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Shi D, Yang Z, Cai Y, Li H, Lin L, Wu D, Zhang S, Guo Q. Research advances in the molecular classification of gastric cancer. Cell Oncol (Dordr) 2024; 47:1523-1536. [PMID: 38717722 PMCID: PMC11466988 DOI: 10.1007/s13402-024-00951-9] [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] [Accepted: 04/13/2024] [Indexed: 06/27/2024] Open
Abstract
Gastric cancer (GC) is a malignant tumor with one of the lowest five-year survival rates. Traditional first-line treatment regimens, such as platinum drugs, have limited therapeutic efficacy in treating advanced GC and significant side effects, greatly reducing patient quality of life. In contrast, trastuzumab and other immune checkpoint inhibitors, such as nivolumab and pembrolizumab, have demonstrated consistent and reliable efficacy in treating GC. Here, we discuss the intrinsic characteristics of GC from a molecular perspective and provide a comprehensive review of classification and treatment advances in the disease. Finally, we suggest several strategies based on the intrinsic molecular characteristics of GC to aid in overcoming clinical challenges in the development of precision medicine and improve patient prognosis.
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Affiliation(s)
- Dike Shi
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road, Hangzhou, 310009, China
| | - Zihan Yang
- Department of Gastroenterology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Yanna Cai
- Department of Gastroenterology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Hongbo Li
- Department of Gastroenterology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China
| | - Lele Lin
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road, Hangzhou, 310009, China
| | - Dan Wu
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road, Hangzhou, 310009, China
| | - Shengyu Zhang
- Department of Gastroenterology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100730, China.
| | - Qingqu Guo
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Zhejiang University School of Medicine, Jiefang Road, Hangzhou, 310009, China.
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Zhou H, Sun D, Song S, Niu Y, Zhang Y, Lan H, Cui J, Liu H, Liu N, Hou H. Efficacy of immunotherapy in ARID1A-mutant solid tumors: a single-center retrospective study. Discov Oncol 2024; 15:213. [PMID: 38847966 PMCID: PMC11161453 DOI: 10.1007/s12672-024-01074-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 06/03/2024] [Indexed: 06/10/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs), especially those targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), have introduced a new treatment landscape for many types of tumors. However, they only achieve a limited therapeutic response. Hence, identifying patients who may benefit from ICIs is currently a challenge. METHODS 47 tumor patients harboring ARID1A mutations were retrospectively studied. The genomic profiling data through next-generation sequencing (NGS) and relevant clinical information were collected and analyzed. Additionally, bioinformatics analysis of the expression of immune checkpoints and immune cell infiltration levels was conducted in ARID1A-mutant gastric cancer (GC). RESULTS ARID1A mutations frequently co-occur with mutations in DNA damage repair (DDR)-associated genes. Among the 35 ARID1A-mutant patients who received immunotherapy, 27 were evaluable., with the objective response rate (ORR) was 48.15% (13/27), and the disease control rate (DCR) was 92.59% (25/27). Moreover, survival assays revealed that ARID1A-mutant patients had longer median overall survival (mOS) after immunotherapy. In ARID1A-mutated GC patients, receiving ICIs treatment indicated longer progressive-free survival (PFS). Additionally, the incidence of microsatellite instability-high (MSI-H), high tumor mutation burden (TMB-H) and Epstein‒Barr virus (EBV) infection was elevated. Bioinformatic analysis showed significant enrichment of immune response and T cell activation pathway within differentially expressed genes in ARID1A-mutant GC group. Finally, ARID1A mutations status was considered to be highly correlated with the level of tumor infiltrating lymphocytes (TILs) and high expression of immune checkpoints. CONCLUSIONS Patients with tumors harboring ARID1A mutations may achieve better clinical outcomes from immunotherapy, especially in GC. ARID1A mutations can lead to genomic instability and reshape the tumor immune microenvironment (TIME), which can be used as a biomarker for immunotherapy.
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Affiliation(s)
- Hai Zhou
- Department of Oncology, The Affiliated Hospital of Qingdao University, No. 7 Jiaxing Road, Qingdao, 266000, Shandong, China
| | - Dantong Sun
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Shanai Song
- Department of Oncology, The Affiliated Hospital of Qingdao University, No. 7 Jiaxing Road, Qingdao, 266000, Shandong, China
| | - Yurong Niu
- Department of Oncology, The Affiliated Hospital of Qingdao University, No. 7 Jiaxing Road, Qingdao, 266000, Shandong, China
| | - Yuming Zhang
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Hongwei Lan
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Jiali Cui
- Department of Oncology, The Affiliated Hospital of Qingdao University, No. 7 Jiaxing Road, Qingdao, 266000, Shandong, China
| | - Houde Liu
- Medical College of Qingdao University, No.308 Ningxia Road, Qingdao, 266000, Shandong, China
| | - Ning Liu
- Department of Oncology, The Affiliated Hospital of Qingdao University, No. 7 Jiaxing Road, Qingdao, 266000, Shandong, China
| | - Helei Hou
- Department of Oncology, The Affiliated Hospital of Qingdao University, No. 7 Jiaxing Road, Qingdao, 266000, Shandong, China.
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Zhang X, Zhang Y, Zhang Q, Lu M, Chen Y, Zhang X, Zhang P. Role of AT-rich interaction domain 1A in gastric cancer immunotherapy: Preclinical and clinical perspectives. J Cell Mol Med 2024; 28:e18063. [PMID: 38041544 PMCID: PMC10902580 DOI: 10.1111/jcmm.18063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/31/2023] [Accepted: 11/14/2023] [Indexed: 12/03/2023] Open
Abstract
The application of immune checkpoint inhibitor (ICI) using monoclonal antibodies has brought about a profound transformation in the clinical outcomes for patients grappling with advanced gastric cancer (GC). Nonetheless, despite these achievements, the quest for effective functional biomarkers for ICI therapy remains constrained. Recent research endeavours have shed light on the critical involvement of modified epigenetic regulators in the pathogenesis of gastric tumorigenesis, thus providing a glimpse into potential biomarkers. Among these regulatory factors, AT-rich interaction domain 1A (ARID1A), a pivotal constituent of the switch/sucrose non-fermentable (SWI/SNF) complex, has emerged as a promising candidate. Investigations have unveiled the pivotal role of ARID1A in bridging the gap between genome instability and the reconfiguration of the tumour immune microenvironment, culminating in an enhanced response to ICI within the landscape of gastric cancer treatment. This all-encompassing review aims to dissect the potential of ARID1A as a valuable biomarker for immunotherapeutic approaches in gastric cancer, drawing from insights garnered from both preclinical experimentation and clinical observations.
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Affiliation(s)
- Xuemei Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Youzhi Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- School of PharmacyHubei University of Science and TechnologyXianningChina
| | - Qiaoyun Zhang
- School of PharmacyHubei University of Science and TechnologyXianningChina
| | - Mengyao Lu
- Department of Oncology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yuan Chen
- Department of Oncology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Xiaoyu Zhang
- Division of Gastrointestinal Surgery, Department of General Surgery, Huai'an Second People's Hospitalthe Affiliated Huai'an Hospital of Xuzhou Medical UniversityHuaianChina
| | - Peng Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
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Anbouhi TS, Sazegar H, Rahimi E. Recognizing the role of Epstein-Barr virus in gastric cancer: transcriptomic insights into malignancy modulation. Virol J 2024; 21:41. [PMID: 38355581 PMCID: PMC10868016 DOI: 10.1186/s12985-024-02307-z] [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: 10/07/2023] [Accepted: 01/29/2024] [Indexed: 02/16/2024] Open
Abstract
BACKGROUND Studies show that Epstein-Barr virus (EBV) infection can play a role in malignancy and increase the risk of gastric cancer (GC). The objective of this research was to pinpoint genes whose expression may be influenced by EBV and play a role in the development of GC. METHODS Candidate genes potentially susceptible to expression modulation in the presence of EBV were identified through the analysis of GSE185627 and GSE51575 datasets. The association of candidate genes with GC and the survival rate of patients was investigated based on the cancer genome atlas (TCGA) data. Also, pathways related to candidate genes were examined through the MsigDB database. The PPI network was used to identify Hub genes. To corroborate the obtained results, we utilized the RT-qPCR method, employing GC samples from both EBV + and EBV-cases, as well as adjacent normal samples. RESULTS Our results showed that genes upregulated by the EBV in the GC cell line, as well as in EBV + samples, are significantly linked to pathways involving the immune response, inflammation, and the P53 pathway. Conversely, genes downregulated by EBV are closely linked to pathways involving cell proliferation and mTORC1. Examining the candidate genes revealed that a considerable portion of genes susceptible to downregulation under the influence of EBV exhibit oncogenic roles based on TCGA data. Moreover, some of these genes are associated with an unfavorable prognosis. Protein-protein interaction network analysis of candidate genes highlighted IFI44L and OAS2 as potential hub genes in the EBV-GC axis. Our RT-qPCR results further validated these findings, demonstrating that the expression levels of IFI44L and OAS2 were higher in EBV + samples compared to both healthy and EBV-samples. CONCLUSION Our study underscores the capacity of EBV to exert regulatory control over genes associated with GC malignancy. In addition to its inflammatory effects, EBV elicits transcriptomic changes that appear to attenuate the progression of GC.
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Affiliation(s)
- Tabassom Sedaghat Anbouhi
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Hossein Sazegar
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Ebrahim Rahimi
- Department of Food Hygiene, Faculty of Veterinary Medicine, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
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Li G, Zhou Z, Wang Z, Wang Z. Assessing Epstein-Barr virus in gastric cancer: clinicopathological features and prognostic implications. Infect Agent Cancer 2023; 18:11. [PMID: 36803802 PMCID: PMC9938970 DOI: 10.1186/s13027-023-00489-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 02/14/2023] [Indexed: 02/21/2023] Open
Abstract
BACKGROUND Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) was a unique molecular subtype of gastric cancer (GC). However, the clinicopathological characteristics and prognostic role of EBV infection remains unclear. We aimed to evaluate the clinicopathological features of EBVaGC and its role on prognosis. METHODS EBV-encoded RNA (EBER) in situ hybridization method was used to evaluate the EBV status in GC. The serum tumor markers AFP, CEA, CA19-9 and CA125 of patients were detected before treatment. HER2 expression and microsatellite instability (MSI) status was evaluated according to established criteria. The relationship between EBV infection and clinicopathological factors as well as its role on prognosis were investigated. RESULTS 420 patients were enrolled in the study and of 53 patients (12.62%) were identified as EBVaGC. EBVaGC was more common in males (p = 0.001) and related to early T stage (p = 0.045), early TNM stage (p = 0.001) and lower level of serum CEA (p = 0.039). No association could be found between EBV infection and HER2 expression, MSI status and other factors (p all > 0.05). Kaplan-Meier analysis revealed that both the overall survival and disease-free survival of EBVaGC patients were similar to that of EBV-negative GC (EBVnGC) patients (p = 0.309 and p = 0.264, respectively). CONCLUSION EBVaGC was more common in males and in patients with the early T stage and TNM stage as well as patients with lower serum CEA level. Difference in overall survival and disease-free survival between EBVaGC and EBVnGC patients cannot be detected.
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Affiliation(s)
- Guanghua Li
- grid.412615.50000 0004 1803 6239Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Zhongshan 2nd Street, No. 58, Guangzhou, 510080 Guangdong China
| | - Zhihao Zhou
- grid.412615.50000 0004 1803 6239Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Zhongshan 2nd Street, No. 58, Guangzhou, 510080 Guangdong China
| | - Zhixiong Wang
- grid.412615.50000 0004 1803 6239Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Zhongshan 2nd Street, No. 58, Guangzhou, 510080 Guangdong China
| | - Zhao Wang
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Sun Yat-Sen University, Zhongshan 2nd Street, No. 58, Guangzhou, 510080, Guangdong, China.
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Kori M, Arga KY. Human oncogenic viruses: an overview of protein biomarkers in viral cancers and their potential use in clinics. Expert Rev Anticancer Ther 2022; 22:1211-1224. [PMID: 36270027 DOI: 10.1080/14737140.2022.2139681] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
INTRODUCTION Although the idea that carcinogenesis might be caused by viruses was first voiced about 100 years ago, today's data disappointingly show that we have not made much progress in preventing and/or treating viral cancers in a century. According to recent studies, infections are responsible for approximately 13% of cancer development in the world. Today, it is accepted and proven by many authorities that Epstein-Barr virus (EBV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Human Herpesvirus 8 (HHV8), Human T-cell Lymphotropic virus 1 (HTLV1) and highly oncogenic Human Papillomaviruses (HPVs) cause or/and contribute to cancer development in humans. AREAS COVERED Considering the insufficient prevention and/or treatment strategies for viral cancers, in this review we present the current knowledge on protein biomarkers of oncogenic viruses. In addition, we aimed to decipher their potential for clinical use by evaluating whether the proposed biomarkers are expressed in body fluids, are druggable, and act as tumor suppressors or oncoproteins. EXPERT OPINION Consequently, we believe that this review will shed light on researchers and provide a guide to find remarkable solutions for the prevention and/or treatment of viral cancers.
