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1
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Korpan M, Puhr HC, Berger JM, Friedrich A, Prager GW, Preusser M, Ilhan-Mutlu A. Current Landscape of Molecular Biomarkers in Gastroesophageal Tumors and Potential Strategies for Co-Expression Patterns. Cancers (Basel) 2025; 17:340. [PMID: 39941712 PMCID: PMC11816248 DOI: 10.3390/cancers17030340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Revised: 01/14/2025] [Accepted: 01/18/2025] [Indexed: 02/16/2025] Open
Abstract
The treatment of metastasized gastroesophageal adenocarcinoma largely depends on molecular profiling based on immunohistochemical procedures. Therefore, the examination of HER2, PD-L1, and dMMR/MSI is recommended by the majority of clinical practice guidelines, as positive expression leads to different treatment approaches. Data from large phase-III trials and consequent approvals in various countries enable physicians to offer their patients several therapy options including immunotherapy, targeted therapy, or both combined with chemotherapy. The introduction of novel therapeutic targets such as CLDN18.2 leads to a more complex decision-making process as a significant number of patients show positive results for the co-expression of other biomarkers besides CLDN18.2. The aim of this review is to summarize the current biomarker landscape of patients with metastatic gastroesophageal tumors, its direct clinical impact on daily decision-making, and to evaluate current findings on biomarker co-expression. Furthermore, possible treatment strategies with multiple biomarker expression are discussed.
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Affiliation(s)
- Martin Korpan
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Christian Doppler Laboratory for Personalized Immunotherapy, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Hannah Christina Puhr
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Christian Doppler Laboratory for Personalized Immunotherapy, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Julia M. Berger
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Christian Doppler Laboratory for Personalized Immunotherapy, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Alexander Friedrich
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Gerald W. Prager
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Matthias Preusser
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Christian Doppler Laboratory for Personalized Immunotherapy, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Aysegül Ilhan-Mutlu
- Division of Oncology, Department of Medicine I, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
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2
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Wang M, Huang K, Fan X, Wang J, Jin Y, Zheng ZJ. Access to radiotherapy in improving gastric cancer care quality and equality. COMMUNICATIONS MEDICINE 2024; 4:225. [PMID: 39488624 PMCID: PMC11531536 DOI: 10.1038/s43856-024-00655-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Accepted: 10/23/2024] [Indexed: 11/04/2024] Open
Abstract
BACKGROUND Quality health services could improve patient outcomes and prognosis. Gastric cancer care was of great disparity across genders. Disparities within radiotherapy units could impact gastric cancer care, potentially exacerbating gender-based inequalities. METHODS We retrieved the disease burden data from Global Burden of Disease 2019. A quality of care index was constructed by applying principal component analysis techniques. The disparity of gastric cancer care across genders was described, and the association of access to radiotherapy with gastric cancer care as well as gender disparity was explored. RESULTS Males receive better quality of gastric cancer care than females, and this gender disparity is widening in middle-low socio-development regions. A positive correlation emerges between the density of radiotherapy facilities and an elevated quality of care, and reduced gender-based disparities. CONCLUSIONS The association between robust radiotherapy access, improved gastric cancer QCI, and reduced gender-based disparities spotlights the imperative of fortifying radiotherapy infrastructure within areas and populations in greatest need.
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Affiliation(s)
- Minmin Wang
- Department of Global Health, School of Public Health, Peking University, Beijing, China
- Institute for Global Health and Development, Peking University, Beijing, China
| | - Kepei Huang
- Department of Global Health, School of Public Health, Peking University, Beijing, China
- Institute for Global Health and Development, Peking University, Beijing, China
| | - Xiaohan Fan
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China
| | - Jia Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, China
| | - Yinzi Jin
- Department of Global Health, School of Public Health, Peking University, Beijing, China.
- Institute for Global Health and Development, Peking University, Beijing, China.
| | - Zhi-Jie Zheng
- Department of Global Health, School of Public Health, Peking University, Beijing, China
- Institute for Global Health and Development, Peking University, Beijing, China
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3
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Arslan Bozdag L, Inan S, Elif Gultekin S. Microsatellite Instability and Loss of Heterozygosity as Prognostic Markers in Oral Squamous Cell Carcinoma: Molecular Mechanisms, Detection Techniques, and Therapeutic Strategies. Genes Chromosomes Cancer 2024; 63:e70002. [PMID: 39470253 DOI: 10.1002/gcc.70002] [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: 10/01/2024] [Accepted: 10/05/2024] [Indexed: 10/30/2024] Open
Abstract
The aim of this study was to conduct a systematic review of research investigating the potential role of microsatellite instability (MSI) and loss of heterozygosity (LOH) in oral squamous cell carcinoma (OSCC), with a focus on molecular mechanisms, detection methods, and therapeutic approaches. Search for articles involved the PubMed and Scopus. Previous retrospective and prospective studies identified variations between oral cancers that exhibit microsatellite stability and LOH. In this search, 294 articles were initially retrieved. Of these, 70 were excluded due to duplication, 106 were identified as ineligible by automated tools, and 24 were excluded as they were published in languages other than English. An additional 94 articles were excluded, 32 of which focused on head and neck cancers broadly, and 8 could not be accessed due to withdrawal. Ultimately, a systematic review was conducted based on 54 selected articles. Among the chromosomes analyzed for MSI and LOH, the highest frequency of LOH was observed on chromosome 9p. The MSI subtype is particularly susceptible to immunotherapeutic methods, such as the use of anti-PD-L1 and anti-CTLA4 antibodies, owing to its strong immunogenicity and ubiquitous expression of immune checkpoint ligands. Given the distinct characteristics and clinical behavior of oral cancer with MSI compared to microsatellite stable disease, it is advisable to incorporate MSI testing into the diagnostic process for all stages of tumor development. This ensured that each patient had received precise and effective treatment.
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Affiliation(s)
- Leyla Arslan Bozdag
- Faculty of Science, Department of Biology, Gazi University, Ankara, Turkey
- Faculty of Dentistry, Department of Oral Pathology, Gazi University, Ankara, Turkey
| | - Sevinç Inan
- Tepebasi Oral Dental Health Centre, Ankara, Turkey
| | - Sibel Elif Gultekin
- Faculty of Dentistry, Department of Oral Pathology, Gazi University, Ankara, Turkey
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4
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Ooki A, Osumi H, Yoshino K, Yamaguchi K. Potent therapeutic strategy in gastric cancer with microsatellite instability-high and/or deficient mismatch repair. Gastric Cancer 2024; 27:907-931. [PMID: 38922524 PMCID: PMC11335850 DOI: 10.1007/s10120-024-01523-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Accepted: 06/12/2024] [Indexed: 06/27/2024]
Abstract
Gastric cancer (GC) is a common malignancy that presents challenges in patient care worldwide. The mismatch repair (MMR) system is a highly conserved DNA repair mechanism that protects genome integrity during replication. Deficient MMR (dMMR) results in an increased accumulation of genetic errors in microsatellite sequences, leading to the development of a microsatellite instability-high (MSI-H) phenotype. Most MSI-H/dMMR GCs arise sporadically, mainly due to MutL homolog 1 (MLH1) epigenetic silencing. Unlike microsatellite-stable (MSS)/proficient MMR (pMMR) GCs, MSI-H/dMMR GCs are relatively rare and represent a distinct subtype with genomic instability, a high somatic mutational burden, favorable immunogenicity, different responses to treatment, and prognosis. dMMR/MSI-H status is a robust predictive biomarker for treatment with immune checkpoint inhibitors (ICIs) due to high neoantigen load, prominent tumor-infiltrating lymphocytes, and programmed cell death ligand 1 (PD-L1) overexpression. However, a subset of MSI-H/dMMR GC patients does not benefit from immunotherapy, highlighting the need for further research into predictive biomarkers and resistance mechanisms. This review provides a comprehensive overview of the clinical, molecular, immunogenic, and therapeutic aspects of MSI-H/dMMR GC, with a focus on the impact of ICIs in immunotherapy and their potential as neoadjuvant therapies. Understanding the complexity and diversity of the molecular and immunological profiles of MSI-H/dMMR GC will drive the development of more effective therapeutic strategies and molecular targets for future precision medicine.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan.
| | - Hiroki Osumi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Koichiro Yoshino
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
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Daliri K, Hescheler J, Pfannkuche KP. Prime Editing and DNA Repair System: Balancing Efficiency with Safety. Cells 2024; 13:858. [PMID: 38786078 PMCID: PMC11120019 DOI: 10.3390/cells13100858] [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: 03/24/2024] [Revised: 04/24/2024] [Accepted: 05/12/2024] [Indexed: 05/25/2024] Open
Abstract
Prime editing (PE), a recent progression in CRISPR-based technologies, holds promise for precise genome editing without the risks associated with double-strand breaks. It can introduce a wide range of changes, including single-nucleotide variants, insertions, and small deletions. Despite these advancements, there is a need for further optimization to overcome certain limitations to increase efficiency. One such approach to enhance PE efficiency involves the inhibition of the DNA mismatch repair (MMR) system, specifically MLH1. The rationale behind this approach lies in the MMR system's role in correcting mismatched nucleotides during DNA replication. Inhibiting this repair pathway creates a window of opportunity for the PE machinery to incorporate the desired edits before permanent DNA repair actions. However, as the MMR system plays a crucial role in various cellular processes, it is important to consider the potential risks associated with manipulating this system. The new versions of PE with enhanced efficiency while blocking MLH1 are called PE4 and PE5. Here, we explore the potential risks associated with manipulating the MMR system. We pay special attention to the possible implications for human health, particularly the development of cancer.
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Affiliation(s)
- Karim Daliri
- Institute for Neurophysiology, Centre for Physiology and Pathophysiology, Medical Faculty and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany (K.P.P.)
- Marga and Walter Boll-Laboratory for Cardiac Tissue Engineering, University of Cologne, 50931 Cologne, Germany
| | - Jürgen Hescheler
- Institute for Neurophysiology, Centre for Physiology and Pathophysiology, Medical Faculty and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany (K.P.P.)
| | - Kurt Paul Pfannkuche
- Institute for Neurophysiology, Centre for Physiology and Pathophysiology, Medical Faculty and University Hospital of Cologne, University of Cologne, 50931 Cologne, Germany (K.P.P.)
