Choi S, Lee SO, Kil SR, Kim CW, Lee BL, Kim WH, Nam BH, Chang MS. Nuclear factor-kappa B inhibition reduces markedly cell proliferation in Epstein-Barr virus-infected stomach cancer, but affects variably in Epstein-Barr virus-negative stomach cancer. Cancer Invest 2010; 28:113-9. [PMID: 19968495 DOI: 10.3109/07357900903095730] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Nuclear factor-kappa B (NF-kappaB) inhibition by NF-kappaB p65-specific siRNA induced a near-cessation of cell proliferation in EBV-positive stomach cancer cell, and notably diminished cell proliferation in EBV- positive Raji lymphoma cell. In EBV-negative stomach cancer cells, NF-kappaB inhibition affected variably cell proliferation. Regardless of cell type, NF-kappaB inhibition suppressed antiapoptotic function of NF-kappaB, and tended to promote the nuclear accumulation of beta-catenin. This inverse relationship between NF-kappaB and beta-catenin was evident in 120 resected gastric carcinomas. Conclusively, NF-kappaB inhibition may be beneficial in the therapy of EBV-positive stomach cancer, but influence variously EBV-negative stomach cancer.
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Affiliation(s)
- Jin-Yong Jeong
- Center for Antimicrobial Resistance and Microbial Genetics, Department of Infectious Diseases, University of Ulsan College of Medicine, Seoul 138-736, Korea
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Trimeche M, Ksiâa F, Ziadi S, Mestiri S, Hachana M, Gacem RB, Sriha B, Korbi S. Prevalence and characteristics of Epstein-Barr virus-associated gastric carcinomas in Tunisia. Eur J Gastroenterol Hepatol 2009; 21:1001-7. [PMID: 19491698 DOI: 10.1097/meg.0b013e32831f1f53] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVE Epstein-Barr virus (EBV) has been linked to gastric carcinoma (GC) with worldwide geographical variations of prevalence ranging from 1 to 18% of cases. Investigations carried out in north Africa have shown that some EBV-associated types of cancers are common in this area. This study was taken to determine the prevalence of EBV-associated GC in Tunisia. METHODS Ninety-six nonselected GC cases (male/female ratio 1.7/1, mean age 60.9 years, range: 20-88 years) were evaluated for the presence of EBV by polymerase chain reaction as well as by in-situ hybridization for EBV-encoded small RNAs (EBERs) and immunohistochemistry for LMP-1 and EBNA-2 expression. RESULTS EBV was detected by polymerase chain reaction in 36% of cases, whereas EBERs were detected in the tumor cells in only four cases (4.1%). Immunohistochemistry for LMP-1 and EBNA-2 was negative in all cases. The mean age for patients harboring EBERs-positive GC was 55.7 years (range: 52-59 years). All EBERs-positive GC cases were males of advanced clinical stage (pT3-pT4). According to Lauren's classification, two cases were of diffuse histological type and two cases were of intestinal type. In three cases, the tumors have a proximal location and in the remaining case the tumor arises in the antrum. All EBV strains detected from EBV-associated GC were exclusively of type A and D, prototype F, and XhoI-maintained variant. CONCLUSION We conclude that the prevalence of EBV-associated GC in Tunisia is low (4.1%), suggesting that this virus is not an important etiological factor in GC arising in north African populations. The clinicopathological profile of EBV-associated GC in Tunisia did not differ markedly from that found elsewhere.
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Affiliation(s)
- Mounir Trimeche
- Department of Pathology, Farhat Hached Hospital, Sousse 4000, Tunisia.
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Lee JH, Kim SH, Han SH, An JS, Lee ES, Kim YS. Clinicopathological and molecular characteristics of Epstein-Barr virus-associated gastric carcinoma: a meta-analysis. J Gastroenterol Hepatol 2009; 24:354-65. [PMID: 19335785 DOI: 10.1111/j.1440-1746.2009.05775.x] [Citation(s) in RCA: 189] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
There is conflicting data regarding the clinicopathological significance of the risk factors associated with Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC). To address this controversy, we performed a meta-analysis for the clinicopathological and molecular characteristics of EBVaGC. The relevant published studies were reviewed according to the defined selection criteria. The effect sizes of the outcome parameters were estimated by an odds ratio or a weighted mean difference. This meta-analysis included 48 studies that encompassed a total of 9738 patients. The frequency of EBVaGC was 8.8%, and EBVaGC was significantly associated with ethnicity. It was more predominant in men and in younger individuals. Interestingly, EBVaGC was more prevalent in Caucasian and Hispanic patients than in Asian ones. EBVaGC developed most often in the cardia and body, and it generally showed the diffuse histological type. EBV was highly prevalent in the patients with lymphoepithelial carcinoma. EBVaGC was closely associated with remnant cancer and a CpG island methylator-high status, but not with Helicobacter pylori infection, a TP53 expression, and p53 mutation. In addition, EBVaGC was not significantly associated with the depth of invasion, lymph node metastasis, or the clinical stage. The clinicopathological and molecular characteristics of EBVaGC are quite different from those of conventional gastric adenocarcinoma. However, further study is needed to determine the effect of EBV on the survival of EBVaGC patients.