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Affiliation(s)
- Medi Kori
- Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey
| | - Kazim Yalcin Arga
- Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey.,Genetic and Metabolic Diseases Research and Investigation Center (GEMHAM), Marmara University, Istanbul, Turkey
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Kim HN, Ahn S, Kim KM. Gastric cancer with Epstein-Barr virus heterogeneity: Evaluation of the frequency, clinicopathologic features, and genomic profiles. Pathol Res Pract 2022; 238:154108. [PMID: 36126450 DOI: 10.1016/j.prp.2022.154108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 08/28/2022] [Accepted: 08/31/2022] [Indexed: 11/27/2022]
Abstract
Epstein-Barr virus (EBV)-associated gastric carcinoma accounts for approximately 10% of gastric carcinomas worldwide and is characterized by distinct clinicopathological features. Recently, the use of EBV as a reliable biomarker for immunotherapy of gastric cancer has been gaining focus. We aimed to investigate the frequency and clinicopathological characteristics of gastric cancer with EBV heterogeneity. EBV status was evaluated using EBV-encoded RNA in situ hybridization in 3499 consecutive surgical cases of gastric cancer. We selected heterogeneous EBV cases and evaluated their clinicopathological features. CD8, programmed death-ligand 1 status, and genomic profiles were separately evaluated in each EBV-positive and EBV-negative area of heterogeneous cases. EBV positivity was identified in 214 (6.1 %) cases, of which four (1.9 %) were found to be EBV heterogeneous. Of the four heterogeneous EBV cases, three were composed of two histologically distinct patterns that correlated with EBV status. The EBV-positive area consisted of poorly differentiated adenocarcinomas with increased lymphocytic infiltration. Notably, the fraction of EBV-positive cells was more infiltrative, and metastatic tumors in the lymph nodes were all EBV-positive. The average number of CD8-positive cells was higher in EBV-positive areas than in EBV-negative areas (P = 0.030). Each EBV-positive and EBV-negative area revealed some different genomic alterations, including FGFR2 amplification. In conclusion, we have reported four cases of gastric cancer with heterogeneous EBV status, which accounted for 1.9% of EBV-positive gastric cancers. Each EBV-positive and-negative area revealed a distinct histological pattern, immune microenvironment, and some different genomic profiles.
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Affiliation(s)
- Han-Na Kim
- Department of Pathology and Translational Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Soomin Ahn
- Department of Pathology and Translational Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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Lamare FA, Khongsti S, Marthong L, Ghosh S, Chenkual S, Dkhar H, Maitra A, Ghosh S. Genome-wide DNA methylation profiling of stomach cancer in the ethnic population of Mizoram, North East India. Genomics 2022; 114:110478. [PMID: 36064073 DOI: 10.1016/j.ygeno.2022.110478] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 08/10/2022] [Accepted: 08/31/2022] [Indexed: 12/01/2022]
Abstract
Stomach cancer is the fifth most common cancer in terms of prevalence and incidence and the fourth leading cause of mortality in men and women worldwide. It is well-established that aberrant DNA methylation in cells can lead to carcinogenesis. The primary objective of our study was to investigate the aberrant DNA methylation status of genes associated with stomach cancer with a particular reference to the ethnic population of Mizoram, North East India. The site-level analysis identified 2883 CpG sites differentially methylated, representing ~922 genes. Out of which 476 Differentially Methylated Positions (DMPs) were promoter-associated, 452 DMPs were hypermethylated, and 24 were hypomethylated. The region-level analysis identified 462 Differentially Methylated Regions (DMRs) corresponding to ~320 genes, of which ~281 genes were hypermethylated and ~ 40 genes were hypomethylated. TCGA analysis showed that some of the genes had been previously implicated in other cancers including stomach cancer. Five hypermethylated genes were selected as candidate genes for further investigations and they have shown to be novel and could serve as candidate hypermethylation biomarkers for stomach cancer in this particular ethnic group.
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Affiliation(s)
- F A Lamare
- Department of Zoology, North-Eastern Hill University (NEHU), Shillong, India
| | - S Khongsti
- Department of Zoology, North-Eastern Hill University (NEHU), Shillong, India
| | - L Marthong
- Department of Zoology, North-Eastern Hill University (NEHU), Shillong, India
| | - S Ghosh
- National Institute of Biomedical Genomics (NIBMG), Kalyani, West Bengal, India
| | | | - H Dkhar
- Nazareth Hospital, Shillong, India
| | - A Maitra
- National Institute of Biomedical Genomics (NIBMG), Kalyani, West Bengal, India
| | - S Ghosh
- Department of Zoology, North-Eastern Hill University (NEHU), Shillong, India.
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Javadzadeh S, Rajkumar U, Nguyen N, Sarmashghi S, Luebeck J, Shang J, Bafna V. FastViFi: Fast and accurate detection of (Hybrid) Viral DNA and RNA. NAR Genom Bioinform 2022; 4:lqac032. [PMID: 35493723 PMCID: PMC9041341 DOI: 10.1093/nargab/lqac032] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 03/04/2022] [Accepted: 03/06/2022] [Indexed: 11/13/2022] Open
Abstract
DNA viruses are important infectious agents known to mediate a large number of human diseases, including cancer. Viral integration into the host genome and the formation of hybrid transcripts are also associated with increased pathogenicity. The high variability of viral genomes, however requires the use of sensitive ensemble hidden Markov models that add to the computational complexity, often requiring > 40 CPU-hours per sample. Here, we describe FastViFi, a fast 2-stage filtering method that reduces the computational burden. On simulated and cancer genomic data, FastViFi improved the running time by 2 orders of magnitude with comparable accuracy on challenging data sets. Recently published methods have focused on identification of location of viral integration into the human host genome using local assembly, but do not extend to RNA. To identify human viral hybrid transcripts, we additionally developed ensemble Hidden Markov Models for the Epstein Barr virus (EBV) to add to the models for Hepatitis B (HBV), Hepatitis C (HCV) viruses and the Human Papillomavirus (HPV), and used FastViFi to query RNA-seq data from Gastric cancer (EBV) and liver cancer (HBV/HCV). FastViFi ran in <10 minutes per sample and identified multiple hybrids that fuse viral and human genes suggesting new mechanisms for oncoviral pathogenicity. FastViFi is available at https://github.com/sara-javadzadeh/FastViFi.
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Affiliation(s)
- Sara Javadzadeh
- Department of Computer Science & Engineering, UC San Diego, La Jolla, California, USA
| | - Utkrisht Rajkumar
- Department of Computer Science & Engineering, UC San Diego, La Jolla, California, USA
| | - Nam Nguyen
- Boundless Bio, Inc. 11099 N Torrey Pines Rd, La Jolla, CA, USA
| | - Shahab Sarmashghi
- Department of Electrical and Computer Engineering, UC San Diego, La Jolla, California, USA
| | - Jens Luebeck
- Bioinformatics & Systems Biology Graduate Program, UC San Diego, La Jolla, California, USA
| | - Jingbo Shang
- Department of Computer Science & Engineering, UC San Diego, La Jolla, California, USA
| | - Vineet Bafna
- Department of Computer Science & Engineering, UC San Diego, La Jolla, California, USA
- Boundless Bio, Inc. 11099 N Torrey Pines Rd, La Jolla, CA, USA
- Moores Cancer Center, UC San Diego, La Jolla, California, USA
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Satou A, Takahara T, Nakamura S. An Update on the Pathology and Molecular Features of Hodgkin Lymphoma. Cancers (Basel) 2022; 14:cancers14112647. [PMID: 35681627 PMCID: PMC9179292 DOI: 10.3390/cancers14112647] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 05/21/2022] [Accepted: 05/24/2022] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Hodgkin lymphomas (HLs) include two main types, classic HL (CHL) and nodular lymphocyte predominant HL (NLPHL). Recent molecular findings in HLs have contributed to dramatic changes in the treatment and identification of tumor characteristics. For example, PD-1/PD-L1 blockade and brentuximab vedotin, an anti-CD30 antibody bearing a cytotoxic compound, are now widely used in patients with CHL. Biological continuity between NLPHL and T-cell/histiocyte-rich large B-cell lymphoma has been highlighted. An era of novel therapeutics for HL has begun. The aim of this paper is to review the morphologic, immunophenotypic, and molecular features of CHL and NLPHL, which must be understood for the development of novel therapeutics. Abstract Hodgkin lymphomas (HLs) are lymphoid neoplasms derived from B cells and consist histologically of large neoplastic cells known as Hodgkin and Reed–Sternberg cells and abundant reactive bystander cells. HLs include two main types, classic HL (CHL) and nodular lymphocyte predominant HL (NLPHL). Recent molecular analyses have revealed that an immune evasion mechanism, particularly the PD-1/PD-L1 pathway, plays a key role in the development of CHL. Other highlighted key pathways in CHL are NF-κB and JAK/STAT. These advances have dramatically changed the treatment for CHL, particularly relapsed/refractory CHL. For example, PD-1 inhibitors are now widely used in relapsed/refractory CHL. Compared with CHL, NLPHL is more characterized by preserved B cell features. Overlapping morphological and molecular features between NLPHL and T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) have been reported, and biological continuity between these two entities has been highlighted. Some THRLBCLs are considered to represent progression from NLPHLs. With considerable new understanding becoming available from molecular studies in HLs, therapies and classification of HLs are continually evolving. This paper offers a summary of and update on the pathological and molecular features of HLs for a better understanding of the diseases.
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Affiliation(s)
- Akira Satou
- Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute 480-1195, Japan;
- Correspondence: ; Tel.: +81-561-62-3311; Fax: +81-561-61-3811
| | - Taishi Takahara
- Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute 480-1195, Japan;
| | - Shigeo Nakamura
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya 466-8550, Japan;
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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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Abstract
Epstein-Barr virus-positive gastric cancer [EBV (+) GC] is associated with EBV infection and is one of the GC subtypes defined by the Cancer Genome Atlas. EBV (+) GC has several distinct genomic or epigenomic features and clinicopathological characteristics compared with other molecular subtypes of GC. Here, we summarize the unique features of EBV (+) GC including the clinical and histopathological features, and discuss associated genetic and epigenetic aberrations. We also discuss noncoding RNAs [EBV-encoded RNAs and EBV-encoded microRNAs (miRNAs)] derived from EBV-infected cells, which have not been described in detail previously. These noncoding RNAs are defined by their roles; for example, EBV-encoded miRNAs play pivotal roles in oncogenesis and tumor progression in EBV (+) GC. We also discuss recent advances in therapeutic modalities for EBV (+) GC, as well as the potential of EBV infection as a predictive biomarker of the response to anti-PD-1 therapy with immune checkpoint inhibitors. We introduce our recent studies focusing on AT-rich interactive domain 1A gene mutations and programmed death ligand-1 overexpression/CD274 copy-number amplification, which are recurrently identified in EBV (+) GC. Finally, based on those findings, we propose potential therapeutic options using candidate-targeted therapies against EBV (+) GC.
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13
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Satou A, Nakamura S. EBV-positive B-cell lymphomas and lymphoproliferative disorders: Review from the perspective of immune escape and immunodeficiency. Cancer Med 2021; 10:6777-6785. [PMID: 34387382 PMCID: PMC8495296 DOI: 10.1002/cam4.4198] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 06/04/2021] [Accepted: 07/28/2021] [Indexed: 01/15/2023] Open
Abstract
Background Epstein‐Barr virus (EBV) is detected in a variety of B‐cell lymphomas (BCLs) and B‐cell lymphoproliferative disorders (B‐LPDs). Immunodeficiency has been considered to play a key role in the pathogenesis of these diseases. In addition, immune escape of tumor cells may also contribute to the development of EBV+ BCLs and B‐LPDs. The PD‐1/PD‐L1 pathway is particularly important for immune escape of tumor cells that contribute to development of lymphoma through suppression of cytotoxic T‐cell function. We now consider PD‐L1 immunohistochemistry (IHC) a very useful method for predicting whether tumor cells of lymphoid malignancies are characterized by the immune escape mechanism. Methods We reviewed articles of EBV+ BCLs and B‐LPDs from the perspective of immune escape and immunodeficiency, particularly focusing on PD‐L1 IHC. Results Based on PD‐L1 IHC, we consider that EBV+ BCL and B‐LPD can be classified into three types: “immunodeficiency”, “immune escape”, and “immunodeficiency + immune escape” type. The immunodeficiency type includes EBV+ diffuse large BCL (DLBCL) of the elderly, EBV+ sporadic Burkitt lymphoma, EBV+ mucocutaneous ulcer, and methotrexate (MTX)‐associated B‐LPD. The immune escape type includes EBV+ classic Hodgkin lymphoma (CHL) and EBV+ DLBCL of the young. The immunodeficiency + immune escape type includes CHL type MTX‐associated LPD and a minor subset of EBV+ DLBCL of the elderly. Conclusions Recently, good results have been reported for immune check‐point inhibitors in treating lymphoma. Lymphomas and LPDs characterized by immune escape are regarded as good candidates for PD1/PD‐L1 blockade therapy. Therefore, from both the clinical and pathological perspective, we suggest that lymphoma diagnosis should be made considering immune escape and immunodeficiency.