- Marga and Walter Boll-Laboratory for Cardiac Tissue Engineering, University of Cologne, 50931 Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany
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6
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Wu H, Ma W, Jiang C, Li N, Xu X, Ding Y, Jiang H. Heterogeneity and Adjuvant Therapeutic Approaches in MSI-H/dMMR Resectable Gastric Cancer: Emerging Trends in Immunotherapy. Ann Surg Oncol 2023; 30:8572-8587. [PMID: 37667098 PMCID: PMC10625937 DOI: 10.1245/s10434-023-14103-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 07/24/2023] [Indexed: 09/06/2023]
Abstract
Gastric cancer (GC) remains one of the world's most common and fatal malignant tumors. With a refined understanding of molecular typing in recent years, microsatellite instability (MSI) has become a major molecular typing approach for gastric cancer. MSI is well recognized for its important role during the immunotherapy of advanced GC. However, its value remains unclear in resectable gastric cancer. The reported incidence of microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) in resectable gastric cancer varies widely, with no consensus reached on the value of postoperative adjuvant therapy in patients with MSI-H/dMMR resectable GC. It has been established that MSI-H/dMMR tumor cells can elicit an endogenous immune antitumor response and ubiquitously express immune checkpoint ligands such as PD-1 or PD-L1. On the basis of these considerations, MSI-H/dMMR resectable GCs are responsive to adjuvant immunotherapy, although limited research has hitherto been conducted. In this review, we comprehensively describe the differences in geographic distribution and pathological stages in patients with MSI-H/dMMR with resectable gastric cancer and explore the value of adjuvant chemotherapy and immunotherapy on MSI-H/dMMR to provide a foothold for the individualized treatment of this patient population.
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Affiliation(s)
- Hui Wu
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Wenyuan Ma
- Zhejiang University School of Medicine, Hangzhou, China
| | - Congfa Jiang
- Department of Hematology and Oncology, Ningbo Forth Hospital, Ningbo, China
| | - Ning Li
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Xin Xu
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China
| | - Yongfeng Ding
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
| | - Haiping Jiang
- Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.
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7
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Skórzewska M, Gęca K, Polkowski WP. A Clinical Viewpoint on the Use of Targeted Therapy in Advanced Gastric Cancer. Cancers (Basel) 2023; 15:5490. [PMID: 38001751 PMCID: PMC10670421 DOI: 10.3390/cancers15225490] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Revised: 11/05/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023] Open
Abstract
The development of therapies for advanced gastric cancer (GC) has made significant progress over the past few years. The identification of new molecules and molecular targets is expanding our understanding of the disease's intricate nature. The end of the classical oncology era, which relied on well-studied chemotherapeutic agents, is giving rise to novel and unexplored challenges, which will cause a significant transformation of the current oncological knowledge in the next few years. The integration of established clinically effective regimens in additional studies will be crucial in managing these innovative aspects of GC. This study aims to present an in-depth and comprehensive review of the clinical advancements in targeted therapy and immunotherapy for advanced GC.
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8
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Deng G, Sun H, Huang R, Pan H, Zuo Y, Zhao R, Du Z, Xue Y, Song H. An oxidative stress biomarkers predict prognosis in gastric cancer patients receiving immune checkpoint inhibitor. Front Oncol 2023; 13:1173266. [PMID: 37546387 PMCID: PMC10400353 DOI: 10.3389/fonc.2023.1173266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 07/03/2023] [Indexed: 08/08/2023] Open
Abstract
Objective The development and advance of gastric cancer are inextricably linked to oxidative and antioxidant imbalance. Although immunotherapy has been shown to be clinically effective, the link between oxidative stress and gastric cancer patients treated with immune checkpoint inhibitor (ICIs) remains unknown. This study aims at looking into the prognostic value of oxidative stress scores in gastric cancer patients treated with ICIs. Methods By taking the propagation to receiver operating characteristic (ROC) we got the best cut-off values, and divided 265 patients receiving ICIs and chemotherapy into high and low GC-Integrated Oxidative Stress Score (GIOSS) groups. We also used Kaplan-Meier and COX regression models to investigate the relationship between oxidative stress biomarkers and prognosis. Results Through both univariate and multivariate analyses, it's shown that GIOSS severs as an independent prognostic factor for progression-free survival (PFS) and Overall survival (OS). Based on GIOSS cutoff values, patients with high GIOSS levels, compared to those with low levels exhibited shorter PFS and OS, both in the high GIOSS group, which performed poorly in the ICIs subgroup and other subgroup analyses. Conclusion GIOSS is a biomarker that responds to systemic oxidative stress in the body and can predict prognosis in patients with gastric cancer who are taking ICIs. Additionally, it might come to medical professionals' aid in making more effective or more suitable treatment plans for gastric cancer.
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9
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Li Y, Wang X, Hou X, Ma X. Could Inhibiting the DNA Damage Repair Checkpoint Rescue Immune-Checkpoint-Inhibitor-Resistant Endometrial Cancer? J Clin Med 2023; 12:jcm12083014. [PMID: 37109350 PMCID: PMC10144486 DOI: 10.3390/jcm12083014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/23/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Endometrial cancer (EC) is increasingly undermining female health worldwide, with poor survival rates for advanced or recurrent/metastatic diseases. The application of immune checkpoint inhibitors (ICIs) has opened a window of opportunity for patients with first-line therapy failure. However, there is a subset of patients with endometrial cancer who remain insensitive to immunotherapy alone. Therefore, it is necessary to develop new therapeutic agents and further explore reliable combinational strategies to optimize the efficacy of immunotherapy. DNA damage repair (DDR) inhibitors as novel targeted drugs are able to generate genomic toxicity and induce cell death in solid tumors, including EC. Recently, growing evidence has demonstrated the DDR pathway modulates innate and adaptive immunity in tumors. In this review, we concentrate on the exploration of the intrinsic correlation between DDR pathways, especially the ATM-CHK2-P53 pathway and the ATR-CHK1-WEE1 pathway, and oncologic immune response, as well as the feasibility of adding DDR inhibitors to ICIs for the treatment of patients with advanced or recurrent/metastatic EC. We hope that this review will offer some beneficial references to the investigation of immunotherapy and provide a reasonable basis for "double-checkpoint inhibition" in EC.
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Affiliation(s)
- Yinuo Li
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiangyu Wang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xin Hou
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xiangyi Ma
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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10
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Diagnosis and clinical implication of collision gastric adenocarcinomas: a case report. Surg Case Rep 2022; 8:193. [PMID: 36207547 PMCID: PMC9547045 DOI: 10.1186/s40792-022-01543-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Accepted: 09/23/2022] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND Collision tumors are a subtype of simultaneous tumors wherein two unrelated tumors collide or infiltrate each other. Collision gastric adenocarcinomas (CGA) are rare and difficult to diagnose, and their clinical implications remain unclear. Herein, we aimed to reveal diagnostic methods for CGA and provide insight into its implications. CASE PRESENTATION Among 1041 cases of gastric cancers (GCs) resected between 2008 and 2018, we included cases of confirmed CGA. Patients' backgrounds, preoperative endoscopy findings, macroscopic imaging findings, and histopathology findings [including immunostaining for CK 7, MUC2, and mismatch repair (MMR) proteins] were investigated. The incidence of CGA was 0.5%: 5 of 81 cases having simultaneous multiple GCs. Tumors were mainly in the distal stomach. The CGA in two cases was between early cancers, in two cases was between early and advanced cancers, and in one case was between advanced cancers. There were three cases of collision between differentiated and undifferentiated types and two cases between differentiated types. Immunostaining with CK7 and MUC2 was useful for diagnosing collision tumor when the histology was similar to each other. Among ten GCs comprising CGA, nine tumors (90%) exhibited deficient MMR proteins, suggesting high microsatellite instability (MSI). CONCLUSIONS CGA is rare and usually found in the distal stomach. Close observation of shape, optimal dissection, and detailed pathological examination, including immunostaining, facilitated diagnosis. CGAs may have high MSI potential.
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11
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Ju MK, Lee JR, Choi Y, Park SY, Sul HJ, Chung HJ, An S, Lee S, Jung E, Kim B, Choi BY, Kim BJ, Kim HS, Lim H, Kang HS, Soh JS, Myung K, Kim KC, Cho JW, Seo J, Kim TM, Lee JY, Kim Y, Kim H, Zang DY. PWWP2B promotes DNA end resection and homologous recombination. EMBO Rep 2022; 23:e53492. [PMID: 35582821 PMCID: PMC9253748 DOI: 10.15252/embr.202153492] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 04/18/2022] [Accepted: 05/02/2022] [Indexed: 11/15/2023] Open
Abstract
Genome instability is one of the leading causes of gastric cancers. However, the mutational landscape of driver genes in gastric cancer is poorly understood. Here, we investigate somatic mutations in 25 Korean gastric adenocarcinoma patients using whole-exome sequencing and show that PWWP2B is one of the most frequently mutated genes. PWWP2B mutation correlates with lower cancer patient survival. We find that PWWP2B has a role in DNA double-strand break repair. As a nuclear protein, PWWP2B moves to sites of DNA damage through its interaction with UHRF1. Depletion of PWWP2B enhances cellular sensitivity to ionizing radiation (IR) and impairs IR-induced foci formation of RAD51. PWWP2B interacts with MRE11 and participates in homologous recombination via promoting DNA end-resection. Taken together, our data show that PWWP2B facilitates the recruitment of DNA repair machinery to sites of DNA damage and promotes HR-mediated DNA double-strand break repair. Impaired PWWP2B function might thus cause genome instability and promote gastric cancer development.