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Affiliation(s)
- Ju-Han Lee
- Department of Pathology, Bioinformatics Interest Group, Korea University Ansan Hospital, Danwon-Gu, Ansan, Korea
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Deyrup AT. Epstein-Barr virus-associated epithelial and mesenchymal neoplasms. Hum Pathol 2008; 39:473-83. [PMID: 18342658 DOI: 10.1016/j.humpath.2007.10.030] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2007] [Revised: 10/29/2007] [Accepted: 10/30/2007] [Indexed: 01/22/2023]
Abstract
Epstein-Barr virus (EBV) is a ubiquitous human pathogen that usually maintains a harmonious relationship with its host. Rarely, this host-virus balance is perturbed, causing a diverse group of malignancies in both immunocompetent and immunosuppressed patients. In addition to its role in hematologic malignancies (Burkitt lymphoma, subsets of Hodgkin and T-cell lymphomas, posttransplant lymphomas), EBV has been implicated in both epithelial (undifferentiated nasopharyngeal carcinoma, a subset of gastric adenocarcinomas) and mesenchymal (EBV-associated smooth muscle tumor, inflammatory pseudotumor-like follicular dendritic cell tumor) neoplasms. This review will focus on EBV-associated epithelial and mesenchymal neoplasms.
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Affiliation(s)
- Andrea T Deyrup
- Department of Pathology, Emory University Atlanta, GA 30322, USA.
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Abstract
Among 185 cases of gastric cancer and 200 controls in Linxian, China, Epstein–Barr virus (EBV) seropositivity was not associated with increased risk of gastric cancer. High EBV nuclear antigen titres were associated with longer survival in cardia cancer cases, possibly due to chance.
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Abdirad A, Ghaderi-Sohi S, Shuyama K, Koriyama C, Nadimi-Barforoosh H, Emami S, Mosavi-Jarrahi A, Nahvijou A, Akiba S. Epstein-Barr virus associated gastric carcinoma: a report from Iran in the last four decades. Diagn Pathol 2007; 2:25. [PMID: 17629938 PMCID: PMC1949397 DOI: 10.1186/1746-1596-2-25] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2007] [Accepted: 07/15/2007] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Epstein-Barr virus has been proved to be associated with many of the human malignancy including gastric carcinoma, one of the most important human malignancies in the world. There has been no study about the presence of EBV in gastric adenocarcinoma in Iran. METHODS We examined the presence of EBV in 273 formalin fixed paraffin-embedded cases of gastric carcinoma from Cancer institute of Tehran University, from 1969 to 2004. In situ hybridization of EBV-encoded small RNA-1 (EBER-1) was conducted. The strain of positive cases was examined by means of polymerase chain reaction and/or restriction fragment length polymorphism analysis. RESULTS We found 9 (3%; 95% CI = 1-5%) EBV positive cases. The gender difference was not statisticaly significant. The proportion of EBV-GC cases in diffuse type was higher than intestinal type (OR = 0.08; 95% CI = 0.002-0.64). EBV-GC cases had no relation with age, location and invasion. Six out of 9 EBV-GC cases were born during the period between 1928 and 1930. All 9 cases were Type A. Prototype F was seen in 6 out of 8 cases. Type "i" was found in 8 cases and type I in 1 case. XhoI+ and XhoI- polymorphism accounted 6 and 3 of the cases, respectively. CONCLUSION Our study is the first to describe the frequency of EBV-GC in Iran and the Middle East, highlighting a very low prevalence with specific clinicopathologic features. The predominance of EBV-GC birth year in a fixed period, suggests that EBV infection or other events at early childhood may be related to the development of EBV-GC later in the life. The predominance of the type "i" and XhoI+ cases are contradictory to other studies in Asia and is similar to what is reported from Latin American countries.