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Affiliation(s)
- Akira Satou
- Department of Surgical Pathology, Aichi Medical University Hospital, Nagakute, Japan
| | - Shigeo Nakamura
- Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, Japan
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14
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Kase K, Saito M, Nakajima S, Takayanagi D, Saito K, Yamada L, Ashizawa M, Nakano H, Hanayama H, Onozawa H, Okayama H, Endo H, Fujita S, Sakamoto W, Saze Z, Momma T, Mimura K, Ohki S, Shiraishi K, Kohno T, Kono K. ARID1A deficiency in EBV-positive gastric cancer is partially regulated by EBV-encoded miRNAs, but not by DNA promotor hypermethylation. Carcinogenesis 2021; 42:21-30. [PMID: 33196828 DOI: 10.1093/carcin/bgaa123] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 10/21/2020] [Accepted: 11/09/2020] [Indexed: 12/11/2022] Open
Abstract
AT-rich interactive domain 1A (ARID1A), which is a tumor suppressor gene, is frequently mutated in Epstein-Barr virus-positive gastric cancer [EBV (+) GC]. While most ARID1A mutations in GC are truncating mutations, leading to loss of ARID1A protein expression, epigenetic modifications appear to contribute to ARID1A deficiency in EBV (+) GC harboring wild-type ARID1A. Based on the significant role of epigenetic modifications in EBV (+) GC that contributes to ARID1A deficiency, the methylation status of ARID1A was evaluated in EBV-infected cells and GC patients using a publicly available microarray and the Cancer Genome Atlas (TCGA) database. EBV-encoded miRNAs that potentially target ARID1A were identified as an additional epigenetic modulator by computational prediction. In vitro experiments were conducted to evaluate how EBV-encoded miRNAs affected ARID1A mRNA and protein levels. In clinical GC samples, the expression of predicted miRNAs and ARID1A and the mutation status of ARID1A was evaluated. As results, ARID1A was not hypermethylated in EBV (+) GC samples or EBV-infected GC cells. EBV infection did not alter ARID1A mRNA levels, suggesting that ARID1A protein deficiency was caused by post-transcriptional gene silencing in ARID1A-WT EBV (+) GC. Overexpression of miR-BART11-3p and miR-BART12, which were identified as miRNAs that potentially bind ARID1A, suppressed ARID1A protein expression in MKN7 and NCI-N87 cells. Highly expressed miR-BART11-3p and miR-BART12 were correlated with decreased ARID1A levels in GC tumors which did not harbor ARID1A mutations. The present findings revealed that ARID1A expression was epigenetically regulated by miR-BART11-3p and miR-BART12 in EBV (+) GC.
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Affiliation(s)
- Koji Kase
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Motonobu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Shotaro Nakajima
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.,Department of Medical Electrophysiology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Daisuke Takayanagi
- Divisioin of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
| | - Katsuharu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Leo Yamada
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Mai Ashizawa
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hiroshi Nakano
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hiroyuki Hanayama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hisashi Onozawa
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hirokazu Okayama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hisahito Endo
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Shotaro Fujita
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Wataru Sakamoto
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Zenichiro Saze
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Tomoyuki Momma
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kosaku Mimura
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan.,Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Shinji Ohki
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kouya Shiraishi
- Divisioin of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
| | - Takashi Kohno
- Divisioin of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
| | - Koji Kono
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan
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15
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Viral Manipulation of the Host Epigenome as a Driver of Virus-Induced Oncogenesis. Microorganisms 2021; 9:microorganisms9061179. [PMID: 34070716 PMCID: PMC8227491 DOI: 10.3390/microorganisms9061179] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 12/13/2022] Open
Abstract
Tumorigenesis due to viral infection accounts for a high fraction of the total global cancer burden (15–20%) of all human cancers. A comprehensive understanding of the mechanisms by which viral infection leads to tumor development is extremely important. One of the main mechanisms by which viruses induce host cell proliferation programs is through controlling the host’s epigenetic machinery. In this review, we dissect the epigenetic pathways through which oncogenic viruses can integrate their genome into host cell chromosomes and lead to tumor progression. In addition, we highlight the potential use of drugs based on histone modifiers in reducing the global impact of cancer development due to viral infection.
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16
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Kim Y, Shin YJ, Wen X, Cho NY, Li M, Kim YJ, Song SH, Kang GH. Alteration in stemness causes exclusivity between Epstein-Barr virus-positivity and microsatellite instability status in gastric cancer. Gastric Cancer 2021; 24:602-610. [PMID: 33386473 DOI: 10.1007/s10120-020-01146-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 11/18/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancer (GC) is a leading cause of cancer morbidity and mortality worldwide. This is due to the heterogeneous features of GC, which consist of a diverse molecular phenotype. Epstein-Barr virus (EBV)-positive GC and microsatellite instability (MSI)-high GC encompass similar epigenetic traits, including high levels of DNA methylation in CpG islands; however, EBV-positive and MSI-high GCs are mutually exclusive. We aimed to elucidate the underlying mechanism of this exclusivity. METHODS We knocked out MLH1 in EBV-positive GC cell lines SNU-719 and NCC24 via CRISPR-Cas9, and evaluated the modified cellular properties in vitro and in vivo. The MSI status of each cell line was screened with two marker capillary electrophoresis, and further diagnosed with five marker capillary electrophoresis and parallel sequencing using 21 markers. RESULTS Initial evaluation showed that cell growth, migration, invasion, and MSI status were not affected by MLH1 silencing. However, with prolonged passage, GC cell lines gradually gained MSI and NCC24 cells were transformed to EBV-positive/MSI-high GC cells after 12 months. Furthermore, MLH1 silencing reduced tumor stemness in SNU-719 and NCC24 regardless of the MSI status in vitro and in vivo. CONCLUSIONS Our findings suggest that EBV-positivity and MSI-high status are mutually exclusive due to the immediate disadvantage in tumor stemness when MLH1 is silenced, whereas the establishment of MSI-high status in EBV-positive GCs required a longer period.
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Affiliation(s)
- Younghoon Kim
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.,Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Ihwa-dong, Jongno-gu, Seoul, 03080, South Korea
| | - Yun-Joo Shin
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Xianyu Wen
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.,Guangdong Research Institute of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Nam-Yun Cho
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.,Department of Cancer Biology, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Meihui Li
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.,Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Ihwa-dong, Jongno-gu, Seoul, 03080, South Korea
| | - Yun-Jee Kim
- Department of Molecular Medicine and Biopharmaceutical Sciences, Cancer Research Center, Seoul National University College of Medicine, Seoul, South Korea
| | - Sang Hyun Song
- Department of Molecular Medicine and Biopharmaceutical Sciences, Cancer Research Center, Seoul National University College of Medicine, Seoul, South Korea
| | - Gyeong Hoon Kang
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea. .,Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Ihwa-dong, Jongno-gu, Seoul, 03080, South Korea.
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17
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Torres K, Landeros N, Wichmann IA, Polakovicova I, Aguayo F, Corvalan AH. EBV miR-BARTs and human lncRNAs: Shifting the balance in competing endogenous RNA networks in EBV-associated gastric cancer. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166049. [PMID: 33401001 DOI: 10.1016/j.bbadis.2020.166049] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 12/04/2020] [Accepted: 12/14/2020] [Indexed: 02/06/2023]
Abstract
Non-coding RNAs (ncRNAs) contribute to the regulation of gene expression. By acting as competing endogenous RNA (ceRNA), long non-coding RNAs (lncRNAs) hijack microRNAs (miRNAs) and inhibit their ability to bind their coding targets. Viral miRNAs can compete with and target the same transcripts as human miRNAs, shifting the balance in networks associated with multiple cellular processes and diseases. Epstein-Barr virus (EBV) is an example of how a subset of viral coding RNA and non-coding RNAs can cause deregulation of human transcripts and contribute to the development of EBV-associated malignancies. EBV non-coding transforming genes include lncRNAs (i.e circular RNAs), and small ncRNAs (i.e. miRNAs). Among the latter, most ongoing research has focused on miR-BARTs whereas target many genes associated with apoptosis and epithelial-mesenchymal transition, in EBV-associated gastric cancer (GC). In this review, we propose to include the interactions between EBV ncRNAs human transcripts in the hypothesis known as "competitive viral and host RNAs". These interactions may shift the balance in biological pathways such as apoptosis and epithelial-mesenchymal transition in EBV-associated gastric cancer.
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Affiliation(s)
- Keila Torres
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile; UC Center for Investigational Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Natalia Landeros
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile; UC Center for Investigational Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ignacio A Wichmann
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile; UC Center for Investigational Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Iva Polakovicova
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile; UC Center for Investigational Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Francisco Aguayo
- Advanced Center for Chronic Diseases, Universidad de Chile, Santiago, Chile; Virology Program, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Alejandro H Corvalan
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile; UC Center for Investigational Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile; Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
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18
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Sun K, Jia K, Lv H, Wang SQ, Wu Y, Lei H, Chen X. EBV-Positive Gastric Cancer: Current Knowledge and Future Perspectives. Front Oncol 2020; 10:583463. [PMID: 33381453 PMCID: PMC7769310 DOI: 10.3389/fonc.2020.583463] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 09/09/2020] [Indexed: 12/16/2022] Open
Abstract
Gastric cancer is the fifth most common malignant tumor and second leading cause of cancer-related deaths worldwide. With the improved understanding of gastric cancer, a subset of gastric cancer patients infected with Epstein–Barr virus (EBV) has been identified. EBV-positive gastric cancer is a type of tumor with unique genomic aberrations, significant clinicopathological features, and a good prognosis. After EBV infects the human body, it first enters an incubation period in which the virus integrates its DNA into the host and expresses the latent protein and then affects DNA methylation through miRNA under the action of the latent protein, which leads to the occurrence of EBV-positive gastric cancer. With recent developments in immunotherapy, better treatment of EBV-positive gastric cancer patients appears achievable. Moreover, studies show that treatment with immunotherapy has a high effective rate in patients with EBV-positive gastric cancer. This review summarizes the research status of EBV-positive gastric cancer in recent years and indicates areas for improvement of clinical practice.
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Affiliation(s)
- Keran Sun
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Keqi Jia
- Department of Pathology, Pathology Department of Hebei Medical University, Shijiazhuang, China
| | - Huifang Lv
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Sai-Qi Wang
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yan Wu
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Huijun Lei
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Xiaobing Chen
- Department of Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
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19
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Epstein-Barr virus-associated gastric cancer: A distinct subtype. Cancer Lett 2020; 495:191-199. [PMID: 32979463 DOI: 10.1016/j.canlet.2020.09.019] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 08/28/2020] [Accepted: 09/21/2020] [Indexed: 12/11/2022]
Abstract
Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC) is a common malignant tumor associated with EBV infection. The molecular classification of gastric carcinoma indicates that EBVaGC is a distinct subtype in terms of oncogenesis and molecular features. Viral proteins, Bam-HI-A rightward transcripts (BART) miRNAs, and Bam-HI A rightward frame 1 (BARF1) promote oncogenesis after EBV infection via the induction of methylation, regulation of host gene expression, and malignant transformation. Together with abnormal mutations and amplification of the host genome as driving factors, interactions between the EBV genome and host genome accelerate carcinogenesis. The molecular profile of EBVaGC is that of EBV driving DNA hypermethylation, frequent phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations, and the overexpression of Janus kinase 2 (JAK2), programmed death ligand-1 (PD-L1), and PD-L2. Clinically, the frequency of lymph node metastasis is lower, and the prognosis is better for EBVaGC than EBV-negative gastric cancer (EBVnGC). Pathologically, EBVaGC is a gastric adenocarcinoma with lymphoid stroma. This review interprets how the EBV genome is involved in the oncogenesis of gastric cancer and describes the molecular and clinicopathological features of EBVaGC.
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20
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Lopez EM, Tanner AM, Du E, Patel SN, Weiss J, Weissler MC, Hackman T, Gupta GP, Zevallos J, Elmore S, Betancourt R, Thorne L, Sheth S, Gulley ML. Decline in circulating viral and human tumor markers after resection of head and neck carcinoma. Head Neck 2020; 43:27-34. [PMID: 32860343 DOI: 10.1002/hed.26444] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 07/12/2020] [Accepted: 08/14/2020] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND DNA sequencing panels can simultaneously quantify human and viral tumor markers in blood. We explored changes in levels of plasma tumor markers following surgical resection of head and neck carcinoma. METHODS In preresection and postresection plasmas, targeted DNA sequencing quantified variants in 28 human cancer genes and levels of oncogenic pathogens (human papillomavirus [HPV], Epstein-Barr virus [EBV], Helicobacter pylori) from 21 patients with head and neck squamous cell carcinoma. RESULTS Preresection, 11 of 21 patients (52%) had detectable tumor markers in plasma, most commonly TP53 mutation or HPV genome. Several days postresection, levels fell to undetectable in 8 of 10 evaluable patients, while two high-stage patients retained circulating tumor markers. CONCLUSIONS Modern sequencing technology can simultaneously quantify human gene variants and oncogenic viral genomes in plasma. Falling levels of cancer-specific markers upon resection can help identify viral and human markers to track at subsequent timepoints as a means to evaluate efficacy of interventions.