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Affiliation(s)
- Min Kyung Ju
- Department of Biological SciencesUlsan National Institute of Science and TechnologyUlsanKorea
| | - Joo Rak Lee
- Department of Biological SciencesUlsan National Institute of Science and TechnologyUlsanKorea
| | - Yeonsong Choi
- Department of Biomedical EngineeringUlsan National Institute of Science and TechnologyUlsanKorea
| | - Seon Young Park
- Department of Biological SciencesResearch Institute of Women’s HealthSookmyung Women's UniversitySeoulKorea
| | - Hee Jung Sul
- Hallym Translational Research InstituteHallym University Sacred Heart HospitalAnyang‐siKorea
| | - Hee Jin Chung
- Department of Biological SciencesUlsan National Institute of Science and TechnologyUlsanKorea
| | - Soyeong An
- Department of Biological SciencesUlsan National Institute of Science and TechnologyUlsanKorea
| | - Semin Lee
- Department of Biomedical EngineeringUlsan National Institute of Science and TechnologyUlsanKorea
| | - Eunyoung Jung
- Department of Biological SciencesResearch Institute of Women’s HealthSookmyung Women's UniversitySeoulKorea
| | - Bohyun Kim
- Hallym Translational Research InstituteHallym University Sacred Heart HospitalAnyang‐siKorea
| | - Bo Youn Choi
- Hallym Translational Research InstituteHallym University Sacred Heart HospitalAnyang‐siKorea
| | - Bum Jun Kim
- Department of Internal MedicineHallym University Sacred Heart HospitalHallym University College of MedicineAnyang‐siKorea
| | - Hyeong Su Kim
- Department of Internal MedicineHallym University Sacred Heart HospitalHallym University College of MedicineAnyang‐siKorea
| | - Hyun Lim
- Department of Internal MedicineHallym University Sacred Heart HospitalHallym University College of MedicineAnyang‐siKorea
| | - Ho Suk Kang
- Department of Internal MedicineHallym University Sacred Heart HospitalHallym University College of MedicineAnyang‐siKorea
| | - Jae Seung Soh
- Department of Internal MedicineHallym University Sacred Heart HospitalHallym University College of MedicineAnyang‐siKorea
| | - Kyungjae Myung
- Department of Biological SciencesUlsan National Institute of Science and TechnologyUlsanKorea
- Center for Genomic Integrity Institute for Basic Science (IBS)UlsanKorea
| | - Kab Choong Kim
- Department of SurgeryHallym University Medical CenterHallym University College of MedicineAnyang‐siKorea
| | - Ji Woong Cho
- Department of SurgeryHallym University Medical CenterHallym University College of MedicineAnyang‐siKorea
| | - Jinwon Seo
- Department of PathologyHallym University Sacred Heart HospitalHallym University College of MedicineAnyang‐siKorea
| | - Tae Moon Kim
- Center for Genomic Integrity Institute for Basic Science (IBS)UlsanKorea
| | - Ja Yil Lee
- Department of Biological SciencesUlsan National Institute of Science and TechnologyUlsanKorea
- Center for Genomic Integrity Institute for Basic Science (IBS)UlsanKorea
| | - Yonghwan Kim
- Department of Biological SciencesResearch Institute of Women’s HealthSookmyung Women's UniversitySeoulKorea
| | - Hongtae Kim
- Department of Biological SciencesUlsan National Institute of Science and TechnologyUlsanKorea
- Center for Genomic Integrity Institute for Basic Science (IBS)UlsanKorea
| | - Dae Young Zang
- Hallym Translational Research InstituteHallym University Sacred Heart HospitalAnyang‐siKorea
- Department of Internal MedicineHallym University Sacred Heart HospitalHallym University College of MedicineAnyang‐siKorea
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12
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Kole C, Charalampakis N, Tsakatikas S, Kouris NI, Papaxoinis G, Karamouzis MV, Koumarianou A, Schizas D. Immunotherapy for gastric cancer: a 2021 update. Immunotherapy 2021; 14:41-64. [PMID: 34784774 DOI: 10.2217/imt-2021-0103] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Gastric cancer, the fifth most frequent cancer and the fourth leading cause of cancer deaths, accounts for a devastating death rate worldwide. Since the majority of patients with gastric cancer are diagnosed at advanced stages, they are not suitable for surgery and present with locally advanced or metastatic disease. Recent advances in immunotherapy have elicited a considerable amount of attention as viable therapeutic options for several cancer types. This work presents a summary of the currently ongoing clinical trials and critically addresses the efficacy of a large spectrum of immunotherapy approaches in the general population for gastric cancer as well as in relation to tumor genetic profiling.
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Affiliation(s)
- Christo Kole
- First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
| | | | - Sergios Tsakatikas
- Department of Medical Oncology, Metaxa Cancer Hospital, Athens, 185 37, Greece
| | - Nikolaos-Iasonas Kouris
- First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
| | - George Papaxoinis
- Second Department of Medical Oncology, Agios Savas Anticancer Hospital, Athens, 115 22, Greece
| | - Michalis V Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, National & Kapodistrian University of Athens, Athens, 115 27, Greece
| | - Anna Koumarianou
- Hematology Oncology Unit, Fourth Department of Internal Medicine, National & Kapodistrian University of Athens, Attikon University Hospital, Athens, 124 62, Greece
| | - Dimitrios Schizas
- First Department of Surgery, National & Kapodistrian University of Athens, Laikon General Hospital, Athens, 115 27, Greece
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13
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Nshizirungu JP, Bennis S, Mellouki I, Benajah DA, Lahmidani N, El Bouhaddoutti H, Ibn Majdoub K, Ibrahimi SA, Pires Celeiro S, Viana-Pereira M, Manuel Reis R. Microsatellite Instability Analysis in Gastric Carcinomas of Moroccan Patients. Genet Test Mol Biomarkers 2021; 25:116-123. [PMID: 33596142 DOI: 10.1089/gtmb.2020.0146] [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] [Indexed: 12/24/2022] Open
Abstract
Aim: To investigate correlations between microsatellite instability (MSI) and the phenotype, clinicopathological features, and overall survival (OS) in Moroccan gastric cancer (GC) patients. We evaluated the mutation frequency of 22 MSI-target genes in MSI-positive tumors. Materials and Methods: MSI evaluation were performed for 97 gastric tumors by multiplex polymerase chain reaction (PCR) using a panel of five quasimonomorphic mononucleotide repeat markers (NR27, NR21, NR24, BAT25, and BAT26). The mutation profiles of 22 MSI-target genes were assessed by multiplex PCR and genotyping. Kaplan-Meier curves, the log-rank test, and the Cox proportional hazard regression model were used to conduct survival analyses. Results: Microsatellite stable (MSS) status was observed in 77/97 (79.4%) gastric cancer samples, MSI-Low in 7 (7.2%) samples, and MSI-High (MSI-H) in 13 (13.4%) cases. The MSI-H phenotype was significantly associated with older age (p = 0.004), tumor location (p < 0.001), and intestinal-type of Lauren classification (p < 0.001). Among the 22 MSI target genes analyzed, the most frequently altered genes were HSP110 (84.6%), EGFR (30.8%), BRCA2 (23.1%), MRE11 (23.1%), and MSH3 (23.1%). Multivariate analysis revealed the MSS phenotype (Hazard ratio, 0.23; 95% confidence interval, 0.7-7.4; p = 0.014) as an independent indicator of poor prognosis in our population. Conclusions: This study is the first analysis of MSI in Moroccan GC patients. MSI-H GCs have distinct clinicopathological features and an improved OS. We have identified candidate target genes altered in MSI-positive tumors with potential clinical implications. These findings can guide immunotherapy designed for Moroccan GC patients.
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Affiliation(s)
- Jean Paul Nshizirungu
- Biomedical and Translational Research Laboratory, Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Sanae Bennis
- Biomedical and Translational Research Laboratory, Faculty of Medicine and Pharmacy, Sidi Mohamed Ben Abdellah University, Fez, Morocco
| | - Ihsane Mellouki
- Faculty of Medicine and Pharmacy, Abdelmalek Essaadi University, Tangier, Morocco
| | - Dafr-Allah Benajah
- Department of Gastroenterology, Hassan II University Hospital, Fez, Morocco
| | - Nada Lahmidani
- Department of Gastroenterology, Hassan II University Hospital, Fez, Morocco
| | | | - Karim Ibn Majdoub
- Department of Visceral Surgery, Hassan II University Hospital, Fez, Morocco
| | - Sidi Adil Ibrahimi
- Department of General Surgery, Hassan II University Hospital, Fez, Morocco
| | - Sónia Pires Celeiro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Marta Viana-Pereira
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - Rui Manuel Reis
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.,Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil
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14
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Huo X, Xiao X, Zhang S, Du X, Li C, Bai Z, Chen Z. Characterization and clinical evaluation of microsatellite instability and loss of heterozygosity in tumor-related genes in gastric cancer. Oncol Lett 2021; 21:430. [PMID: 33868468 PMCID: PMC8045158 DOI: 10.3892/ol.2021.12691] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Accepted: 02/10/2021] [Indexed: 12/24/2022] Open
Abstract
Microsatellite instability (MSI) detection is widely used in the diagnosis and prognosis evaluation of colorectal cancer. However, for gastric cancer (GC), there is no standard panel of microsatellites (MSs) used in clinical guidance. The present study aimed to identify useful predictors of the clinical features and for the prognosis of GC, based on an investigation of MSI and loss of heterozygosity (LOH) in tumor-related genes. First, from 20 tumor-related genes which were proven to be important to the development of GC, 91 MSs were identified, and PCR amplification, short tandem repeat scanning analysis and TA clone sequencing were used to analyze MSI and LOH in the first set of 90 GC samples. Subsequently, the same method was used to detect the MSI/LOH of the optimized loci in the second set of 136 GC samples. MSI/LOH in the mismatch repair genes was highly consistent with that in oncogenes and tumor suppressor genes, respectively. The length of the core sequence was a main factor for the MSI/LOH rate. The MSI of 12 single loci was significantly associated with lymph node metastasis. The MSI in TP53-1 and the LOH in MGMT-10 were significantly associated with early stages of tumor infiltration depth. The LOH in MGMT-10, PTN-2 and MCC-17 was significantly associated with TNM stage. The LOH in TP53-1 and ERBB2-12 was associated with adenocarcinoma. The MSI/LOH in 6 single loci of 5 tumor-related genes was associated with poor prognosis of GC. The present study demonstrated that the MSI/LOH of loci in tumor-associated genes was associated with 4 clinicopathological characteristics and outcomes of GC. These results may provide potential specific biomarkers for the clinical prediction and treatment of GC.
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Affiliation(s)
- Xueyun Huo
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China.,Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
| | - Xiaoqin Xiao
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China.,Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
| | - Shuangyue Zhang
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China.,Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
| | - Xiaoyan Du
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China.,Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
| | - Changlong Li
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China.,Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
| | - Zhigang Bai
- Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China.,Department of General Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, P.R. China.,Department of General Surgery, National Clinical Research Center for Digestive Diseases, Beijing 100050, P.R. China
| | - Zhenwen Chen
- School of Basic Medical Sciences, Capital Medical University, Beijing 100069, P.R. China.,Tumor Model Laboratory, Beijing Key Laboratory of Cancer Invasion and Metastasis Research, Beijing 100069, P.R. China
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15
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Prognostic impact of microsatellite instability in gastric cancer. Contemp Oncol (Pozn) 2021; 25:68-71. [PMID: 33911985 PMCID: PMC8063893 DOI: 10.5114/wo.2021.104939] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 11/06/2020] [Indexed: 11/17/2022] Open
Abstract
Gastric cancer is a common and deadly cancer. Several factors are associated with its prognosis; however, controversy exists about the role of microsatellite instability (MSI). We aimed to determine the 5-year overall survival (OS) of MSI in gastric adenocarcinoma. A cross-sectional study was carried out on gastric adenocarcinoma in clinical stages I to III treated with D2 gastrectomy between 2010-2013. MSI was demonstrated by immunohistochemistry. We performed a survival analysis comparing cases with and without MSI. From 102 cases, 9.8% showed MSI. The median age was 63 years (range 33-91 years), and 57.8% were men. The more prevalent site of occurrence was the antrum (46.1%), 78.5% of the cases presented in stage III, 47.1% were of the diffuse type, 45.1% were of an intestinal type, and 7.8% were mixed. MSI cases were associated with lower clinical stages (stages I-II) and with better 5-year OS (100 vs. 47 months, p = 0.017). In a multivariate analysis, MSI was independently associated with better survival (HR = 0.209, 95% CI: 0.046-0.945, p = 0.042). MSI gastric cancers presented in early clinical stages and had favourable prognosis compared with non-MSI cancers.