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Affiliation(s)
- Afshin Abdirad
- The Cancer Research Center, the Cancer Institute, Tehran University of Medical Sciences, Imam Khomeini Medical Center, Keshavarz Blvd., Tehran, Iran
| | - Siavash Ghaderi-Sohi
- The Cancer Research Center, the Cancer Institute, Tehran University of Medical Sciences, Imam Khomeini Medical Center, Keshavarz Blvd., Tehran, Iran
| | - Karem Shuyama
- Department of Epidemiology and Preventive Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Japan
| | - Chihaya Koriyama
- Department of Epidemiology and Preventive Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Japan
| | - Hosain Nadimi-Barforoosh
- The Cancer Research Center, the Cancer Institute, Tehran University of Medical Sciences, Imam Khomeini Medical Center, Keshavarz Blvd., Tehran, Iran
| | - Sara Emami
- The Cancer Research Center, the Cancer Institute, Tehran University of Medical Sciences, Imam Khomeini Medical Center, Keshavarz Blvd., Tehran, Iran
| | - Alireza Mosavi-Jarrahi
- The Cancer Research Center, the Cancer Institute, Tehran University of Medical Sciences, Imam Khomeini Medical Center, Keshavarz Blvd., Tehran, Iran
| | - Azin Nahvijou
- The Cancer Research Center, the Cancer Institute, Tehran University of Medical Sciences, Imam Khomeini Medical Center, Keshavarz Blvd., Tehran, Iran
| | - Suminori Akiba
- Department of Epidemiology and Preventive Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Japan
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Begnami MD, Montagnini AL, Vettore AL, Nonogaki S, Brait M, Simoes-Sato AY, Seixas AQA, Soares FA. Differential expression of apoptosis related proteins and nitric oxide synthases in Epstein Barr associated gastric carcinomas. World J Gastroenterol 2006; 12:4959-65. [PMID: 16937490 PMCID: PMC4087397 DOI: 10.3748/wjg.v12.i31.4959] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the incidence of Epstein Barr virus associated gastric carcinoma (GC) in Brazil and compare the expressions of apoptosis related proteins and nitric oxide synthases between EBV positive and negative gastric carcinoma.
METHODS: In situ hybridization of EBV-encoded small RNA-1 (EBER-1) and PCR was performed to identify the presence of EBV in GCs. Immunohistochemistry was used to identify expressions of bcl-2, bcl-xl, bak, bax, p53, NOS-1, NOS-2, and NOS-3 proteins in 25 EBV positive GCs and in 103 EBV negative GCS.
RESULTS: 12% of the cases of GC (25/208) showed EBER-1 and EBNA-1 expression. The cases were preferentially of diffuse type with intense lymphoid infiltrate in the stroma. EBV associated GCs showed higher expression of bcl-2 protein and lower expression of bak protein than in EBV negative GCs. Indeed, expressions of NOS-1 and NOS-3 were frequently observed in EBV associated GCs.
CONCLUSION: Our data suggest that EBV infection may protect tumor cells from apoptosis, giving them the capacity for permanent cell cycling and proliferation. In addition, EBV positive GCs show high expression of constitutive NOS that could influence tumor progression and aggressiveness.
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Affiliation(s)
- Maria D Begnami
- Department of Pathology, Hospital do Câncer A C Camargo, São Paulo, SP 01519010, Brazil.
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van Beek J, zur Hausen A, Snel SN, Berkhof J, Kranenbarg EK, van de Velde CJH, van den Brule AJC, Middeldorp JM, Meijer CJLM, Bloemena E. Morphological Evidence of an Activated Cytotoxic T-Cell Infiltrate in EBV-Positive Gastric Carcinoma Preventing Lymph Node Metastases. Am J Surg Pathol 2006; 30:59-65. [PMID: 16330943 DOI: 10.1097/01.pas.0000176428.06629.1e] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Recently, we showed that Epstein-Barr virus (EBV)-positive gastric carcinoma (GC) forms a distinct clinicopathologic entity with a better prognosis due to lower incidence of lymph node metastases (LN+). Here we investigated whether in EBV-positive GC more pronounced activation of cellular immune responses is associated with absence of (micro)metastases. Twenty EBV-positive primary tumors (PT) (9 LN+) were matched with 28 EBV-negative GC (11 LN+) for T- and N-stage, gender, and age. The PT (n = 28) and its LNs were analyzed by EBER RNA in situ hybridization and by immunohistochemistry for MHC class I and II expression, for CD3, CD8, CD4, CD20, CD56, CD83, and Granzyme B (GzB) expression. In LN metastases of EBV-positive GC, the EBV genome is maintained, excluding tumor escape by virus deletion. All GC express MHC class I independently of EBV status. In comparison with EBV-negative GC, EBV-positive GC have higher expression of MHC class II on the tumor cells (P = 0.029) and a more extensive infiltrate (P < 0.0001) of activated GzB+ CD8+ T cells (P = 0.028), which is most abundant in those EBV-positive tumors that do not metastasize (P < 0.0001). In addition, in EBV-positive GC without metastases, the infiltrate contains higher numbers of mature dendritic cells (DC) (P = 0.018). At present, the antigenic target has to be determined. These data support the notion that local triggering of cellular immune responses in EBV-positive GC prevents lymph node metastasis formation.