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Affiliation(s)
- Erin M Lopez
- Department of Otolaryngology-Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - April Michelle Tanner
- Department of Otolaryngology-Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Eugenie Du
- Department of Otolaryngology-Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Samip N Patel
- Department of Otolaryngology-Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jared Weiss
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Department of Medicine, Oncology Division, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Mark C Weissler
- Department of Otolaryngology-Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Trevor Hackman
- Department of Otolaryngology-Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Gaorav P Gupta
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jose Zevallos
- Department of Otolaryngology-Head and Neck Surgery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Sandra Elmore
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Renee Betancourt
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Leigh Thorne
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Siddharth Sheth
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Department of Medicine, Oncology Division, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Margaret L Gulley
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.,Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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21
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Fiches GN, Zhou D, Kong W, Biswas A, Ahmed EH, Baiocchi RA, Zhu J, Santoso N. Profiling of immune related genes silenced in EBV-positive gastric carcinoma identified novel restriction factors of human gammaherpesviruses. PLoS Pathog 2020; 16:e1008778. [PMID: 32841292 PMCID: PMC7473590 DOI: 10.1371/journal.ppat.1008778] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 09/04/2020] [Accepted: 07/05/2020] [Indexed: 12/24/2022] Open
Abstract
EBV-associated gastric cancer (EBVaGC) is characterized by high frequency of DNA methylation. In this study, we investigated how epigenetic alteration of host genome contributes to pathogenesis of EBVaGC through the analysis of transcriptomic and epigenomic datasets from NIH TCGA (The Cancer Genome Atlas) consortium. We identified that immune related genes (IRGs) is a group of host genes preferentially silenced in EBV-positive gastric cancers through DNA hypermethylation. Further functional characterizations of selected IRGs reveal their novel antiviral activity against not only EBV but also KSHV. In particular, we showed that metallothionein-1 (MT1) and homeobox A (HOXA) gene clusters are down-regulated via EBV-driven DNA hypermethylation. Several MT1 isoforms suppress EBV lytic replication and release of progeny virions as well as KSHV lytic reactivation, suggesting functional redundancy of these genes. In addition, single HOXA10 isoform exerts antiviral activity against both EBV and KSHV. We also confirmed the antiviral effect of other dysregulated IRGs, such as IRAK2 and MAL, in scenario of EBV and KSHV lytic reactivation. Collectively, our results demonstrated that epigenetic silencing of IRGs is a viral strategy to escape immune surveillance and promote viral propagation, which is overall beneficial to viral oncogenesis of human gamma-herpesviruses (EBV and KSHV), considering that these IRGs possess antiviral activities against these oncoviruses.
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Affiliation(s)
- Guillaume N. Fiches
- Department of Pathology, Ohio State University College of Medicine, Columbus, Ohio, United States of America
| | - Dawei Zhou
- Department of Pathology, Ohio State University College of Medicine, Columbus, Ohio, United States of America
| | - Weili Kong
- Gladstone Institute of Virology and Immunology, University of California, San Francisco, California, United States of America
| | - Ayan Biswas
- Department of Pathology, Ohio State University College of Medicine, Columbus, Ohio, United States of America
| | - Elshafa H. Ahmed
- Division of Hematology, Department of Internal Medicine, Ohio State University College of Medicine, Columbus, Ohio, United States of America
| | - Robert A. Baiocchi
- Division of Hematology, Department of Internal Medicine, Ohio State University College of Medicine, Columbus, Ohio, United States of America
| | - Jian Zhu
- Department of Pathology, Ohio State University College of Medicine, Columbus, Ohio, United States of America
| | - Netty Santoso
- Department of Pathology, Ohio State University College of Medicine, Columbus, Ohio, United States of America
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22
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Kayamba V, Butt J, Waterboer T, Besa E, Choudhry N, Hamasuku A, Julius P, Heimburger DC, Atadzhanov M, Kelly P. Molecular profiling of gastric cancer in a population with high HIV prevalence reveals a shift to MLH1 loss but not the EBV subtype. Cancer Med 2020; 9:3445-3454. [PMID: 32207245 PMCID: PMC7221426 DOI: 10.1002/cam4.3001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 02/19/2020] [Accepted: 03/01/2020] [Indexed: 12/29/2022] Open
Abstract
The human immunodeficiency virus (HIV) pandemic heavily affects sub-Saharan Africa. It is associated with persistently active Epstein-Barr virus (EBV) infection. To determine if this translates into increased frequency of EBV-associated gastric cancer (EBVaGC), we evaluated molecular profiles of gastric cancer (GC) in Zambia. Patients with GC or premalignant gastric lesions were enrolled in Lusaka, Zambia. We used patients without any of these lesions as a control group. Chromogenic in situ hybridization (CISH) on tumor tissue was used to identify EBVaGC. To identify the microsatellite unstable subtype, immunofluorescence staining for MutL homolog 1 (MLH1) was used. Exposure to EBV and HIV was assessed serologically. We enrolled 369 patients (median age 52 years [IQR 41-65]; 198 (54%) female). Of these, 72 (20%) had GC and 35 (9%) had gastric premalignant lesions (PL). CISH identified EBVaGC in 5/44 (11%) of those with adequate tissue, while MLH1 loss was identified in 29/45 (64%). Both GC and PL were associated with the highest titers of antibodies to Early antigen-diffuse (OR 2.5, 95% CI 1.0-6.1, P = .048 and OR 3.9, 95% CI 1.1-12.9, P = .03, respectively) at high concentrations. Human immunodeficiency virus infection was associated with a range of antibodies to EBV, but not with any cancer subtype. Despite the association of HIV with persistent EBV, the proportion of EBVaGC in Zambia is similar to populations with a low prevalence of HIV infection. The proportion of microsatellite unstable tumors may be higher than other populations.
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Affiliation(s)
- Violet Kayamba
- Tropical Gastroenterology & Nutrition GroupDepartment of Internal MedicineLusakaZambia
- University of Zambia School of MedicineLusakaZambia
| | - Julia Butt
- Cancer Control and Population Sciences ProgramDuke Cancer InstituteDuke UniversityDurhamNCUSA
- Department of Population Health SciencesDuke UniversityDurhamNCUSA
- Infection and Cancer Epidemiology GroupGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Tim Waterboer
- Infection and Cancer Epidemiology GroupGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Ellen Besa
- Tropical Gastroenterology & Nutrition GroupDepartment of Internal MedicineLusakaZambia
| | - Naheed Choudhry
- Blizard InstituteBarts & The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
| | | | - Peter Julius
- University of Zambia School of MedicineLusakaZambia
| | - Douglas C. Heimburger
- Vanderbilt Institute for Global Health and Department of MedicineVanderbilt University Medical CenterNashvilleTNUSA
| | | | - Paul Kelly
- Tropical Gastroenterology & Nutrition GroupDepartment of Internal MedicineLusakaZambia
- University of Zambia School of MedicineLusakaZambia
- Blizard InstituteBarts & The London School of Medicine and DentistryQueen Mary University of LondonLondonUK
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23
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PD-L1 expression combined with microsatellite instability/CD8+ tumor infiltrating lymphocytes as a useful prognostic biomarker in gastric cancer. Sci Rep 2019; 9:4633. [PMID: 30874607 PMCID: PMC6420501 DOI: 10.1038/s41598-019-41177-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 02/26/2019] [Indexed: 01/01/2023] Open
Abstract
While the importance of programmed death-ligand 1 (PD-L1), mutation burden caused by microsatellite instability (MSI), and CD8+ tumor infiltrating lymphocytes (TILs) has become evident, the significance of PD-L1 expression on prognosis still remains controversial. We evaluated the usefulness of combined markers of PD-L1 and MSI or CD8+ TILs as a prognostic biomarker in gastric cancer. A total of 283 patients with gastric cancer were reviewed retrospectively. PD-L1 expression on >5% tumor cells was defined as PD-L1-positive. PD-L1-positive rate was 15.5% (44/283). PD-L1 positivity was significantly correlated with invasive and advanced cancer and also significantly correlated with MSI, whereas no significance was observed with CD8+ TILs. Kaplan-Meier analysis showed that PD-L1 positivity significantly correlated with a poor prognosis (p = 0.0025). Multivariate analysis revealed that PD-L1 positivity was an independent poor prognostic factor (hazard ratio [HR]: 1.97, p = 0.0106) along with diffuse histological type and lymph node metastases. Combinations of PD-L1 and MSI (HR: 2.18) or CD8+ TILs (HR: 2.57) were stronger predictive factors for prognosis than PD-L1 alone. In conclusion, combined markers of PD-L1 and MSI or CD8+ TILs may be more useful prognostic biomarkers in gastric cancer, and better clarify the immune status of gastric cancer patients.
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24
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Hassounah NB, Malladi VS, Huang Y, Freeman SS, Beauchamp EM, Koyama S, Souders N, Martin S, Dranoff G, Wong KK, Pedamallu CS, Hammerman PS, Akbay EA. Identification and characterization of an alternative cancer-derived PD-L1 splice variant. Cancer Immunol Immunother 2019; 68:407-420. [PMID: 30564890 PMCID: PMC6428600 DOI: 10.1007/s00262-018-2284-z] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 12/06/2018] [Indexed: 12/17/2022]
Abstract
Therapeutic blockade of the PD-1/PD-L1 axis is recognized as an effective treatment for numerous cancer types. However, only a subset of patients respond to this treatment, warranting a greater understanding of the biological mechanisms driving immune evasion via PD-1/PD-L1 signaling and other T-cell suppressive pathways. We previously identified a head and neck squamous cell carcinoma with human papillomavirus integration in the PD-L1 locus upstream of the transmembrane domain-encoding region, suggesting expression of a truncated form of PD-L1 (Parfenov et al., Proc Natl Acad Sci USA 111(43):15544-15549, 2014). In this study, we extended this observation by performing a computational analysis of 33 other cancer types as well as human cancer cell lines, and identified additional PD-L1 isoforms with an exon 4 enrichment expressed in 20 cancers and human cancer cell lines. We demonstrate that cancer cell lines with high expression levels of exon 4-enriched PD-L1 generate a secreted form of PD-L1. Further biochemical studies of exon 4-enriched PD-L1 demonstrated that this form is secreted and maintains the capacity to bind PD-1 as well as to serve as a negative regulator on T cell function, as measured by inhibition of IL-2 and IFNg secretion. Overall, we have demonstrated that truncated forms of PD-L1 exist in numerous cancer types, and have validated that truncated PD-L1 can be secreted and negatively regulate T cell function.
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Affiliation(s)
- Nadia B Hassounah
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Venkat S Malladi
- Department of Bioinformatics, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Bioinformatics Core Facility, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Yi Huang
- Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA
- Simmons Comprehensive Cancer Center, Dallas, TX, USA
| | - Samuel S Freeman
- Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Ellen M Beauchamp
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Shohei Koyama
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Nicholas Souders
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Sunil Martin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Glenn Dranoff
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Department of Medical Oncology and Cancer Vaccine Center, Dana Farber Cancer Institute, Boston, MA, USA
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Kwok-Kin Wong
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Ludwig Institute for Cancer, Boston, MA, USA
- Belfer Institute for Applied Cancer Science, Boston, MA, USA
| | - Chandra S Pedamallu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Peter S Hammerman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
- Cancer Program, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
- Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Esra A Akbay
- Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA.
- Simmons Comprehensive Cancer Center, Dallas, TX, USA.