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16
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Salari S, Ghadyani M, Karimi M, Mortezazadeh M, Vahedifard F. Immunohistochemical Expression Pattern of MLH1, MSH2, MSH6, and PMS2 in Tumor Specimen of Iranian Gastric Carcinoma Patients. J Gastrointest Cancer 2021; 53:192-196. [PMID: 33411254 DOI: 10.1007/s12029-020-00566-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/07/2020] [Indexed: 11/28/2022]
Abstract
BACKGROUND Gastric cancer is the third leading cause of cancer-related death. Determining molecular and histopathologic tumor features, which may contribute to the development or progression of gastric cancer, can improve the prognosis. Expression patterns of DNA repair proteins such as MLH1, MSH2, MSH6, and PMS2 that are associated with microsatellite instability (MSI) are some of the markers that are useful in predicting the prognosis of gastric cancer. PURPOSE The purpose was to determine the immunohistochemical expression pattern of MLH1, MSH2, MSH6, and PMS2 in tumor specimens of Iranian gastric carcinoma patients. METHODS In this prospective cohort, 186 consecutive patients with gastric cancer, attending Taleghani Hospital, were enrolled. The immunohistochemical expression patterns of MLH1, MSH2, MSH6, and PMS2 in tumor specimens among them were determined. RESULTS The results of this study demonstrated that 91.4% of our gastric cancer patients were negative for MSI, and 8.6% of them were MSI positive. The positive MSI was seen in 5.9% and 15.7% of male and female subjects, respectively, with a significant difference (P = 0.043). The other variables were not related to MSI results (P > 0.05). CONCLUSION According to the obtained results, the expression of MLH1, MSH2, MSH6, and PMS2 in tumor specimens is positive in 8.6% of the total Iranian gastric cancer sample size, which is mainly positive in female subjects. However, it is not related to the location and stage of the tumor.
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Affiliation(s)
- Sina Salari
- Medical Oncology, Hematology and Bone Marrow Transplantation, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mojtaba Ghadyani
- Medical Oncology, Hematology and Bone Marrow Transplantation, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdi Karimi
- Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Farzan Vahedifard
- Firoozgar Hospital, Iran University of Medical Sciences, Valadi Street, Valiasr Sq, 1593748711, Tehran, Iran.
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17
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Re VD, Brisotto G, Repetto O, De Zorzi M, Caggiari L, Zanussi S, Alessandrini L, Canzonieri V, Miolo G, Puglisi F, Belluco C, Steffan A, Cannizzaro R. Overview of Epstein-Barr-Virus-Associated Gastric Cancer Correlated with Prognostic Classification and Development of Therapeutic Options. Int J Mol Sci 2020; 21:E9400. [PMID: 33321820 PMCID: PMC7764600 DOI: 10.3390/ijms21249400] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/07/2020] [Accepted: 12/08/2020] [Indexed: 02/08/2023] Open
Abstract
Gastric cancer (GC) is a deadly disease with poor prognosis that is characterized by heterogeneity. New classifications based on histologic features, genotypes, and molecular phenotypes, for example, the Cancer Genome Atlas subtypes and those by the Asian Cancer Research Group, help understand the carcinogenic differences in GC and have led to the identification of an Epstein-Barr virus (EBV)-related GC subtype (EBVaGC), providing new indications for tailored treatment and prognostic factors. This article provides a review of the features of EBVaGC and an update on the latest insights from EBV-related research with a particular focus on the strict interaction between EBV infection and the gastric tumor environment, including the host immune response. This information may help increase our knowledge of EBVaGC pathogenesis and the mechanisms that sustain the immune response of patients since this mechanism has been demonstrated to offer a survival advantage in a proportion of patients with GC.
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Affiliation(s)
- Valli De Re
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Giulia Brisotto
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Ombretta Repetto
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Mariangela De Zorzi
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Laura Caggiari
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Stefania Zanussi
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Lara Alessandrini
- Pathology, Department of Medicine DIMED, University of Padova, 61-35121 Padova, Italy;
| | - Vincenzo Canzonieri
- Surgical and Health Sciences, Department of Medical, University of Trieste Medical School, 34100 Trieste, Italy;
- Pathology, Department of Translational Research, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy
| | - Gianmaria Miolo
- Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy; (G.M.); (F.P.)
| | - Fabio Puglisi
- Medical Oncology and Cancer Prevention, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy; (G.M.); (F.P.)
- Department of Medicine, University of Udine, 33100 Udine, Italy
| | - Claudio Belluco
- Surgical Oncology, Department of Surgery, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy;
| | - Agostino Steffan
- Immunopathology and Cancer Biomarkers, Department of Translational Research, Bioproteomic Facility, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33077 Aviano, Italy; (G.B.); (O.R.); (M.D.Z.); (L.C.); (S.Z.); (A.S.)
| | - Renato Cannizzaro
- Gastroenterology, Department of Medical Oncology, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano, Italy;
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18
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De Souza ALPB. Finding the hot spot: identifying immune sensitive gastrointestinal tumors. Transl Gastroenterol Hepatol 2020; 5:48. [PMID: 33073043 DOI: 10.21037/tgh.2019.12.11] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 12/06/2019] [Indexed: 12/16/2022] Open
Abstract
Although researchers have been trying to harness the immune system for over 100 years, the advent of immune checkpoint blockers (ICB) marks an era of significant clinical outcomes in various metastatic solid tumors, characterized by complete and durable responses. ICBs are monoclonal antibodies that target either of a pair of transmembrane molecules in tumors or T-cells involved in immune evasion. Currently 2 ICBs targeting the checkpoint program death 1 (PD-1), nivolumab and pembrolizumab, and one cytotoxic lymphocyte antigen-4 (CTLA-4) inhibitor (ipilimumab) are approved in gastrointestinal malignancies. We review herein the current evidence on predictive biomarkers for ICB response in gastrointestinal tumors. A review of literature based on the National Cancer Institute list of FDA-approved drugs for neoplasms and FDA-approved therapies at the FDA website was performed. An initial literature review was based on the American Association for Clinical Research meeting 2019, the American Society of Clinical Oncology meeting 2019 and the European Society of Medical Oncology 2019 proceedings. A systematic search of PubMed was performed involving MeSH browser terms such as biomarkers, immunotherapy, gastrointestinal diseases and neoplasms. When appropriate, American and British terms were used in the search. The most relevant predictor of response to ICBs is microsatellite instability (MSI) and the data is strongest for colorectal cancer. At least 3 prospective trials show evidence of PD-L1 as a predictive biomarker for ICB response in gastroesophageal malignancies. At least one prospective trial has described tumor mutational burden high (TMB-H), independent of MSI, as predictive of response in anal and biliary tract carcinomas. DNA Polymerase Epsilon (POLE) or delta (POL-D) mutations have been implicated in a subset of MSS colorectal cancer with TMB-H but this biomarker requires prospective validation. There is evolving data based on retrospective observations that gene alterations predicting acquired resistance and hyper-progression. Ongoing clinical research is assessing the role of the human microbiome and RNA-editing complex mutations as predictive biomarkers of response to ICBs. MSI has the strongest predictive power among current biomarkers for ICB response in gastrointestinal cancers. Data continue to accumulate from ongoing clinical trials and new biomarkers are emerging from pre-clinical studies, suggesting that drug combinations targeting pathways complimentary to the PD-1/PD-L1 axis inhibition will define a robust field of clinical research.
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19
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Cai L, Sun Y, Wang K, Guan W, Yue J, Li J, Wang R, Wang L. The Better Survival of MSI Subtype Is Associated With the Oxidative Stress Related Pathways in Gastric Cancer. Front Oncol 2020; 10:1269. [PMID: 32850385 PMCID: PMC7399340 DOI: 10.3389/fonc.2020.01269] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 06/18/2020] [Indexed: 12/29/2022] Open
Abstract
Background: Gastric cancer (GC) is the third leading fatal cancer in the world and its incidence ranked second among all malignant tumors in China. The molecular classification of GC, proposed by the The Cancer Genome Atlas (TCGA), was added to the updated edition (2019) of WHO classification for digestive system tumor. Although MSI and EBV subtypes appeared as ever-increasingly significant roles in immune checkpoint inhibitor therapy, the underlying mechanisms are still unclear. Methods: We systematically summarized the relationship between EBV, d-MMR/MSI-H subtypes and clinicopathological parameters in 271 GC cases. Furthermore, GSE62254/ACRG and TCGA-STAD datasets, originated from Gene Expression Omnibus (GEO) and TCGA respectively, were analyzed to figure out the prognosis related molecular characteristics by bioinformatics methods. Results: Patients with MSI subtype had better prognosis than the MSS subtype (P = 0.013) and considered as an independent biomarker by the univariate analysis (P = 0.017) and multivariate analysis (P = 0.050). While there was no significant difference between EBV positive and negative tissues (P = 0.533). The positive prognostic value conferred by MSI in different cohorts was revalidated via the clinical analysis of GSE62254/ACRG and TCGA-STAD datasets regardless of race. Then key gene module that tightly associated with better status and longer OS time for MSI cases was obtained from weighted gene co-expression network analysis(WGCNA). NUBP2 and ENDOG were screened from the gene cluster and oxidative phosphorylation, reactive oxygen species(ROS) and glutathione metabolism were analyzed to be the differential pathways in their highly expressed groups. Conclusions: Our results manifested the significant prognostic value of MSI in Chinese GC cohort and comparisons with other populations. More opportunities to induce apoptosis of cancer cells, led by the unbalance between antioxidant system and ROS accumulation, lay foundations for unveiling the better prognosis in MSI phenotype through the bioinformatics analysis.