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Affiliation(s)
- Josine van Beek
- Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, the Netherlands
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Chang MS, Kim WH. Epstein-Barr virus in human malignancy: a special reference to Epstein-Barr virus associated gastric carcinoma. Cancer Res Treat 2005; 37:257-67. [PMID: 19956524 PMCID: PMC2785932 DOI: 10.4143/crt.2005.37.5.257] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Epstein-Bar virus (EBV), a human herpesvirus, establishes a life-long persistent infection in 90 approximately 95% of human adult population worldwide. EBV is the etiologic agent of infectious mononucleosis, and EBV is associated with a variety of human malignancy including lymphoma and gastric carcinoma. Recently, EBV has been classified as group 1 carcinogen by the WHO International Agency for Research on Cancer. Evidence is presented which suggests that failures of the EBV-specific immunity may play a role in the pathogenesis of EBV-associated malignancy. At present, the precise mechanisms by which EBV transforms B lymphocytes have been disclosed. Encouragingly, they have had enough success so far to keep them enthusiastic about novel therapeutic trial in the field of EBV-associated lymphoma. However, information on EBV-associated gastric carcinoma is still at dawn. This article reviews EBV biology, immunological response of EBV infection, unique oncogenic property of EBV, peculiarity of EBV-associated gastric carcinoma, and lastly, EBV-targeted therapy and vaccination.
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Affiliation(s)
- Mee Soo Chang
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
- Department of Pathology, Seoul National University Boramae Hospital, Seoul, Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
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Lee HS, Chang MS, Yang HK, Lee BL, Kim WH. Epstein-barr virus-positive gastric carcinoma has a distinct protein expression profile in comparison with epstein-barr virus-negative carcinoma. Clin Cancer Res 2004; 10:1698-705. [PMID: 15014022 DOI: 10.1158/1078-0432.ccr-1122-3] [Citation(s) in RCA: 99] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE EBV has been detected in 2-16% of gastric carcinomas. However, there is little information available about the gene expression profile of EBV-positive gastric carcinomas. EXPERIMENTAL DESIGN EBV infection was examined using EBV-encoded small RNAs (EBERs) in situ hybridization, and 63 (5.6%) of 1127 consecutive gastric carcinomas were found to be EBV-positive. The expressions of 27 tumor-associated proteins were evaluated immunohistochemically in 63 EBV-positive gastric carcinomas and 287 EBV-negative carcinomas using the tissue array method. In addition, the genotype of EBV was investigated by PCR amplification of LMP1 (latent membrane protein 1), Epstein-Barr nuclear antigen 2 (EBNA2), and EBNA3B genes. RESULTS EBV-positive gastric carcinomas are characterized by the presence of lymphoid stroma, proximal location, and predominance in males. In comparison with EBV-negative carcinomas, EBV-positive carcinomas showed frequent loss of expression of p16, smad4, FHIT, and KAI-1 (kangai 1; P < 0.05), but retained the expression of APC (adenomatous polyposis coli), DCC (deleted in colorectal cancer), and some DNA repair proteins (P < 0.05). There was negative association between EBV infection and the expression of MUC1, MUC2, MUC5AC, p53, CEA, C-erbB2, and smad7. Using hierarchical cluster analysis, we divided EBV-positive gastric carcinomas into two clusters. Those patients with cluster 1 (42 cases) carcinomas had a better prognosis than those with cluster 2 (12 cases; P = 0.0002) or those with EBV-negative carcinomas (280 cases; P = 0.0251). Fifty-one (92.7%) of 55 EBV-positive carcinomas demonstrated the 30-bp deletion in LMP1 gene, and 53 (96.4%) of 55 cases were type 1 for EBNA2 and EBNA3B genes. CONCLUSION EBV-positive gastric carcinomas have a distinct protein expression profile as well as distinct clinicopathological features, as compared with EBV-negative carcinomas. The subclassification of EBV-positive carcinomas, by hierarchical cluster analysis, is significantly associated with patient survival.