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25
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Xu M, Zhang WL, Zhu Q, Yao YY, Feng QS, Zhang Z, Peng RJ, Jia WH, He GP, Feng L, Zeng ZL, Luo B, Xu RH, Zeng MS, Zhao WL, Chen SJ, Zeng YX, Jiao Y, Zeng YX, Jiao Y. Genome-wide profiling of Epstein-Barr virus integration by targeted sequencing in Epstein-Barr virus associated malignancies. Theranostics 2019; 9:1115-1124. [PMID: 30867819 PMCID: PMC6401403 DOI: 10.7150/thno.29622] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 01/18/2019] [Indexed: 12/13/2022] Open
Abstract
Rationale: Epstein-Barr virus (EBV) is associated with multiple malignancies with expression of viral oncogenic proteins and chronic inflammation as major mechanisms contributing to tumor development. A less well-studied mechanism is the integration of EBV into the human genome possibly at sites which may disrupt gene expression or genome stability. Methods: We sequenced tumor DNA to profile the EBV sequences by hybridization-based enrichment. Bioinformatic analysis was used to detect the breakpoints of EBV integrations in the genome of cancer cells. Results: We identified 197 breakpoints in nasopharyngeal carcinomas and other EBV-associated malignancies. EBV integrations were enriched at vulnerable regions of the human genome and were close to tumor suppressor and inflammation-related genes. We found that EBV integrations into the introns could decrease the expression of the inflammation-related genes, TNFAIP3, PARK2, and CDK15, in NPC tumors. In the EBV genome, the breakpoints were frequently at oriP or terminal repeats. These breakpoints were surrounded by microhomology sequences, consistent with a mechanism for integration involving viral genome replication and microhomology-mediated recombination. Conclusion: Our finding provides insight into the potential of EBV integration as an additional mechanism mediating tumorigenesis in EBV associated malignancies.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Yi-Xin Zeng
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.,State Key Lab of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Collaborative Innovation Center for Cancer Medicine, Beijing, China
| | - Yuchen Jiao
- State Key Lab of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College; Collaborative Innovation Center for Cancer Medicine, Beijing, China
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26
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Zhou H, Tan S, Li H, Lin X. Expression and significance of EBV, ARID1A and PIK3CA in gastric carcinoma. Mol Med Rep 2019; 19:2125-2136. [PMID: 30747208 PMCID: PMC6390055 DOI: 10.3892/mmr.2019.9886] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 12/14/2018] [Indexed: 12/13/2022] Open
Abstract
AT-rich interaction domain 1A (ARID1A) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA) serve important roles in the formation and development of numerous malignancies including gastric cancer. Accumulating evidence has demonstrated that Epstein-Barr virus (EBV) is a pathogenic virus associated with gastric cancer. The present study aimed to investigate the association between EBV infection, and the expression levels of ARID1A and PIK3CA in gastric cancer. EBER in situ hybridization was performed to detect EBV infection. Immunohistochemistry was used to assess the expression levels of ARID1A and PIK3CA in gastric cancer and adjacent normal tissues. A total of 58 gastric cancer and 10 adjacent normal tissues were tested for genetic mutations via single nucleotide polymorphism genotyping assays. Fluorescent polymerase chain reaction was used to detect EBV infection; 9.3% (28/300) of gastric cancer samples were positive for EBV, whereas, all adjacent normal tissues were negative. ARID1A and PIK3CA were negatively correlated in gastric cancer (r=−0.167). The expression levels of ARID1A and PIK3CA in gastric cancer were significantly associated with the depth of invasion of gastric cancer. A total of 62.1% (36/58) of tumor samples exhibited mutations in ARID1A, whereas, 13.8% (8/58) presented mutations in PIK3CA. Notably, EBV-associated gastric cancer (EBVaGC) samples with PIK3CA mutations additionally exhibited ARID1A mutations. Although in the present study it was identified that ARID1A and PIK3CA were negatively correlated in EBVaGC, further studies are required to investigate the association among ARID1A, PIK3CA and EBV in gastric cancer.
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Affiliation(s)
- Huan Zhou
- Department of Pathology, Central South University, Xiangya School of Medicine, Affiliated Haikou Hospital, Haikou, Hainan 570208, P.R. China
| | - Shun Tan
- Department of Pathology, Central South University, Xiangya School of Medicine, Affiliated Haikou Hospital, Haikou, Hainan 570208, P.R. China
| | - Hong Li
- Department of Pathology, Central South University, Xiangya School of Medicine, Affiliated Haikou Hospital, Haikou, Hainan 570208, P.R. China
| | - Xiangtao Lin
- Department of Pathology, Central South University, Xiangya School of Medicine, Affiliated Haikou Hospital, Haikou, Hainan 570208, P.R. China
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27
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Abdallah MOE, Algizouli UK, Suliman MA, Abdulrahman RA, Koko M, Fessahaye G, Shakir JH, Fahal AH, Elhassan AM, Ibrahim ME, Mohamed HS. EBV Associated Breast Cancer Whole Methylome Analysis Reveals Viral and Developmental Enriched Pathways. Front Oncol 2018; 8:316. [PMID: 30151354 PMCID: PMC6099083 DOI: 10.3389/fonc.2018.00316] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 07/24/2018] [Indexed: 01/18/2023] Open
Abstract
Background: Breast cancer (BC) ranks among the most common cancers in Sudan and worldwide with hefty toll on female health and human resources. Recent studies have uncovered a common BC signature characterized by low frequency of oncogenic mutations and high frequency of epigenetic silencing of major BC tumor suppressor genes. Therefore, we conducted a pilot genome-wide methylome study to characterize aberrant DNA methylation in breast cancer. Results: Differential methylation analysis between primary tumor samples and normal samples from healthy adjacent tissues yielded 20,188 differentially methylated positions (DMPs), which is further divided into 13,633 hypermethylated sites corresponding to 5339 genes and 6,555 hypomethylated sites corresponding to 2811 genes. Moreover, bioinformatics analysis revealed epigenetic dysregulation of major developmental pathways including hippo signaling pathway. We also uncovered many clues to a possible role for EBV infection in BC. Conclusion: Our results clearly show the utility of epigenetic assays in interrogating breast cancer tumorigenesis, and pinpointing specific developmental and viral pathways dysregulation that might serve as potential biomarkers or targets for therapeutic interventions.
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Affiliation(s)
- Mohammad O E Abdallah
- Department of Molecular Biology, Institute of Endemic Disease, University of Khartoum, Khartoum, Sudan
| | - Ubai K Algizouli
- Department of Molecular Biology, Institute of Endemic Disease, University of Khartoum, Khartoum, Sudan
| | - Maram A Suliman
- Department of Molecular Biology, Institute of Endemic Disease, University of Khartoum, Khartoum, Sudan
| | - Rawya A Abdulrahman
- Department of Molecular Biology, Institute of Endemic Disease, University of Khartoum, Khartoum, Sudan
| | - Mahmoud Koko
- Department of Molecular Biology, Institute of Endemic Disease, University of Khartoum, Khartoum, Sudan
| | - Ghimja Fessahaye
- Department of Molecular Biology, Institute of Endemic Disease, University of Khartoum, Khartoum, Sudan
| | - Jamal H Shakir
- Department of Surgery, Khartoum Teaching Hospital, Khartoum, Sudan
| | - Ahmed H Fahal
- Department of Surgery, Faculty of Medicine, University of Khartoum, Khartoum, Sudan
| | - Ahmed M Elhassan
- Department of Molecular Biology, Institute of Endemic Disease, University of Khartoum, Khartoum, Sudan
| | - Muntaser E Ibrahim
- Department of Molecular Biology, Institute of Endemic Disease, University of Khartoum, Khartoum, Sudan
| | - Hiba S Mohamed
- Department of Molecular Biology, Institute of Endemic Disease, University of Khartoum, Khartoum, Sudan.,Department of Biology, Taibah University, Medina, Saudi Arabia
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28
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Battaglin F, Naseem M, Puccini A, Lenz HJ. Molecular biomarkers in gastro-esophageal cancer: recent developments, current trends and future directions. Cancer Cell Int 2018; 18:99. [PMID: 30008616 PMCID: PMC6042434 DOI: 10.1186/s12935-018-0594-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 06/28/2018] [Indexed: 12/12/2022] Open
Abstract
Gastro-esophageal adenocarcinomas (GEA) represent a severe global health burden and despite improvements in the multimodality treatment of these malignancies the prognosis of patients remains poor. HER2 overexpression/amplification has been the first predictive biomarker approved in clinical practice to guide patient selection for targeted treatment with trastuzumab in advanced gastric and gastro-esophageal junction cancers. More recently, immunotherapy has been approved for the treatment of GEA and PD-L1 expression is now a biomarker required for the administration of pembrolizumab in these diseases. Significant progress has been made in recent years in dissecting the genomic makeup of GEA in order to identify distinct molecular subtypes linked to distinct patterns of molecular alterations. GEA have been found to be highly heterogeneous malignances, representing a challenge for biomarkers discovery and targeted treatment development. The current review focuses on an overview of established and novel promising biomarkers in GEA, covering recent molecular classifications from TCGA and ACRG. Main elements of molecular heterogeneity are discussed, as well as emerging mechanisms of primary and secondary resistance to HER2 targeted treatment and recent biomarker-driven trials. Future perspectives on the role of epigenetics, miRNA/lncRNA and liquid biopsy, and patient-derived xenograft models as a new platform for molecular-targeted drug discovery in GEA are presented. Our knowledge on the genomic landscape of GEA continues to evolve, uncovering the high heterogeneity and deep complexity of these tumors. The availability of new technologies and the identification of promising novel biomarker will be critical to optimize targeted treatment development in a setting where therapeutic options are currently lacking. Nevertheless, clinical validation of novel biomarkers and treatment strategies still represents an issue.
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Affiliation(s)
- Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 5410, Los Angeles, CA 90033 USA
- Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV-IRCCS, 35128 Padua, Italy
| | - Madiha Naseem
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 5410, Los Angeles, CA 90033 USA
| | - Alberto Puccini
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 5410, Los Angeles, CA 90033 USA
- Oncologia Medica 1, Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, Suite 5410, Los Angeles, CA 90033 USA
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29
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El‐Zimaity H, Di Pilato V, Novella Ringressi M, Brcic I, Rajendra S, Langer R, Dislich B, Tripathi M, Guindi M, Riddell R. Risk factors for esophageal cancer: emphasis on infectious agents. Ann N Y Acad Sci 2018; 1434:319-332. [DOI: 10.1111/nyas.13858] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 03/30/2018] [Accepted: 04/24/2018] [Indexed: 12/17/2022]
Affiliation(s)
| | - Vincenzo Di Pilato
- Department of Clinical and Experimental MedicineUniversity of Florence Florence Italy
| | - Maria Novella Ringressi
- Department of Surgery and Translational MedicineUniversity of Florence Florence Italy
- Gastrointestinal Surgery UnitFlorence Careggi University Hospital Florence Italy
| | - Iva Brcic
- Institute of PathologyMedical University of Graz Graz Austria
| | - Shanmugarajah Rajendra
- Gastro‐Intestinal Viral Oncology GroupIngham Institute for Applied Medical Research, Liverpool Sydney New South Wales Australia
- South Western Sydney Clinical SchoolUniversity of New South Wales, Kensington Sydney New South Wales Australia
- Department of Gastroenterology & HepatologyBankstown‐Lidcombe Hospital, South Western Sydney Local Health Network, Bankstown Sydney New South Wales Australia
| | - Rupert Langer
- Institute of PathologyUniversity of Bern Bern Switzerland
| | - Bastian Dislich
- Institute of PathologyKantonsspital Baselland Liestal Switzerland
| | - Monika Tripathi
- Cambridge University HospitalsNHS Foundation Trust Cambridge UK
| | - Maha Guindi
- Department of Pathology and laboratory MedicineCedars‐Sinai Medical Center Los Angeles California
| | - Robert Riddell
- Department of Pathology and Laboratory MedicineMount Sinai Hospital Toronto Ontario Canada
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30
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Polakovicova I, Jerez S, Wichmann IA, Sandoval-Bórquez A, Carrasco-Véliz N, Corvalán AH. Role of microRNAs and Exosomes in Helicobacter pylori and Epstein-Barr Virus Associated Gastric Cancers. Front Microbiol 2018; 9:636. [PMID: 29675003 PMCID: PMC5895734 DOI: 10.3389/fmicb.2018.00636] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 03/19/2018] [Indexed: 12/17/2022] Open
Abstract
Emerging evidence suggests that chronic inflammation caused by pathogen infection is connected to the development of various types of cancer. It is estimated that up to 20% of all cancer deaths is linked to infections and inflammation. In gastric cancer, such triggers can be infection of the gastric epithelium by either Helicobacter pylori (H. pylori), a bacterium present in half of the world population; or by Epstein-Barr virus (EBV), a double-stranded DNA virus which has recently been associated with gastric cancer. Both agents can establish lifelong inflammation by evolving to escape immune surveillance and, under certain conditions, contribute to the development of gastric cancer. Non-coding RNAs, mainly microRNAs (miRNAs), influence the host innate and adaptive immune responses, though long non-coding RNAs and viral miRNAs also alter these processes. Reports suggest that chronic infection results in altered expression of host miRNAs. In turn, dysregulated miRNAs modulate the host inflammatory immune response, favoring bacterial survival and persistence within the gastric mucosa. Given the established roles of miRNAs in tumorigenesis and innate immunity, they may serve as an important link between H. pylori- and EBV-associated inflammation and carcinogenesis. Example of this is up-regulation of miR-155 in H. pylori and EBV infection. The tumor environment contains a variety of cells that need to communicate with each other. Extracellular vesicles, especially exosomes, allow these cells to deliver certain type of information to other cells promoting cancer growth and metastasis. Exosomes have been shown to deliver not only various types of genetic information, mainly miRNAs, but also cytotoxin-associated gene A (CagA), a major H. pylori virulence factor. In addition, a growing body of evidence demonstrates that exosomes contain genetic material of viruses and viral miRNAs and proteins such as EBV latent membrane protein 1 (LMP1) which are delivered into recipient cells. In this review, we focus on the dysregulated H. pylori- and EBV-associated miRNAs while trying to unveil possible causal mechanisms. Moreover, we discuss the role of exosomes as vehicles for miRNA delivery in H. pylori- and EBV-related carcinogenesis.