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Affiliation(s)
- Lei Cai
- Department of Pathology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yeqi Sun
- Department of Pathology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kezhou Wang
- Department of Pathology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Wenbin Guan
- Department of Pathology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Juanqing Yue
- Department of Pathology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Junlei Li
- Department of Pathology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ruifen Wang
- Department of Pathology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Lifeng Wang
- Department of Pathology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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20
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Auslander N, Wolf YI, Koonin EV. Interplay between DNA damage repair and apoptosis shapes cancer evolution through aneuploidy and microsatellite instability. Nat Commun 2020; 11:1234. [PMID: 32144251 PMCID: PMC7060240 DOI: 10.1038/s41467-020-15094-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 02/14/2020] [Indexed: 02/07/2023] Open
Abstract
Driver mutations and chromosomal aneuploidy are major determinants of tumorigenesis that exhibit complex relationships. Here, we identify associations between driver mutations and chromosomal aberrations that define two tumor clusters, with distinct regimes of tumor evolution underpinned by unique sets of mutations in different components of DNA damage response. Gastrointestinal and endometrial tumors comprise a separate cluster for which chromosomal-arm aneuploidy and driver mutations are mutually exclusive. The landscape of driver mutations in these tumors is dominated by mutations in DNA repair genes that are further linked to microsatellite instability. The rest of the cancer types show a positive association between driver mutations and aneuploidy, and a characteristic set of mutations that involves primarily genes for components of the apoptotic machinery. The distinct sets of mutated genes derived here show substantial prognostic power and suggest specific vulnerabilities of different cancers that might have therapeutic potential.
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Affiliation(s)
- Noam Auslander
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, 20894, USA.
| | - Yuri I Wolf
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, 20894, USA
| | - Eugene V Koonin
- National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, 20894, USA.
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21
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Renaud F, Svrcek M. [Hereditary gastric cancer: Challenges for the pathologist in 2020]. Ann Pathol 2020; 40:95-104. [PMID: 32147190 DOI: 10.1016/j.annpat.2020.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 01/26/2020] [Accepted: 02/05/2020] [Indexed: 12/24/2022]
Abstract
Gastric cancer is the third most common cancer worldwide. The majority of gastric cancers are sporadic but familial clustering is seen in more than 10% of cases. This manuscript is divided into two parts. The first part is dedicated to the non-syndromic hereditary gastric cancer, particularly the hereditary diffuse gastric cancer (HDGC) and other gastric polyposes including the recently described GAPPS (Gastric adenocarcinoma and proximal polyposis of the stomach). The second part concerns the syndromic gastric cancer, namely the HNPCC syndrome (Hereditary Non Polyposis Colorectal Cancer) occurring as part of a genetic predisposition syndrome to cancer. Recent advances in oncogenetics and next generation sequencing technology have enabled the identification of new entities. This enhancement in knowledge regarding inherited syndromes predisposing to gastric cancer has consequently improved the management of patients and their families. In this context, pathologists play a major role in identifying particular morphologic entities prompting genetic investigation. The aim of this manuscript is to provide an update on the current knowledge about hereditary gastric cancer.
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Affiliation(s)
- Florence Renaud
- Sorbonne université, Inserm, unité Mixte de Recherche Scientifique 938, SIRIC CURAMUS, centre de recherche Saint-Antoine, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue Nationale contre le cancer, 75012 Paris, France; Service d'anatomie et cytologie pathologiques, hôpital Saint-Antoine, AP-HP, 184, rue du Faubourg-Saint-Antoine, 75571 Paris cedex 12, France.
| | - Magali Svrcek
- Sorbonne université, Inserm, unité Mixte de Recherche Scientifique 938, SIRIC CURAMUS, centre de recherche Saint-Antoine, équipe instabilité des microsatellites et cancer, équipe labellisée par la Ligue Nationale contre le cancer, 75012 Paris, France; Service d'anatomie et cytologie pathologiques, hôpital Saint-Antoine, AP-HP, 184, rue du Faubourg-Saint-Antoine, 75571 Paris cedex 12, France
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22
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Afshari F, Soleyman-Jahi S, Keshavarz-Fathi M, Roviello G, Rezaei N. The promising role of monoclonal antibodies for gastric cancer treatment. Immunotherapy 2020; 11:347-364. [PMID: 30678552 DOI: 10.2217/imt-2018-0093] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer (GC) is the second leading cause of cancer-related death world-wide. Despite improvements in prevention, early detection and various therapeutic options, the prognosis is still poor. GC is often diagnosed at an advanced stage with survivals less than 1 year. Chemotherapy as the mainstay of treatment in advanced stage is not of notable advantages, underlining the need for novel more effective therapeutic options. Based on current knowledge of molecular and cellular mechanisms, a number of novel biologic approaches such as monoclonal antibodies have been recently introduced for cancer treatment that mainly affect the immune system or target signaling pathways playing role in cancer and metastasis development. In this review, various monoclonal antibodies for GC therapy were explained.
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Affiliation(s)
- Farzaneh Afshari
- Cancer Immunology Project (CIP), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Saeed Soleyman-Jahi
- Digestive Diseases Research Cores Center, Division of Gastroenterology, School of Medicine, Washington University, St. Louis, USA.,Cancer Immunology Project (CIP), Universal Scientific Education & Research Network (USERN), St. Louis, USA.,Cancer Research Center, Cancer Institute of Iran, Tehran, Iran
| | - Mahsa Keshavarz-Fathi
- Cancer Immunology Project (CIP), Universal Scientific Education & Research Network (USERN), Tehran, Iran.,Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Giandomenico Roviello
- Medical Oncology Unit, Department of Oncology, San Donato Hospital, Via Nenni 20, Arezzo, Italy.,Cancer Immunology Project (CIP), Universal Scientific Education & Research Network (USERN), Arezzo, Italy
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Cancer Immunology Project (CIP), Universal Scientific Education & Research Network (USERN), Sheffield, UK
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23
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Microsatellite instability in mismatch repair and tumor suppressor genes and their expression profiling provide important targets for the development of biomarkers in gastric cancer. Gene 2019; 710:48-58. [PMID: 31145962 DOI: 10.1016/j.gene.2019.05.051] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 05/13/2019] [Accepted: 05/25/2019] [Indexed: 12/24/2022]
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24
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Martinez-Ciarpaglini C, Fleitas-Kanonnikoff T, Gambardella V, Llorca M, Mongort C, Mengual R, Nieto G, Navarro L, Huerta M, Rosello S, Roda D, Tarazona N, Navarro S, Ribas G, Cervantes A. Assessing molecular subtypes of gastric cancer: microsatellite unstable and Epstein-Barr virus subtypes. Methods for detection and clinical and pathological implications. ESMO Open 2019; 4:e000470. [PMID: 31231566 PMCID: PMC6555614 DOI: 10.1136/esmoopen-2018-000470] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 02/07/2019] [Accepted: 02/13/2019] [Indexed: 02/06/2023] Open
Abstract
Background The molecular classification of gastric cancer recognises two subtypes prone to immune checkpoint blockade: the microsatellite unstable and the Epstein-Barr virus (EBV)-related tumours. We aim to assess the concordance between immunohistochemistry and PCR for microsatellite status evaluation, and explore the value of microsatellite instability (MSI) and EBV as predictive survival factors. Material and methods We collected 246 consecutively diagnosed gastric cancer cases in all stages and evaluated the microsatellite status using immunohistochemistry for mismatched repair (MMR) proteins and PCR. EBV expression was studied through in situ hybridisation. Results Forty-five (18%) cases presented MSI and 13 (6%) were positive for EBV. MSI was associated with female sex, older age, distal location and distal non-diffuse type of the modified Lauren classification. EBV expression was most frequent in proximal location and proximal non-diffuse type. The sensitivity, specificity, positive predictive value and negative predictive value of immunohistochemistry for the microsatellite study were 91%, 98%, 91% and 98%, respectively. In the multivariate analysis, MSI was an independent predictor of favourable tumour-specific survival (TSS) in stages I–III (MSI: HR: 0.37, 95% CI 0.12 to 0.95, p=0.04). Conclusions The MSI status and the EBV expression should be incorporated in routine pathological report for two reasons. First, MSI defines a different pathological entity with a better outcome. Second, MSI and EBV may be useful biomarkers to identify patients who will respond to immune checkpoint blockade inhibitors. For this purpose, immunohistochemical study for MMR proteins and in situ hybridisation study for EBV evaluation are feasible and cost-effective methods.
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Affiliation(s)
- Carolina Martinez-Ciarpaglini
- Department of Pathology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Tania Fleitas-Kanonnikoff
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Valentina Gambardella
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Marta Llorca
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Cristina Mongort
- Department of Pathology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Regina Mengual
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Gema Nieto
- Department of Pathology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Lara Navarro
- Department of Pathology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Marisol Huerta
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Susana Rosello
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Desamparados Roda
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Noelia Tarazona
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Samuel Navarro
- Department of Pathology, Hospital Clinico Universitario of Valencia, Biomedical Research Institute INCLIVA, Valencia, Spain
| | - Gloria Ribas
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
| | - Andrés Cervantes
- Department of Medical Oncology, Biomedical Research Institute INCLIVA, CIBERONC, University of Valencia, Valencia, Spain
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25
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The significance of gene mutations across eight major cancer types. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2019; 781:88-99. [PMID: 31416581 DOI: 10.1016/j.mrrev.2019.04.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2017] [Revised: 04/11/2019] [Accepted: 04/30/2019] [Indexed: 12/12/2022]
Abstract
Mutations occur spontaneously, which can be induced by either chemicals (e.g. benzene) or biological factors (e.g. virus). Not all mutations cause noticeable changes in cellular functions. However, mutation in key cellular genes leads to developmental disorders. It is one of the main ways in which proto-oncogenes can be changed into their oncogenic state. The progressive accumulation of multiple mutations throughout life leads to cancer. In the past few decades, extensive research on cancer biology has discovered many genes and pathways having role in cancer development. In this review, we tried to summarize the current knowledge of mutational effect on different cancer types and its consequences in brief for future reference and guidance of researchers in cancer biology.
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26
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Xing R, Zhou Y, Yu J, Yu Y, Nie Y, Luo W, Yang C, Xiong T, Wu WKK, Li Z, Bing Y, Lin S, Zhang Y, Hu Y, Li L, Han L, Yang C, Huang S, Huang S, Zhou R, Li J, Wu K, Fan D, Tang G, Dou J, Zhu Z, Ji J, Fang X, Lu Y. Whole-genome sequencing reveals novel tandem-duplication hotspots and a prognostic mutational signature in gastric cancer. Nat Commun 2019; 10:2037. [PMID: 31048690 PMCID: PMC6497673 DOI: 10.1038/s41467-019-09644-6] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 03/22/2019] [Indexed: 01/22/2023] Open
Abstract
Genome-wide analysis of genomic signatures might reveal novel mechanisms for gastric cancer (GC) tumorigenesis. Here, we analysis structural variations (SVs) and mutational signatures via whole-genome sequencing of 168 GCs. Our data demonstrates diverse models of complex SVs operative in GC, which lead to high-level amplification of oncogenes. We find varying proportion of tandem-duplications (TDs) among individuals and identify 24 TD hotspots involving well-established cancer genes such as CCND1, ERBB2 and MYC. Specifically, we nominate a novel hotspot involving the super-enhancer of ZFP36L2 presents in approximately 10% GCs from different cohorts, the oncogenic role of which is further confirmed by experimental data. In addition, our data reveal a mutational signature, specifically occurring in noncoding region, significantly enriched in tumors with cadherin 1 mutations, and associated with poor prognoses. Collectively, our data suggest that TDs might serve as an important mechanism for cancer gene activation and provide a novel signature for stratification. Structural variations in gastric cancer impact progression. Here, the authors perform whole-genome sequencing on 168 gastric cancer patients and identified tandem-duplications of super-enhancer ZFP36L2 in 10% of gastric cancer, and mutational signatures in tumors with cadherin 1 mutations that associated with poor prognoses.