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Affiliation(s)
- Hye Seung Lee
- Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
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Kerroucha R, Hervieu V, Chambonnière ML, Mège-Lechevallier F, Poncet G, Boulez J, Tanière P, Scoazec JY. Adénocarcinomes de l’estomac et de l’œsophage distal. Ann Pathol 2004; 24:228-35. [PMID: 15480257 DOI: 10.1016/s0242-6498(04)93957-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
AIMS Our study aimed to evaluate the incidence of EBV-associated adenocarcinomas of the stomach and distal esophagus in Lyons area and to assess their phenotypic characteristics. METHODS 85 cases of gastric adenocarcinomas and 40 cases of esophageal adenocarcinomas were screened for EBV by in situ hybridization (EBER-1 and -2) and immunohistochemistry (LMP1 and EBNA-1); all cases positive for EBER by in situ hybridization were studied by PCR for demonstration of EBV DNA. The clinical, histological and immunophenotypic features of EBV-associated adenocarcinomas were assessed. RESULTS 5 cases of EBV-associated adenocarcinomas, all gastric, were identified in our series (5.8%); one was diagnosed in a migrant from Algeria, a region of high endemia of EBV infection. 3 cases were located in the proximal stomach, 1 in the distal; 1 was diffuse. 4 cases were of the intestinal histological type. Proliferation index and microvessel density were high in all 5 cases. The expression of tumor markers was markedly heterogeneous from one case to another. CONCLUSIONS Our study shows that EBV infection is restricted to gastric adenocarcinomas. Its incidence is evaluated to 5.8% in our series: this shows that Lyons area must be considered as a low risk area. In the absence of specific histological or phenotypic features, the screening of EBV+gastric adenocarcinomas is possible only with special techniques.
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Affiliation(s)
- Rabah Kerroucha
- Service Central d'Anatomie et Cytologie Pathologiques, Hôpital Edouard Herriot, Lyon
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van Beek J, zur Hausen A, Klein Kranenbarg E, van de Velde CJH, Middeldorp JM, van den Brule AJC, Meijer CJLM, Bloemena E. EBV-Positive Gastric Adenocarcinomas: A Distinct Clinicopathologic Entity With a Low Frequency of Lymph Node Involvement. J Clin Oncol 2004; 22:664-70. [PMID: 14966089 DOI: 10.1200/jco.2004.08.061] [Citation(s) in RCA: 209] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Purpose Epstein-Barr virus (EBV) is detected in a substantial subgroup of gastric adenocarcinomas worldwide. We have previously reported that these EBV-positive gastric carcinomas carry distinct genomic aberrations. In the present study, we analyzed a large cohort of EBV-positive and EBV-negative gastric adenocarcinomas for their clinicopathologic features to determine whether they constitute a different clinical entity. Patients and Methods Using a validated polymerase chain reaction/enzyme immunoassay–based prescreening method in combination with EBER1/2-RNA in situ hybridization, EBV was detected in the tumor cells of 7.2% (n = 41) of the gastric carcinomas from the Dutch D1D2 trial (N = 566; mean follow-up, 9 years). EBV status was correlated with clinicopathologic features collected for the Dutch D1D2 trial. Results EBV-positive gastric carcinomas occurred significantly more frequently in males (P < .0001) and in younger patients (P = .012). Most were of the intestinal type according to the Laurén classification (P = .047) or tubular according to the WHO classification (P = .006) and located in the proximal part of the stomach (P < .0001). A significantly lower tumor-node-metastasis system-stage (P = .026) was observed in the patients with EBV-carrying carcinomas, which was solely explained by less lymph node (LN) involvement (P = .034) in these cases. In addition, a better prognosis, as reflected by a longer disease-free period (P = .04) and a significant better cancer-related survival (P = .02), was observed for these patients, which could be explained by less LN involvement, less residual disease, and younger patient age. Conclusion EBV-carrying gastric adenocarcinomas are a distinct entity of carcinomas, characterized not only by unique genomic aberrations, but also by distinct clinicopathologic features associated with significantly better prognosis.
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Affiliation(s)
- Josine van Beek
- Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands
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