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Affiliation(s)
- Iva Polakovicova
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC Center for Investigational Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology-Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Sofia Jerez
- Department of Hematology-Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Ignacio A Wichmann
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC Center for Investigational Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology-Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Nicolás Carrasco-Véliz
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alejandro H Corvalán
- Advanced Center for Chronic Diseases, Pontificia Universidad Católica de Chile, Santiago, Chile.,UC Center for Investigational Oncology, Pontificia Universidad Católica de Chile, Santiago, Chile.,Department of Hematology-Oncology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
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31
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Böger C, Behrens HM, Mathiak M, Krüger S, Kalthoff H, Röcken C. PD-L1 is an independent prognostic predictor in gastric cancer of Western patients. Oncotarget 2018; 7:24269-83. [PMID: 27009855 PMCID: PMC5029700 DOI: 10.18632/oncotarget.8169] [Citation(s) in RCA: 214] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 03/02/2016] [Indexed: 12/14/2022] Open
Abstract
Targeting the PD-1/PD-L1 immune checkpoint signaling is a novel promising treatment strategy in several tumor entities, and it is suggested that PD-L1/PD-1 expression is predictive for a PD-1/PD-L1 checkpoint inhibitor treatment response. We investigated the expression of PD-L1 and PD-1 by immunohistochemistry in a large and well characterized gastric cancer (GC) cohort of Caucasian patients, consisting of 465 GC samples and 15 corresponding liver metastases. Staining results were correlated with clinico-pathological characteristics and survival. PD-L1 expression was found in tumor cells of 140 GCs (30.1%) and 9 liver metastases (60%) respectively in immune cells of 411 GCs (88.4%) and 11 liver metastases (73.3%). PD-1 was expressed in tumor infiltrating lymphocytes in 250 GCs (53.8%) and in 11 liver metastases (73.3%). PD-L1 expression was significantly more prevalent in men, GCs of the proximal stomach, unclassified, papillary, Her2/neu-positive, Epstein-Barr-virus-positive, microsatellite instable, and PIK3CA-mutated GCs. A high PD-L1/PD-1 expression was associated with a significantly better patient outcome, and PD-L1 turned out to be an independent survival prognosticator. The correlation of PD-L1/PD-1 expression with distinct clinico-pathological patient characteristics may serve as a surrogate marker of PD-L1-positive GCs and may direct the use of immune checkpoint treatment strategies.
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Affiliation(s)
- Christine Böger
- Department of Pathology, Christian-Albrechts-University, Kiel, Germany
| | | | - Micaela Mathiak
- Department of Pathology, Christian-Albrechts-University, Kiel, Germany
| | - Sandra Krüger
- Department of Pathology, Christian-Albrechts-University, Kiel, Germany
| | - Holger Kalthoff
- Department of Experimental Cancer Research, Christian-Albrechts-University, Kiel, Germany
| | - Christoph Röcken
- Department of Pathology, Christian-Albrechts-University, Kiel, Germany
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32
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Zhang J, Huang T, Zhou Y, Cheng ASL, Yu J, To KF, Kang W. The oncogenic role of Epstein-Barr virus-encoded microRNAs in Epstein-Barr virus-associated gastric carcinoma. J Cell Mol Med 2017; 22:38-45. [PMID: 28990284 PMCID: PMC5742672 DOI: 10.1111/jcmm.13354] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 07/15/2017] [Indexed: 12/13/2022] Open
Abstract
Epstein–Barr virus (EBV) infection is detected in various epithelial malignancies, such as nasopharyngeal carcinoma (NPC) and gastric cancer (GC). EBV comprises some unique molecular features and encodes viral genes and microRNAs (miRNAs) by its own DNA sequence. EBV genes are required to maintain latency and contribute to oncogenic property. miRNAs encoded by EBV have been shown to contribute to initiation and progression of EBV‐related malignancies. By a number of genomic profiling studies, some EBV miRNAs were confirmed to be highly expressed in EBV‐associated gastric cancer (EBVaGC) samples and cell lines. The majority host targets of the EBV miRNAs are important for promoting cell growth and inhibiting apoptosis, facilitating cell survival and immune evasion. However, the integrated molecular mechanisms related to EBV miRNAs remain to be investigated. In this review, we summarized the crucial role of EBV miRNAs in epithelial malignancies, especially in EBVaGC. Collectively, EBV miRNAs play a significant role in the viral and host gene regulation network. Understanding the comprehensive potential targets and relevant functions of EBV miRNAs in gastric carcinogenesis might provide better clinical translation.
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Affiliation(s)
- Jinglin Zhang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Tingting Huang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Yuhang Zhou
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Alfred S L Cheng
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.,School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Jun Yu
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China.,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China.,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong SAR, China.,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, China
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Fountzilas G, Psyrri A, Giannoulatou E, Tikas I, Manousou K, Rontogianni D, Ciuleanu E, Ciuleanu T, Resiga L, Zaramboukas T, Papadopoulou K, Bobos M, Chrisafi S, Tsolaki E, Markou K, Giotakis E, Koutras A, Psoma E, Kalogera-Fountzila A, Skondra M, Bamia C, Pectasides D, Kotoula V. Prevalent somaticBRCA1mutations shape clinically relevant genomic patterns of nasopharyngeal carcinoma in Southeast Europe. Int J Cancer 2017; 142:66-80. [DOI: 10.1002/ijc.31023] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 08/01/2017] [Indexed: 12/16/2022]
Affiliation(s)
- George Fountzilas
- Laboratory of Molecular Oncology; Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki; Thessaloniki Greece
- Faculty of Medicine, School of Health Sciences; Aristotle University of Thessaloniki; Thessaloniki Greece
| | - Amanda Psyrri
- Division of Oncology, Second Department of Internal Medicine; Attikon University Hospital; Athens Greece
| | - Eleni Giannoulatou
- Victor Chang Cardiac Research Institute; Darlinghurst NSW Australia
- The University of New South Wales; Kensington NSW Australia
| | - Ioannis Tikas
- Laboratory of Molecular Oncology; Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki; Thessaloniki Greece
| | - Kyriaki Manousou
- Section of Biostatistics, Hellenic Cooperative Oncology Group; Data Office; Athens Greece
| | | | | | - Tudor Ciuleanu
- Institute of Oncology Ion Chiricuta and UMF Iuliu Hatieganu; Cluj-Napoca Romania
| | - Liliana Resiga
- Department of Pathology; Ion Chiricuta Cancer Institute; Cluj Romania
| | - Thomas Zaramboukas
- Department of Pathology; School of Health Sciences, Faculty of Medicine, Aristotle University of Thessaloniki; Thessaloniki Greece
| | - Kyriaki Papadopoulou
- Laboratory of Molecular Oncology; Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki; Thessaloniki Greece
| | - Mattheos Bobos
- Laboratory of Molecular Oncology; Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki; Thessaloniki Greece
| | - Sofia Chrisafi
- Laboratory of Molecular Oncology; Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki; Thessaloniki Greece
| | - Eleftheria Tsolaki
- Laboratory of Molecular Oncology; Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki; Thessaloniki Greece
| | - Konstantinos Markou
- First Department of Otorhinolaryngology; AHEPA Hospital, School of Health Sciences, Faculty of Medicine, Aristotle University of Thessaloniki; Thessaloniki Greece
| | - Evangelos Giotakis
- Department of Otolaryngology Head and Neck Surgery; Hippokration Hospital, National and Kapodistrian University of Athens; Athens Greece
| | - Angelos Koutras
- Division of Oncology, Department of Medicine; University Hospital, University of Patras Medical School; Patras Greece
| | - Elsa Psoma
- Department of Radiology; AHEPA Hospital, School of Health Sciences, Faculty of Medicine, Aristotle University of Thessaloniki; Thessaloniki Greece
| | - Anna Kalogera-Fountzila
- Department of Radiology; AHEPA Hospital, School of Health Sciences, Faculty of Medicine, Aristotle University of Thessaloniki; Thessaloniki Greece
| | - Maria Skondra
- Oncology Section, Second Department of Internal Medicine; Hippokration Hospital; Athens
| | - Christina Bamia
- Department of Hygiene, Epidemiology and Medical Statistics; National and Kapodistrian University of Athens, Medical School; Athens Greece
| | - Dimitrios Pectasides
- Oncology Section, Second Department of Internal Medicine; Hippokration Hospital; Athens
| | - Vassiliki Kotoula
- Laboratory of Molecular Oncology; Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki; Thessaloniki Greece
- Department of Pathology; School of Health Sciences, Faculty of Medicine, Aristotle University of Thessaloniki; Thessaloniki Greece
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34
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Carrasco-Avino G, Riquelme I, Padilla O, Villaseca M, Aguayo FR, Corvalan AH. The conundrum of the Epstein-Barr virus-associated gastric carcinoma in the Americas. Oncotarget 2017; 8:75687-75698. [PMID: 29088902 PMCID: PMC5650457 DOI: 10.18632/oncotarget.18497] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2016] [Accepted: 05/29/2017] [Indexed: 02/07/2023] Open
Abstract
Epstein-Barr virus-associated gastric carcinoma shows a higher prevalence in the Americas than Asia. We summarize all studies of Epstein Barr virus-associated gastric carcinoma in the Americas, focusing on host characteristics, environmental associations and phylogeographic diversity of Epstein-Barr virus strains. In the Americas, the prevalence of Epstein Barr virus-associated gastric carcinoma is 11.4%, more frequent in males and portray predominantly diffuse-type histology. EBERs, EBNAs, BARTs and LMP are the highest expressed genes; their variations in healthy individuals may explain the phylogeographic diversity of Epstein-Barr virus across the region. Gastric cancer cases harbor exclusively the western genotype (subtype D and kept Xho I site), suggesting a disrupted co-evolution between the pathogen and its host. Epstein-Barr virus-associated gastric carcinoma molecular subtype cases from The Cancer Genome Atlas display PIK3CA gene mutations, amplification of JAK2, PD-L1 and PD-L2 and CpG island methylator phenotype, leading to more extensive methylation of host and viral genomes than any other subtypes from the study. Environmental conditions include negative- and positive- associations with being firstborn child and smoking, respectively. A marginal association with H. pylori has also been reported. Lymphoepithelioma-like carcinoma is associated with Epstein Barr virus in 80%-86% of cases, most of which have been included as part of Epstein Barr virus-associated gastric carcinoma series (prevalence 1.1%-7.6%). Whether these cases represent a variant of Epstein-Barr virus-associated gastric carcinoma is discussed. We propose novel research strategies to solve the conundrum of the high prevalence of Epstein-Barr virus-associated gastric carcinoma in the Americas.
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Affiliation(s)
- Gonzalo Carrasco-Avino
- Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Catolica de Chile, Santiago, Chile
- Department of Pathology, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Ismael Riquelme
- Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de la Frontera, Temuco, Chile
- Department of Pathology, Universidad de la Frontera, Temuco, Chile
| | - Oslando Padilla
- Department of Public Health, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Miguel Villaseca
- Department of Pathology, Universidad de la Frontera, Temuco, Chile
| | - Francisco R. Aguayo
- Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Catolica de Chile, Santiago, Chile
- Department of Basic and Clinical Oncology, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Alejandro H. Corvalan
- Advanced Center for Chronic Diseases (ACCDIS), Pontificia Universidad Catolica de Chile, Santiago, Chile
- UC-Center for Investigational Oncology (CITO), Pontificia Universidad Catolica de Chile, Santiago, Chile
- Department of Hematology and Oncology, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
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35
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Alarcón A, Figueroa U, Espinoza B, Sandoval A, Carrasco-Aviño G, Aguayo FR, Corvalan AH. Epstein-Barr Virus–Associated Gastric Carcinoma: The Americas’ Perspective. Gastric Cancer 2017. [DOI: 10.5772/intechopen.70201] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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The Methylation Status and Expression of Epstein-Barr Virus Early Genes BARF1 and BHRF1 in Epstein-Barr Virus-Associated Gastric Carcinomas. Gastroenterol Res Pract 2017; 2017:3804146. [PMID: 28487730 PMCID: PMC5405596 DOI: 10.1155/2017/3804146] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2016] [Revised: 03/01/2017] [Accepted: 03/08/2017] [Indexed: 02/07/2023] Open
Abstract
Epstein-Barr virus (EBV) is an important DNA virus which establishes latent infection in human malignancies. Expression of EBV-encoded genes in the associated tumors is strongly modulated by promoter CpG methylation of EBV genome. This study aimed to explore the methylation status of the promoters of EBV BamHI-A rightward frame 1 (BARF1) and BamHI-H rightward open reading frame 1 (BHRF1) and their influence on transcriptional expression, to further understand the roles of BARF1 and BHRF1 in the occurrence of EBV-associated cancer. We evaluated the methylation status of BARF1 and BHRF1 promoters in 43 EBV-associated gastric carcinoma (EBVaGC) tissues and EBV-positive cell lines. Their expressions were evaluated by real-time quantitative PCR. We found that the promoters of BARF1 and BHRF1 were methylated by varying degrees in different EBV-positive cell lines and were almost hypermethylated in all EBVaGC tissues. The methylation status of BARF1 and BHRF1 promoters were significantly reduced by 5-Aza-CdR along with the increasing gene expressions. Hypermethylation of Ap and Hp mediates the frequent silencing of BARF1 and BHRF1 in EBV-associated tumors, which could be reactivated by a demethylation agent, suggesting that promoter demethylation and activation is important for BARF1 and BHRF1 transcription and their further action.