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Affiliation(s)
- Rui Xing
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 100142, Beijing, China.
| | - Yong Zhou
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Shenzhen, 518000, China
| | - Yingyan Yu
- Department of Surgery, Rui-jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Shanxi, 710032, China
| | - Wen Luo
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Chao Yang
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Teng Xiong
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - William K K Wu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Shenzhen, 518000, China
| | - Zhongwu Li
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Yang Bing
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Shuye Lin
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Yaping Zhang
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Yingqi Hu
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 100142, Beijing, China
| | - Lin Li
- Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumours, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, 200025, Shanghai, China
| | - Lijuan Han
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 510120, Guangzhou, China
| | - Chen Yang
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 510120, Guangzhou, China
| | - Shaogang Huang
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 510120, Guangzhou, China
| | - Suiping Huang
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 510120, Guangzhou, China
| | - Rui Zhou
- College of Life Science and Technology, Huazhong Agricultural University, 430070, Wuhan, China
| | - Jing Li
- College of Life Science and Technology, Huazhong Agricultural University, 430070, Wuhan, China
| | - Kaichun Wu
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Shanxi, 710032, China
| | - Daiming Fan
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Shanxi, 710032, China
| | - Guangbo Tang
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Shanxi, 710032, China
| | - Jianhua Dou
- State Key Laboratory of Cancer Biology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Shanxi, 710032, China
| | - Zhenggang Zhu
- Department of Surgery, Rui-jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, China
| | - Jiafu Ji
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 100142, Beijing, China.
| | - Xiaodong Fang
- The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, 510120, Guangzhou, China.
| | - Youyong Lu
- Laboratory of Molecular Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, 100142, Beijing, China. .,Department of Medical Oncology, Beijing Hospital, 100730, Beijing, China.
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Identification of gene expression levels in primary melanoma associated with clinically meaningful characteristics. Melanoma Res 2019; 28:380-389. [PMID: 29975213 DOI: 10.1097/cmr.0000000000000473] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Factors influencing melanoma survival include sex, age, clinical stage, lymph node involvement, as well as Breslow thickness, presence of tumor-infiltrating lymphocytes based on histological analysis of primary melanoma, mitotic rate, and ulceration. Identification of genes whose expression in primary tumors is associated with these key tumor/patient characteristics can shed light on molecular mechanisms of melanoma survival. Here, we show results from a gene expression analysis of formalin-fixed paraffin-embedded primary melanomas with extensive clinical annotation. The Cancer Genome Atlas data on primary melanomas were used for validation of nominally significant associations. We identified five genes that were significantly associated with the presence of tumor-infiltrating lymphocytes in the joint analysis after adjustment for multiple testing: IL1R2, PPL, PLA2G3, RASAL1, and SGK2. We also identified two genes significantly associated with melanoma metastasis to the regional lymph nodes (PIK3CG and IL2RA), and two genes significantly associated with sex (KDM5C and KDM6A). We found that LEF1 was significantly associated with Breslow thickness and CCNA2 and UBE2T with mitosis. RAD50 was the gene most significantly associated with survival, with a higher level of expression associated with worse survival.
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28
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Haron NH, Mohamad Hanif EA, Abdul Manaf MR, Yaakub JA, Harun R, Mohamed R, Mohamed Rose I. Microsatellite Instability and Altered Expressions of MLH1 and MSH2 in Gastric Cancer. Asian Pac J Cancer Prev 2019; 20:509-517. [PMID: 30803214 PMCID: PMC6897031 DOI: 10.31557/apjcp.2019.20.2.509] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2018] [Accepted: 01/30/2019] [Indexed: 02/06/2023] Open
Abstract
Introduction: Microsatellite instability (MSI) is a hallmark of defective DNA mismatch repair (MMR) of genes especially MLH1 and MSH2. It is frequently involved in the carcinogenesis of various tumours including gastric cancer (GC). However, MSI in GCs have not been reported in Malaysia before. Objective: This study was conducted to determine the microsatellite instability (MSI) status in gastric cancer by microsatellite analysis, sequencing, its association with MLH1 and MSH2 protein expression and H.pylori infection by immunohistochemistry. Method: A total of 60 gastric cancer cases were retrieved. DNA was extracted from paired normal and tumour tissues while MLH1 and MSH2 protein expression as well as H. pylori status were determined by IHC staining. For microsatellite analysis, polymerase chain reaction (PCR) was performed for paired tissue samples using a panel of five microsatellite markers. MSI-positive results were subjected for DNA sequencing to assess mutations in the MLH1 and MSH2 genes. Results: Microsatellite analysis identified ten MSI positive cases (16.7%), out of which only six cases (10.3%) showed absence of MLH1 (n=3) or MSH2 (n=3) protein expression by IHC. The most frequent microsatellite marker in MSI positive cases was BAT26 (90%). Nine of ten MSI positive cases were intestinal type with one diffuse and all were located distally. H. pylori infection was detected in 13 of 60 cases (21.7%) including in three MSI positive cases. All these results however were not statistically significant. Our sequencing data displayed novel mutations. However these data were not statistically correlated with expression levels of MLH1 and MSH2 proteins by IHC. This may be due to small sample size to detect small or moderately sized effects. Conclusion: The frequency of MSI in this study was comparable with published results. Determination of affected MMR genes by more than two antibodies may increase the sensitivity of IHC to that of MSI analysis.
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Affiliation(s)
- Nor Hasyimah Haron
- Department of Pathology, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur, Malaysia
- UKM Medical Molecular Biology Institute (UMBI), University Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Cheras, Kuala Lumpur.
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29
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From Tumor Immunology to Immunotherapy in Gastric and Esophageal Cancer. Int J Mol Sci 2018; 20:ijms20010013. [PMID: 30577521 PMCID: PMC6337592 DOI: 10.3390/ijms20010013] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2018] [Revised: 12/15/2018] [Accepted: 12/17/2018] [Indexed: 12/24/2022] Open
Abstract
Esophageal and gastric cancers represent tumors with poor prognosis. Unfortunately, radiotherapy, chemotherapy, and targeted therapy have made only limited progress in recent years in improving the generally disappointing outcome. Immunotherapy with checkpoint inhibitors is a novel treatment approach that quickly entered clinical practice in malignant melanoma and renal cell cancer, but the role in esophageal and gastric cancer is still poorly defined. The principal prognostic/predictive biomarkers for immunotherapy efficacy currently considered are PD-L1 expression along with defects in mismatch repair genes resulting in microsatellite instability (MSI-H) phenotype. The new molecular classification of gastric cancer also takes these factors into consideration. Available reports regarding PD-1, PD-L1, PD-L2 expression and MSI status in gastric and esophageal cancer are reviewed to summarize the clinical prognostic and predictive role together with potential clinical implications. The most important recently published clinical trials evaluating checkpoint inhibitor efficacy in these tumors are also summarized.
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30
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Ratti M, Lampis A, Hahne JC, Passalacqua R, Valeri N. Microsatellite instability in gastric cancer: molecular bases, clinical perspectives, and new treatment approaches. Cell Mol Life Sci 2018; 75:4151-4162. [PMID: 30173350 PMCID: PMC6182336 DOI: 10.1007/s00018-018-2906-9] [Citation(s) in RCA: 157] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 08/13/2018] [Accepted: 08/14/2018] [Indexed: 12/15/2022]
Abstract
Gastric cancer is one of the most aggressive malignancies, with limited treatment options in both locally advanced and metastatic setting, resulting in poor prognosis. Based on genomic characterization, stomach tumour has recently been described as a heterogeneous disease composed by different subtypes, each of them with peculiar molecular aspects and specific clinical behaviour. With an incidence of 22% among all western gastric tumour cases, stomach cancer with microsatellite instability was identified as one of these subgroups. Retrospective studies and limited prospective trials reported differences between gastric cancers with microsatellite stability and those with instability, mainly concerning clinical and pathological features, but also in regard to immunological microenvironment, correlation with prognostic value, and responses to treatment. In particular, gastric cancer with microsatellite instability constitutes a small but relevant subgroup associated with older age, female sex, distal stomach location, and lower number of lymph-node metastases. Emerging data attribute to microsatellite instability status a favourable prognostic meaning, whereas the poor outcomes reported after perioperative chemotherapy administration suggest a detrimental role of cytotoxic drugs in this gastric cancer subgroup. The strong immunogenicity and the widespread expression of immune-checkpoint ligands make microsatellite instability subtype more vulnerable to immunotherapeutic approach, e.g., with anti-PD-L1 and anti-CTLA4 antibodies. Since gastric cancer with microsatellite instability shows specific features and clinical behaviour not overlapping with microsatellite stable disease, microsatellite instability test might be suitable for inclusion in a diagnostic setting for all tumour stages to guarantee the most targeted and effective treatment to every patient.