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37
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Ramos MFKP, Pereira MA, Dias AR, Faraj SF, Zilberstein B, Cecconello I, de Mello ES, Ribeiro Junior U. Lymphoepithelioma-like gastric carcinoma: clinicopathological characteristics and infection status. J Surg Res 2017; 210:159-168. [PMID: 28457323 DOI: 10.1016/j.jss.2016.11.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2016] [Revised: 11/02/2016] [Accepted: 11/04/2016] [Indexed: 02/05/2023]
Abstract
BACKGROUND Lymphoepithelioma-like gastric carcinoma (LLGC) is a rare subtype of gastric carcinoma (GC) characterized by prominent lymphocytic infiltration. LLGC may be associated with latent Epstein-Barr virus (EBV) infection or microsatellite instability (MSI). This study aims to assess the clinicopathological characteristics, EBV infection, and MSI status in LLGC. METHODS A retrospective analysis of GC patients submitted to potentially curative resection between 2009 and 2014 was performed. The LLGC subtype specimens were examined for EBV by in situ hybridization and MSI by immunohistochemical analysis. The LLGC profile was analyzed accordingly to clinicopathological parameters. RESULTS From 255 patients, seven were identified on the pathological report as LLGC. Six cases were EBV-positive and one had MSI, showing loss of MLH1 and PMS2 expression. LLGC was more frequently seen in men, and the mean age was 69 years. When compared to non-LLGC, LLGC cases were larger (∼5.8 cm) poorly differentiated tumors and had lower incidence of lymph node metastasis (P = 0.045). Mean number of lymph nodes dissected in the LLGC group was 39.5, and only one patient had a single positive lymph node. In addition, two patients presented associated lesions. LLGC was not associated with HER-2, chromogranin and synaptophysin positivity or Helicobacter pylori infection. CONCLUSIONS Distinct pathological aspects and clinical behavior of LLGC reinforce the need for proper recognition of this histological subtype to choose better therapeutic approaches.
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Affiliation(s)
| | - Marina Alessandra Pereira
- Department of Gastroenterology, Hospital das Clínicas, Cancer Institute, University of São Paulo Medical School, Sao Paulo, Brazil
| | - Andre Roncon Dias
- Department of Gastroenterology, Hospital das Clínicas, Cancer Institute, University of São Paulo Medical School, Sao Paulo, Brazil
| | - Sheila Friedrich Faraj
- Department of Gastroenterology, Hospital das Clínicas, Cancer Institute, University of São Paulo Medical School, Sao Paulo, Brazil
| | - Bruno Zilberstein
- Department of Gastroenterology, Hospital das Clínicas, Cancer Institute, University of São Paulo Medical School, Sao Paulo, Brazil
| | - Ivan Cecconello
- Department of Gastroenterology, Hospital das Clínicas, Cancer Institute, University of São Paulo Medical School, Sao Paulo, Brazil
| | - Evandro Sobroza de Mello
- Department of Gastroenterology, Hospital das Clínicas, Cancer Institute, University of São Paulo Medical School, Sao Paulo, Brazil
| | - Ulysses Ribeiro Junior
- Department of Gastroenterology, Hospital das Clínicas, Cancer Institute, University of São Paulo Medical School, Sao Paulo, Brazil
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38
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Zhang C, Powell SE, Betel D, Shah MA. The Gastric Microbiome and Its Influence on Gastric Carcinogenesis: Current Knowledge and Ongoing Research. Hematol Oncol Clin North Am 2017; 31:389-408. [PMID: 28501083 DOI: 10.1016/j.hoc.2017.01.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastric malignancies are a leading cause of cancer-related death worldwide. At least 2 microbial species are currently linked to carcinogenesis and the development of cancer within the human stomach. These include the bacterium Helicobacter pylori and the Epstein-Barr virus. In recent years, there has been increasing evidence that within the human gastrointestinal tract it is not only pathogenic microbes that impact human health but also the corresponding autochthonous microbial communities. This article reviews the gastrointestinal microbiome as it relates primarily to mechanisms of disease and carcinogenesis within the upper gastrointestinal tract.
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Affiliation(s)
- Chao Zhang
- Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA; Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA
| | - Sarah Ellen Powell
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA
| | - Doron Betel
- Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA; Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA
| | - Manish A Shah
- Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA; Gastrointestinal Oncology Program, Center for Advanced Digestive Care, Sandra and Edward Meyer Cancer Center, New York-Presbyterian Hospital, Weill Cornell Medicine, New York, NY 10021, USA.
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Bartley AN, Washington MK, Colasacco C, Ventura CB, Ismaila N, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol 2017; 35:446-464. [PMID: 28129524 DOI: 10.1200/jco.2016.69.4836] [Citation(s) in RCA: 267] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Context ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. Objectives To establish an evidence-based guideline for HER2 testing in patients with GEA, formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. Design The College of American Pathologists (CAP), American Society for Clinical Pathology (ASCP), and the American Society of Clinical Oncology (ASCO) convened an Expert Panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. Results The Panel is proposing 11 recommendations with strong agreement from the open comment participants. Recommendations The Panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and an HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. Conclusion This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
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Affiliation(s)
- Angela N Bartley
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Mary Kay Washington
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Carol Colasacco
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Christina B Ventura
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Nofisat Ismaila
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Al B Benson
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Alfredo Carrato
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Margaret L Gulley
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Dhanpat Jain
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Sanjay Kakar
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Helen J Mackay
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Catherine Streutker
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Laura Tang
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Megan Troxell
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jaffer A Ajani
- Angela N. Bartley, St Joseph Mercy Hospital, Ann Arbor, MI; Mary Kay Washington, Vanderbilt University Medical Center, Nashville, TN; Carol Colasacco and Christina B. Ventura, College of American Pathologists, Northfield; Al B. Benson III, Northwestern University, Chicago, IL; Nofisat Ismaila, American Society of Clinical Oncology, Alexandria, VA; Alfredo Carrato, Ramón y Cajal University Hospital, Madrid, Spain; Margaret L. Gulley, University of North Carolina, Chapel Hill, NC; Dhanpat Jain, Yale University School of Medicine, New Haven, CT; Sanjay Kakar, University of California, San Francisco, CA; Helen J. Mackay, Princess Margaret Cancer Centre; Catherine Streutker, St Michael's Hospital, University of Toronto, Toronto, Canada; Laura Tang, Memorial Sloan Kettering Cancer Center, New York, NY; Megan Troxell, Stanford University Medical Center, Stanford, CA; and Jaffer A. Ajani, The University of Texas MD Anderson Cancer Center, Houston, TX
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朱 晓, 李 夏, 李 素, 于 红. Advances in research of Epstein-Barr virus-associated gastric carcinoma. Shijie Huaren Xiaohua Zazhi 2017; 25:1375. [DOI: 10.11569/wcjd.v25.i15.1375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Saakyan SV, Myakoshina EB, Krichevskaya GI, Slepova OS, Panteleeva OG, Andryushin AE, Khoroshilova IP, Zakharova GP. Testing patients with uveal melanoma for herpesvirus infections. Vopr Virusol 2016; 61:284-287. [PMID: 36494989 DOI: 10.18821/0507-4088-2016-61-6-284-287] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Indexed: 12/13/2022]
Abstract
Results of comprehensive ELISA tests of blood serum for the presence of IgM-, IgA-, and IgG-antibodies to herpes simplex virus types 1 and 2, cytomegalovirus, Epstein-Barr virus, human herpesvirus 6, human herpes virus 8 type, Chlamydia trachomatis in 38 patients with uveal melanoma are presented. The polymerase chain reaction was used to detect DNA of these pathogens in tumor biopsies, vitreous body of 10 enucleated eyes, as well as in plasma IgG-antibodies to HHV 6 were revealed in 50% of patients; IgG-antibodies to HHV 8, in 5.3% of patients. Among the 16 patients with uveal melanoma at advanced stages, 6 patients had antibodies indicative of EBV reactivation (1.2-3.3). Chlamydia trachomatis genome was detected in both biopsies; in one of them, in conjunction with EBV and CMV DNA . Tissue samples from the identified infectious agents were related only to the spindle-cell histologic type AB of uveal melanoma. In plasma, genomes of pathogens were not determined. The results indicate the presence of infectious agents in patients with uveal melanoma and require further study of the pathogenetic role of infections in the pathogenesis of uveal melanoma.
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Affiliation(s)
- S V Saakyan
- Helmholtz Moscow Research Institute of Eye Diseases
| | | | | | - O S Slepova
- Helmholtz Moscow Research Institute of Eye Diseases
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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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Bartley AN, Washington MK, Ventura CB, Ismaila N, Colasacco C, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Arch Pathol Lab Med 2016; 140:1345-1363. [PMID: 27841667 DOI: 10.5858/arpa.2016-0331-cp] [Citation(s) in RCA: 105] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT - ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. OBJECTIVES - To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. DESIGN - The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. RESULTS - The panel is proposing 11 recommendations with strong agreement from the open-comment participants. RECOMMENDATIONS - The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. CONCLUSIONS - This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
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Affiliation(s)
- Angela N Bartley
- From the Department of Pathology, St. Joseph Mercy Hospital, Ann Arbor, Michigan (Dr Bartley); the Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee (Dr Washington); Surveys (Ms Ventura) and Governance (Ms Colasacco), College of American Pathologists, Northfield, Illinois; Quality and Guidelines Department, American Society of Clinical Oncology, Alexandria, Virginia (Dr Ismaila); the Division of Hematology/Oncology, Northwestern University, Chicago, Illinois (Dr Benson); Medical Oncology Department, Ramon y Cajal University Hospital, Madrid, Spain (Dr Carrato); the Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill (Dr Gulley); the Department of Pathology, Yale University School of Medicine, New Haven, Connecticut (Dr Jain); the Department of Pathology and Laboratory Medicine, UCSF, San Francisco, California (Dr Kakar); the Division of Medical Oncology and Hematology, University of Toronto/Sunnybrook Odette Cancer Centre, Toronto, Ontario, Canada (Dr Mackay); the Department of Laboratory Medicine, St. Michael's Hospital, Toronto, Ontario, Canada (Dr Streutker); the Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York (Dr Tang); the Department of Pathology, Stanford University Medical Center, Stanford, California (Dr Troxell); and the Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston (Dr Ajani)
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Bartley AN, Washington MK, Ventura CB, Ismaila N, Colasacco C, Benson AB, Carrato A, Gulley ML, Jain D, Kakar S, Mackay HJ, Streutker C, Tang L, Troxell M, Ajani JA. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology. Am J Clin Pathol 2016; 146:647-669. [PMID: 28077399 PMCID: PMC6272805 DOI: 10.1093/ajcp/aqw206] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
CONTEXT ERBB2 (erb-b2 receptor tyrosine kinase 2 or HER2) is currently the only biomarker established for selection of a specific therapy for patients with advanced gastroesophageal adenocarcinoma (GEA). However, there are no comprehensive guidelines for the assessment of HER2 in patients with GEA. OBJECTIVES To establish an evidence-based guideline for HER2 testing in patients with GEA, to formalize the algorithms for methods to improve the accuracy of HER2 testing while addressing which patients and tumor specimens are appropriate, and to provide guidance on clinical decision making. DESIGN The College of American Pathologists, American Society for Clinical Pathology, and American Society of Clinical Oncology convened an expert panel to conduct a systematic review of the literature to develop an evidence-based guideline with recommendations for optimal HER2 testing in patients with GEA. RESULTS The panel is proposing 11 recommendations with strong agreement from the open-comment participants. RECOMMENDATIONS The panel recommends that tumor specimen(s) from all patients with advanced GEA, who are candidates for HER2-targeted therapy, should be assessed for HER2 status before the initiation of HER2-targeted therapy. Clinicians should offer combination chemotherapy and a HER2-targeted agent as initial therapy for all patients with HER2-positive advanced GEA. For pathologists, guidance is provided for morphologic selection of neoplastic tissue, testing algorithms, scoring methods, interpretation and reporting of results, and laboratory quality assurance. CONCLUSIONS This guideline provides specific recommendations for assessment of HER2 in patients with advanced GEA while addressing pertinent technical issues and clinical implications of the results.