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Affiliation(s)
- Margherita Ratti
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
- Division of Oncology, Medical Department, ASST di Cremona, Ospedale di Cremona, Cremona, Italy
| | - Andrea Lampis
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Jens C Hahne
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
| | - Rodolfo Passalacqua
- Division of Oncology, Medical Department, ASST di Cremona, Ospedale di Cremona, Cremona, Italy
| | - Nicola Valeri
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
- Department of Medicine, The Royal Marsden NHS Foundation Trust, London, UK
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31
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Mizuguchi A, Takai A, Shimizu T, Matsumoto T, Kumagai K, Miyamoto S, Seno H, Marusawa H. Genetic features of multicentric/multifocal intramucosal gastric carcinoma. Int J Cancer 2018; 143:1923-1934. [DOI: 10.1002/ijc.31578] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 04/06/2018] [Accepted: 04/18/2018] [Indexed: 02/06/2023]
Affiliation(s)
- Aya Mizuguchi
- Department of Gastroenterology and HepatologyGraduate School of Medicine, Kyoto UniversityKyoto Japan
| | - Atsushi Takai
- Department of Gastroenterology and HepatologyGraduate School of Medicine, Kyoto UniversityKyoto Japan
| | - Takahiro Shimizu
- Department of Gastroenterology and HepatologyGraduate School of Medicine, Kyoto UniversityKyoto Japan
| | - Tomonori Matsumoto
- Department of Gastroenterology and HepatologyGraduate School of Medicine, Kyoto UniversityKyoto Japan
| | - Ken Kumagai
- Department of Gastroenterology and HepatologyGraduate School of Medicine, Kyoto UniversityKyoto Japan
| | - Shin'ichi Miyamoto
- Department of Gastroenterology and HepatologyGraduate School of Medicine, Kyoto UniversityKyoto Japan
| | - Hiroshi Seno
- Department of Gastroenterology and HepatologyGraduate School of Medicine, Kyoto UniversityKyoto Japan
| | - Hiroyuki Marusawa
- Department of Gastroenterology and HepatologyGraduate School of Medicine, Kyoto UniversityKyoto Japan
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32
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Hang X, Li D, Wang J, Wang G. Prognostic significance of microsatellite instability‑associated pathways and genes in gastric cancer. Int J Mol Med 2018; 42:149-160. [PMID: 29717769 PMCID: PMC5979886 DOI: 10.3892/ijmm.2018.3643] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 04/04/2018] [Indexed: 12/20/2022] Open
Abstract
The aim of the present study was to reveal the potential molecular mechanisms of microsatellite instability (MSI) on the prognosis of gastric cancer (GC). The investigation was performed based on an RNAseq expression profiling dataset downloaded from The Cancer Genome Atlas, including 64 high‑level MSI (MSI‑H) GC samples, 44 low‑level MSI (MSI‑L) GC samples and 187 stable microsatellite (MSI‑S) GC samples. Differentially expressed genes (DEGs) were identified between the MSI‑H, MSI‑L and MSI‑S samples. Pathway enrichment analysis was performed for the identified DEGs and the pathway deviation scores of the significant enrichment pathways were calculated. A Multi‑Layer Perceptron (MLP) classifier, based on the different pathways associated with the MSI statuses was constructed for predicting the outcome of patients with GC, which was validated in another independent dataset. A total of 190 DEGs were selected between the MSI‑H, MSI‑L and MSI‑S samples. The MLP classifier was established based on the deviation scores of 10 significant pathways, among which antigen processing and presentation, and inflammatory bowel disease pathways were significantly enriched with HLA‑DRB5, HLA‑DMA, HLA‑DQA1 and HLA‑DRA; the measles, toxoplasmosis and herpes simplex infection pathways were significantly enriched with Janus kinase 2 (JAK2), caspase‑8 (CASP8) and Fas. The classifier performed well on an independent validation set with 100 GC samples. Taken together, the results indicated that MSI status may affect GC prognosis, partly through the antigen processing and presentation, inflammatory bowel disease, measles, toxoplasmosis and herpes simplex infection pathways. HLA‑DRB5, HLA‑DMA, HLA‑DQA1, HLA‑DRA, JAK2, CASP8 and Fas may be predictive factors for prognosis in GC.
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Affiliation(s)
- Xiaosheng Hang
- Department of Medical Oncology, Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062
| | | | - Jianping Wang
- Department of Radiation, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215008
| | - Ge Wang
- Cancer Center, Changzhou No. 2 People's Hospital, Changzhou, Jiangsu 213002, P.R. China
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Chivu-Economescu M, Matei L, Necula LG, Dragu DL, Bleotu C, Diaconu CC. New therapeutic options opened by the molecular classification of gastric cancer. World J Gastroenterol 2018; 24:1942-1961. [PMID: 29760539 PMCID: PMC5949709 DOI: 10.3748/wjg.v24.i18.1942] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 04/12/2018] [Accepted: 04/23/2018] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most lethal and aggressive cancers, being the third cause of cancer related death worldwide. Even with radical gastrectomy and the latest generation of molecular chemotherapeutics, the numbers of recurrence and mortality remains high. This is due to its biological heterogeneity based on the interaction between multiple factors, from genomic to environmental factors, diet or infections with various pathogens. Therefore, understanding the molecular characteristics at a genomic level is critical to develop new treatment strategies. Recent advances in GC molecular classification provide the unique opportunity to improve GC therapy by exploiting the biomarkers and developing novel targeted therapy specific to each subtype. This article highlights the molecular characteristics of each subtype of gastric cancer that could be considered in shaping a therapeutic decision, and also presents the completed and ongoing clinical trials addressed to those targets. The implementation of the novel molecular classification system will allow a preliminary patient selection for clinical trials, a mandatory issue if it is desired to test the efficacy of a certain inhibitor to the given target. This will represent a substantial advance as well as a powerful tool for targeted therapy. Nevertheless, translating the scientific results into new personalized treatment opportunities is needed in order to improve clinical care, the survival and quality of life of patients with GC.
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Affiliation(s)
- Mihaela Chivu-Economescu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Lilia Matei
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Laura G Necula
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
- Nicolae Cajal Institute, Titu Maiorescu University, Bucharest 040441, Romania
| | - Denisa L Dragu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Coralia Bleotu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
| | - Carmen C Diaconu
- Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, Bucharest 030304, Romania
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Jin S, Xu B, Yu L, Fu Y, Wu H, Fan X, Wei J, Liu B. The PD-1, PD-L1 expression and CD3+ T cell infiltration in relation to outcome in advanced gastric signet-ring cell carcinoma, representing a potential biomarker for immunotherapy. Oncotarget 2018; 8:38850-38862. [PMID: 28418918 PMCID: PMC5503577 DOI: 10.18632/oncotarget.16407] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 02/24/2017] [Indexed: 12/13/2022] Open
Abstract
Recent data supports a potentially significant role for immune checkpoint inhibitors in the treatment of gastric cancer. However, there are few data on the clinical implications of immunotherapy markers in gastric signet-ring cell carcinoma (SRCC). We evaluated the expression of programmed cell death protein-1 (PD-1), programmed cell death ligand 1(PD-L1), infiltration by CD3+ T cell, microsatellite instability (MSI), and Epstein-Barr Virus (EBV), and the relationship of each factor to survival in 89 advanced SRCC patients. All patients received 5-FU-based first-line chemotherapy. PD-L1 and PD-1 were expressed in 40.4% and 18.0% of the patients, respectively. There was a significant correlation between PD-L1 and PD-1 expression (r=0.363, p<0.001). There was loss of at least 1 of the 4 DNA mismatch repair (DNA-MMR) gene proteins in 32.6% of samples. Only 1 case out of 89 was EBV positive, with concurrent PD-L1 positivity, a high degree of CD3+ T cell infiltration and MSI. Increased CD3+ T cells numbers was associated with increased PD-1 expression (r=0.256, p=0.012) and MSI status (r=0.208, p=0.049). High CD3+ T cell infiltration was related to better OS (23.7 months, 95% CI: 19.0-38.0 vs 15.8 months, 95% CI: 13.0-22.0, p=0.033), but was not an independent prognostic factor for survival after multivariate analysis (HR=0.68, 95% CI: 0.42-1.10, p=0.116). CD3+ T cell was more infiltrated in PD-1 positive, tumors with MSI and were associated with better OS, indicating an adaptive immune resistance may be occurring. Further research into the cancer immunotherapy markers of SRCC immune microenvironment may highlight targets for immunotherapy.
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Affiliation(s)
- Shenying Jin
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, China.,The Comprehensive Cancer Center of Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing 210008, China
| | - Bo Xu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, China
| | - Lixia Yu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, China
| | - Yao Fu
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Hongyan Wu
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Xiangshan Fan
- Department of Pathology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Jia Wei
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, China
| | - Baorui Liu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing 210008, China
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Ammannagari N, Atasoy A. Current status of immunotherapy and immune biomarkers in gastro-esophageal cancers. J Gastrointest Oncol 2018; 9:196-207. [PMID: 29564185 DOI: 10.21037/jgo.2017.06.12] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Gastroesophageal (GE) cancers continue to be a significant cause of mortality globally. Despite therapeutic advances in oncology, the prognosis of advanced GE cancer remains exceedingly poor. Immunotherapy has caused a major paradigm shift in the field of oncology. Not all patients benefit from these agents and several studies are trying to identify predictive and prognostic biomarkers to better inform and guide treatment decisions. The potential role of immunotherapy in GE cancers is emerging. These cancer types are molecularly and immunologically heterogeneous, and this heterogeneity influences the tumor microenvironment posing a significant challenge to studying biomarkers of response to immunotherapy. Here in this article, we discuss the need for new therapeutic approaches in GE cancers, review the emerging data on the activity of checkpoint inhibitors and the role of biomarkers in this setting.
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Affiliation(s)
| | - Ajlan Atasoy
- Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
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Yuza K, Nagahashi M, Watanabe S, Takabe K, Wakai T. Hypermutation and microsatellite instability in gastrointestinal cancers. Oncotarget 2017; 8:112103-112115. [PMID: 29340115 PMCID: PMC5762383 DOI: 10.18632/oncotarget.22783] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 11/13/2017] [Indexed: 02/07/2023] Open
Abstract
Recent progress in cancer genome analysis using next-generation sequencing has revealed a high mutation burden in some tumors. The particularly high rate of somatic mutation in these tumors correlates with the generation of neo-antigens capable of eliciting an immune response. Identification of hypermutated tumors is therefore clinically valuable for selecting patients suitable for immunotherapy treatment. There are several known causes of hypermutation in tumors, such as ultraviolet light in melanoma, tobacco smoke in lung cancer, and excessive APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) activity in breast and gastric cancer. In gastrointestinal cancers, one of the leading causes of hypermutation is a defect in DNA mismatch repair, which results in microsatellite instability (MSI). This review will focus on the frequency, characteristics and genomic signature of hypermutated gastrointestinal cancers with MSI. Detection of tumor hypermutation in cancer is expected to not only predict the clinical benefit of immune checkpoint inhibitor treatment, but also to provide better surgical strategies for the patients with hypermutated tumors. Thus, in an era of precision medicine, identification of hypermutation and MSI will play an important role directing surgical and chemotherapeutic treatment.