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Affiliation(s)
- Angela N Bartley
- From the Department of Pathology, St Joseph Mercy Hospital, Ann Arbor, MI
| | - Mary Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, Nashville, TN
| | | | - Nofisat Ismaila
- Quality and Guidelines Department, American Society of Clinical Oncology, Alexandria, VA
| | - Carol Colasacco
- Surveys and Governance, College of American Pathologists, Northfield, IL
| | - Al B Benson
- Division of Hematology/Oncology, Northwestern University, Chicago, IL
| | - Alfredo Carrato
- Medical Oncology Department, Ramon y Cajal University Hospital, Madrid, Spain
| | - Margaret L Gulley
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill
| | - Dhanpat Jain
- Department of Pathology, Yale University School of Medicine, New Haven, CT
| | - Sanjay Kakar
- Department of Pathology and Laboratory Medicine, UCSF, San Francisco, CA
| | - Helen J Mackay
- Division of Medical Oncology and Hematology, University of Toronto/Sunnybrook Odette Cancer Centre, Toronto, Canada
| | | | - Laura Tang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Megan Troxell
- Department of Pathology, Stanford University Medical Center, Stanford, CA
| | - Jaffer A Ajani
- Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston
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Su S, Zou Z, Chen F, Ding N, Du J, Shao J, Li L, Fu Y, Hu B, Yang Y, Sha H, Meng F, Wei J, Huang X, Liu B. CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer. Oncoimmunology 2016; 6:e1249558. [PMID: 28197365 DOI: 10.1080/2162402x.2016.1249558] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 10/01/2016] [Accepted: 10/13/2016] [Indexed: 12/22/2022] Open
Abstract
The successful use of immune cell checkpoint inhibitors PD-1 and PD-L1, over the past 5 y has raised the concern of using immunotherapy to treat various cancers. Epstein-Barr virus-associated gastric cancer (EBVaGC) exhibits high infiltration of lymphocytes and high amplification of immune-related genes including PD-L1 as distinguished from Epstein-Barr virus-non-associated gastric cancer (EBVnGC). Here, we presume that this PD-1/PD-L1 pathway may hinder the efficacy of adoptive T cell therapy toward EBVaGC. These studies reveal possibility of generating PD-1-disrupted CTL by CRISPR-Cas9 system and demonstrate enhanced immune response of these PD-1-disrupted CTLs to the EBV-LMP2A antigen and superior cytotoxicity to the EBV-positive gastric cancer cell. In addition, when combined with low-dose radiotherapy, these PD-1-disrupted CTLs mediated an impressive antitumor effect in a xenograft mouse model of EBVaGC. Taken together, these studies illustrate PD-1/PD-L1-mediated immune tolerance of EBVaGC and provide a new strategy for targeting immune checkpoints to break the tolerance for the T cell-based adoptive therapy.
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Affiliation(s)
- Shu Su
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China
| | - Zhengyun Zou
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China
| | - Fangjun Chen
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China
| | - Naiqing Ding
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China
| | - Juan Du
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China
| | - Jie Shao
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China
| | - Lin Li
- Department of Pathology of Drum Tower Hospital, Medical School of Nanjing University , Nanjing, China
| | - Yao Fu
- Department of Pathology of Drum Tower Hospital, Medical School of Nanjing University , Nanjing, China
| | - Bian Hu
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, National Resource Center for Mutant Mice , Nanjing, China
| | - Yang Yang
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China
| | - Huizi Sha
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China
| | - Fanyan Meng
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China
| | - Jia Wei
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China
| | - Xingxu Huang
- MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of Nanjing University, National Resource Center for Mutant Mice, Nanjing, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, China
| | - Baorui Liu
- The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University , Nanjing, China
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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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Treece AL, Duncan DL, Tang W, Elmore S, Morgan DR, Dominguez RL, Speck O, Meyers MO, Gulley ML. Gastric adenocarcinoma microRNA profiles in fixed tissue and in plasma reveal cancer-associated and Epstein-Barr virus-related expression patterns. J Transl Med 2016; 96:661-71. [PMID: 26950485 PMCID: PMC5767475 DOI: 10.1038/labinvest.2016.33] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 12/09/2015] [Accepted: 01/12/2016] [Indexed: 12/27/2022] Open
Abstract
MicroRNA expression in formalin-fixed paraffin-embedded tissue (FFPE) or plasma may add value for cancer management. The GastroGenus miR Panel was developed to measure 55 cancer-specific human microRNAs, Epstein-Barr virus (EBV)-encoded microRNAs, and controls. This Q-rtPCR panel was applied to 100 FFPEs enriched for adenocarcinoma or adjacent non-malignant mucosa, and to plasma of 31 patients. In FFPE, microRNAs upregulated in malignant versus adjacent benign gastric mucosa were hsa-miR-21, -155, -196a, -196b, -185, and -let-7i. Hsa-miR-18a, 34a, 187, -200a, -423-3p, -484, and -744 were downregulated. Plasma of cancer versus non-cancer controls had upregulated hsa-miR-23a, -103, and -221 and downregulated hsa-miR-378, -346, -486-5p, -200b, -196a, -141, and -484. EBV-infected versus uninfected cancers expressed multiple EBV-encoded microRNAs, and concomitant dysregulation of four human microRNAs suggests that viral infection may alter cellular biochemical pathways. Human microRNAs were dysregulated between malignant and benign gastric mucosa and between plasma of cancer patients and non-cancer controls. Strong association of EBV microRNA expression with known EBV status underscores the ability of microRNA technology to reflect disease biology. Expression of viral microRNAs in concert with unique human microRNAs provides novel insights into viral oncogenesis and reinforces the potential for microRNA profiles to aid in classifying gastric cancer subtypes. Pilot studies of plasma suggest the potential for a noninvasive addition to cancer diagnostics.
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MESH Headings
- Adenocarcinoma/genetics
- Adenocarcinoma/metabolism
- Adenocarcinoma/virology
- Aged
- Aged, 80 and over
- Case-Control Studies
- Epstein-Barr Virus Infections/genetics
- Epstein-Barr Virus Infections/metabolism
- Epstein-Barr Virus Infections/virology
- Female
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic
- Herpesvirus 4, Human/genetics
- Herpesvirus 4, Human/isolation & purification
- Humans
- Male
- MicroRNAs/blood
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Middle Aged
- Pilot Projects
- RNA, Neoplasm/blood
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- RNA, Viral/blood
- RNA, Viral/genetics
- RNA, Viral/metabolism
- Stomach Neoplasms/genetics
- Stomach Neoplasms/metabolism
- Stomach Neoplasms/virology
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Affiliation(s)
- Amanda L Treece
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Daniel L Duncan
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Weihua Tang
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Sandra Elmore
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Douglas R Morgan
- Division of Gastroenterology, Hepatology, and Nutrition; Department of Medicine, Vanderbilt University, Nashville, TN, USA
| | - Ricardo L Dominguez
- Department of Gastroenterology, Western Regional Hospital, Santa Rosa de Copan, Honduras
| | - Olga Speck
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Michael O Meyers
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Margaret L Gulley
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Kayamba V, Monze M, Asombang AW, Zyambo K, Kelly P. Serological response to Epstein-Barr virus early antigen is associated with gastric cancer and human immunodeficiency virus infection in Zambian adults: a case-control study. Pan Afr Med J 2016; 23:45. [PMID: 27217871 PMCID: PMC4862785 DOI: 10.11604/pamj.2016.23.45.8503] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 02/07/2016] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Gastric cancer is one of the major causes of cancer related deaths, but data from sub-Saharan Africa are very scanty. The cancer genome atlas (TCGA) initiative confirmed Epstein-Barr virus (EBV) related cancer as a distinct subtype, and we set out to look for serological evidence of its role in a sub-Saharan African patient group. METHODS We used stored serum samples obtained from a gastric cancer case-control study conducted between 2010 and 2012 in Lusaka, Zambia. A total of 147 patients were included with 51 gastric adenocarcinoma cases and 96 age and sex matched controls. The presence of antibodies to EBV nuclear antigen-1 (EBNA-1) and early antigen (EA) was determined using commercially available ELISA kits. Data were analysed in STATA Stata Corp, College Station TX. RESULTS Over 90% of all the samples analysed were positive for antibodies to EBNA-1. The presence of antibodies to EBV EA was significantly higher in gastric cancer cases than in controls, (OR 4.38; 95% CI 1.53-13.06, P = 0.0027), with an attributable risk of 23%. HIV infection was also associated with EBV EA seroprevalence (OR 10.97; 95% CI 2.26 -13.06, P = 0.001) but not EBNA-1 (OR 0.81; 95% CI 0.10 -38.75, P = 0.596). There was no association of EBV infection with age below 45 years, Helicobacter pylori infection, intestinal metaplasia, gastric atrophy or inflammation. CONCLUSION We therefore conclude that EBV exposure is common among Zambian adults and that EBV EA seropositivity is associated with gastric cancer and HIV infection, but not premalignant lesions.
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Affiliation(s)
- Violet Kayamba
- Tropical Gastroenterology & Nutrition Group, University of Zambia School of Medicine, Nationalist Road, Lusaka, Zambia
| | - Mwaka Monze
- University Teaching Hospital, Nationalist Road, Lusaka, Zambia
| | - Akwi Wasi Asombang
- Division of Gastroenterology and Hepatology, University of Missouri-Columbia School of Medicine, MO, USA
| | - Kanekwa Zyambo
- Tropical Gastroenterology & Nutrition Group, University of Zambia School of Medicine, Nationalist Road, Lusaka, Zambia
| | - Paul Kelly
- Tropical Gastroenterology & Nutrition Group, University of Zambia School of Medicine, Nationalist Road, Lusaka, Zambia; Blizard Institute, Barts & The London School of Medicine and Dentistry, Turner Street, London, UK
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Kanat O, O’Neil B, Shahda S. Targeted therapy for advanced gastric cancer: A review of current status and future prospects. World J Gastrointest Oncol 2015; 7:401-410. [PMID: 26690491 PMCID: PMC4678387 DOI: 10.4251/wjgo.v7.i12.401] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Revised: 09/18/2015] [Accepted: 10/23/2015] [Indexed: 02/05/2023] Open
Abstract
In the West in particular, the vast majority of gastric cancer (GC) patients present with advanced-stage disease. Although combination chemotherapy is still the most important component of treatment for these patients, it confers a modest survival advantage. Recently, increased knowledge of the key molecular signaling pathways involved in gastric carcinogenesis has led to the discovery of specific molecular-targeted therapeutic agents. Some of these agents such as trastuzumab and ramucirumab have changed the treatment paradigm for this disease. In this paper, we will summarize the current clinical status of targeted drug therapy in the management of GC.
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Abate F, Ambrosio MR, Mundo L, Laginestra MA, Fuligni F, Rossi M, Zairis S, Gazaneo S, De Falco G, Lazzi S, Bellan C, Rocca BJ, Amato T, Marasco E, Etebari M, Ogwang M, Calbi V, Ndede I, Patel K, Chumba D, Piccaluga PP, Pileri S, Leoncini L, Rabadan R. Distinct Viral and Mutational Spectrum of Endemic Burkitt Lymphoma. PLoS Pathog 2015; 11:e1005158. [PMID: 26468873 PMCID: PMC4607508 DOI: 10.1371/journal.ppat.1005158] [Citation(s) in RCA: 116] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 08/19/2015] [Indexed: 12/15/2022] Open
Abstract
Endemic Burkitt lymphoma (eBL) is primarily found in children in equatorial regions and represents the first historical example of a virus-associated human malignancy. Although Epstein-Barr virus (EBV) infection and MYC translocations are hallmarks of the disease, it is unclear whether other factors may contribute to its development. We performed RNA-Seq on 20 eBL cases from Uganda and showed that the mutational and viral landscape of eBL is more complex than previously reported. First, we found the presence of other herpesviridae family members in 8 cases (40%), in particular human herpesvirus 5 and human herpesvirus 8 and confirmed their presence by immunohistochemistry in the adjacent non-neoplastic tissue. Second, we identified a distinct latency program in EBV involving lytic genes in association with TCF3 activity. Third, by comparing the eBL mutational landscape with published data on sporadic Burkitt lymphoma (sBL), we detected lower frequencies of mutations in MYC, ID3, TCF3 and TP53, and a higher frequency of mutation in ARID1A in eBL samples. Recurrent mutations in two genes not previously associated with eBL were identified in 20% of tumors: RHOA and cyclin F (CCNF). We also observed that polyviral samples showed lower numbers of somatic mutations in common altered genes in comparison to sBL specimens, suggesting dual mechanisms of transformation, mutation versus virus driven in sBL and eBL respectively.
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Affiliation(s)
- Francesco Abate
- Department of Systems Biology, Columbia University College of Physicians and Surgeons, New York, New York, United States of America
- Department of Biomedical Informatics, Columbia University College of Physicians and Surgeons, New York, New York, United States of America
| | | | - Lucia Mundo
- Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy
| | - Maria Antonella Laginestra
- Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy
| | - Fabio Fuligni
- Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy
| | - Maura Rossi
- Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy
| | - Sakellarios Zairis
- Department of Systems Biology, Columbia University College of Physicians and Surgeons, New York, New York, United States of America
| | - Sara Gazaneo
- Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy
| | - Giulia De Falco
- Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy
- School of Biological and Chemical Sciences, Queen Mary University of London, London, United Kingdom
| | - Stefano Lazzi
- Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy
| | - Cristiana Bellan
- Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy
| | - Bruno Jim Rocca
- Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy
| | - Teresa Amato
- Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy
| | - Elena Marasco
- Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy
| | - Maryam Etebari
- Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy
| | | | | | | | | | | | - Pier Paolo Piccaluga
- Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy
| | - Stefano Pileri
- Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy
- Unit of Haematopathology, European Institute of Oncology, Milan and Bologna University School of Medicine, Bologna, Italy
| | - Lorenzo Leoncini
- Department of Medical Biotechnologies, Section of Pathology, University of Siena, Siena, Italy
- Department of Experimental, Diagnostic, and Specialty Medicine (DIMES), S. Orsola-Malpighi Hospital, Bologna University School of Medicine, Bologna, Italy
| | - Raul Rabadan
- Department of Systems Biology, Columbia University College of Physicians and Surgeons, New York, New York, United States of America
- Department of Biomedical Informatics, Columbia University College of Physicians and Surgeons, New York, New York, United States of America
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