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Affiliation(s)
- Kizuki Yuza
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata City, Niigata 951-8510, Japan
| | - Masayuki Nagahashi
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata City, Niigata 951-8510, Japan
| | - Satoshi Watanabe
- Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata City, Niigata 951-8510, Japan
| | - Kazuaki Takabe
- Breast Surgery, Department of Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
- Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, The State University of New York, Buffalo, NY 14203, USA
| | - Toshifumi Wakai
- Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata City, Niigata 951-8510, Japan
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Polom K, Marano L, Marrelli D, De Luca R, Roviello G, Savelli V, Tan P, Roviello F. Meta-analysis of microsatellite instability in relation to clinicopathological characteristics and overall survival in gastric cancer. Br J Surg 2017; 105:159-167. [PMID: 29091259 DOI: 10.1002/bjs.10663] [Citation(s) in RCA: 189] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Revised: 02/03/2017] [Accepted: 07/06/2017] [Indexed: 12/14/2022]
Abstract
BACKGROUND Several associations between microsatellite instability (MSI) and other clinicopathological factors have been reported in gastric cancer, but the results have been ambiguous. This systematic review and meta-analysis investigated the relationship between MSI and overall survival and clinicopathological characteristics of patients with gastric cancer. METHODS A systematic literature search of the PubMed, Cochrane and Ovid databases until 31 January 2016 was performed in accordance with the PRISMA statement. The articles were screened independently according to PICO (population, intervention, comparator, outcome) eligibility criteria. All eligible articles were evaluated independently by two reviewers for risk of bias according to the Quality In Prognosis Study tool. RESULTS Overall, 48 studies with a total of 18 612 patients were included. MSI was found in 9·2 per cent of patients (1718 of 18 612), and was associated with female sex (odds ratio (OR) 1·57, 95 per cent c.i. 1·31 to 1·89; P < 0·001), older age (OR 1·58, 2·20 to 1·13; P < 0·001), intestinal Laurén histological type (OR 2·23, 1·94 to 2·57; P < 0·001), mid/lower gastric location (OR 0·38, 0·32 to 0·44; P < 0·001), lack of lymph node metastases (OR 0·70, 0·57 to 0·86, P < 0·001) and TNM stage I-II (OR 1·77, 1·47 to 2·13; P < 0·001). The pooled hazard ratio for overall survival of patients with MSI versus those with non-MSI gastric cancer from 21 studies was 0·69 (95 per cent c.i. 0·56 to 0·86; P < 0·001). CONCLUSION MSI in gastric cancer was associated with good overall survival, reflected in several favourable clinicopathological tumour characteristics.
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Affiliation(s)
- K Polom
- Department General Surgery and Surgical Oncology, University of Siena, Siena, Italy.,Department of Surgical Oncology, Medical University of Gdansk, Gdansk, Poland
| | - L Marano
- General, Minimally Invasive and Robotic Surgery, Department of Surgery, San Matteo degli Infermi Hospital, Spoleto, Italy
| | - D Marrelli
- Department General Surgery and Surgical Oncology, University of Siena, Siena, Italy
| | - R De Luca
- Department of Surgical Oncology, National Cancer Research Centre-Istituto Tumori G. Paolo II, Bari, Italy
| | - G Roviello
- Department of Oncology, Medical Oncology Unit, San Donato Hospital, Arezzo, Italy.,Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy
| | - V Savelli
- Department General Surgery and Surgical Oncology, University of Siena, Siena, Italy
| | - P Tan
- Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, Genome Institute of Singapore, Cancer Science Institute of Singapore, National University of Singapore, and Cellular and Molecular Research, National Cancer Centre, Singapore
| | - F Roviello
- Department General Surgery and Surgical Oncology, University of Siena, Siena, Italy
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Clinicopathologic Characteristics of Microsatellite Instable Gastric Carcinomas Revisited: Urgent Need for Standardization. Appl Immunohistochem Mol Morphol 2017; 25:12-24. [PMID: 26371427 PMCID: PMC5147042 DOI: 10.1097/pai.0000000000000264] [Citation(s) in RCA: 96] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Microsatellite instable gastric cancer (MSI-GC) is a specific molecular subtype of GC. We studied the phenotypes, genotypes, and clinicopathologic characteristics of MSI-GC in a white GC cohort and compared our findings with an extended literature review. The study cohort consisted of 482 patients. Specimens were available from 452 cases and were used for immunostaining (MLH1, PMS2, MSH2, MSH6) and molecular biological analyses (BAT-25, BAT-26, NR-21, NR-24, NR-27; Epstein-Barr virus in situ hybridization). Thirty-four (7.5%) GCs were MSI. Loss of MLH1 and/or PMS2 was found in 30 (88%) MSI-GC, 3 (9%) showed loss of MSH2 and/or MSH6. One (3%) MSI-GC was identified only by molecular biological testing. A single case was heterogeneous and contained microsatellite-stable and instable tumor areas. Twenty-one (62%) MSI-GCs showed unusual histologic features. MSI-GC was not found in diffuse-type or Epstein-Barr virus-positive GC. MSI-GC was significantly more prevalent in elderly patients, distal stomach, and was associated with a significantly lower number of lymph node metastases and a significantly better overall and tumor-specific survival. MSI-GC constitutes a small but relevant subgroup of GC with distinct clinicopathologic characteristics. Our literature review illustrates the shortcomings of missing standardized testing algorithms with prevalences of MSI-GC ranging from 0% to 44.5%. Future studies should test the hypothesis that patients with MSI-GCs may not need adjuvant/perioperative chemotherapy. However, this will require a standardized, quality-controlled diagnostic algorithm of MSI for GC.
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Comparison between mononucleotide and dinucleotide marker panels in gastric cancer with loss of hMLH1 or hMSH2 expression. Int J Biol Markers 2017; 32:e352-e356. [PMID: 28525661 DOI: 10.5301/ijbm.5000266] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/22/2017] [Indexed: 01/27/2023]
Abstract
BACKGROUND DNA mismatch repair deficiency is an important molecular mechanism of genetic instability in gastric cancer, and a high instability at microsatellites is associated with favorable prognosis. We compared mononucleotide and dinucleotide microsatellite instability (MSI) marker panels in 56 paired gastric tumor and normal samples. METHODS The mononucleotide marker panel (mono panel) consisted of 8 markers: BAT25, BAT26, BAT40, BAT-RII, NR21, NR22, NR24 and NR27. The dinucleotide marker panel (di panel) contained D2S123, D5S346, D17S250, D17S261, D17S520, D18S34 and D18S58. The NCI panel was used as reference panel. RESULTS Among 13 gastric tumors showing no hMLH1 or hMSH2 expression, 8 MSI-H (high) and 5 MSI-L (low) were identified. The analytical sensitivities of the NCI, mono and di panels to detect unstable MSI were 61.5% (8/13), 76.9% (10/13) and 84.6% (11/13), respectively. The size change of allele shift was statistically greater in the mono panel than in the di panel (p = 0.02 by Mann-Whitney U-test). The BAT40 (69.2%, 9/13) and D18S34 (76.9%, 10/13) markers showed high sensitivity for determination of MSI status. CONCLUSIONS To improve the detection rate of MSI in gastric cancer with loss of hMLH1 or hMSH2 expression, the kind of MSI marker may need to be considered more, instead of the repetitive type of marker. Thus, an MSI panel designed with a combination of both BAT40 and D18S34 is suggested for providing more accurate and sensitive MSI analysis in gastric cancer.
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40
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Kim JW, Lee HS, Nam KH, Ahn S, Kim JW, Ahn SH, Park DJ, Kim HH, Lee KW. PIK3CA mutations are associated with increased tumor aggressiveness and Akt activation in gastric cancer. Oncotarget 2017; 8:90948-90958. [PMID: 29207615 PMCID: PMC5710896 DOI: 10.18632/oncotarget.18770] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 06/10/2017] [Indexed: 12/19/2022] Open
Abstract
PIK3CA mutations are frequent in gastric cancer. However, their pathological and clinical implications are still unclear. We analyzed the clinicopathological characteristics according to the PIK3CA mutation status of patients with stage IB–IV disease who underwent gastrectomy between May 2003 and Dec. 2005 (cohort 1; n = 302) and of those with stage IV disease who received gastrectomy between Jul. 2006 and Dec. 2012 (cohort 2; n = 120). PIK3CA mutations were detected in 40 patients (13.2%) in cohort 1. In these patients, PIK3CA-mutant tumors were more frequently located in the upper third of the stomach (p = 0.021) and significantly showed poorly differentiated histology (p = 0.018) and increased lymphatic (p = 0.015), vascular (p = 0.005), and perineural invasion (p = 0.026). In addition, these tumors showed significantly increased lymphocyte and neutrophil infiltration in cancer stroma (p < 0.001), Epstein–Barr virus positivity (p < 0.001), and microsatellite instability (p = 0.015). Cytoplasmic Akt expression was significantly increased in these tumors (p = 0.001). In cohort 2, PIK3CA mutations were identified in 15 patients (12.5%). PIK3CA-mutant tumors showed significantly increased vascular invasion (p = 0.019) and microsatellite instability (p = 0.041). In addition, cytoplasmic Akt expression was also significantly increased (p = 0.018). However, in both cohorts, PIK3CA mutations were not associated with the prognosis of patients. In conclusion, PIK3CA mutations were associated with increased tumor aggressiveness, especially in locoregional disease, and Akt activation in gastric cancer. Our data suggest that PIK3CA-mutated gastric cancer is a distinct disease entity, which might need a different therapeutic approach.
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Affiliation(s)
- Ji-Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| | - Kyung Han Nam
- Department of Pathology, Haeundae Paik Hospital, Inje University College of Medicine, Busan 48108, Korea
| | - Soyeon Ahn
- Medical Research Collaborating Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| | - Jin Won Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| | - Sang-Hoon Ahn
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| | - Do Joong Park
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| | - Hyung-Ho Kim
- Department of Surgery, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
| | - Keun-Wook Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam 13620, Korea
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Abstract
Gastric cancer is the fifth most incident and the third most common cause of cancer-related death in the world. Infection with Helicobacter pylori is the major risk factor for this disease. Gastric cancer is the final outcome of a cascade of events that takes decades to occur and results from the accumulation of multiple genetic and epigenetic alterations. These changes are crucial for tumor cells to expedite and sustain the array of pathways involved in the cancer development, such as cell cycle, DNA repair, metabolism, cell-to-cell and cell-to-matrix interactions, apoptosis, angiogenesis, and immune surveillance. Comprehensive molecular analyses of gastric cancer have disclosed the complex heterogeneity of this disease. In particular, these analyses have confirmed that Epstein-Barr virus (EBV)-positive gastric cancer is a distinct entity. The identification of gastric cancer subtypes characterized by recognizable molecular profiles may pave the way for a more personalized clinical management and to the identification of novel therapeutic targets and biomarkers for screening, prognosis, prediction of response to treatment, and monitoring of gastric cancer progression.
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42
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Shen H, Zhong M, Wang W, Liao P, Yin X, Rotroff D, Knepper TC, Mcleod HL, Zhou C, Xie S, Li W, Xu B, He Y. EBV infection and MSI status significantly influence the clinical outcomes of gastric cancer patients. Clin Chim Acta 2017; 471:216-221. [PMID: 28601671 DOI: 10.1016/j.cca.2017.06.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Revised: 06/02/2017] [Accepted: 06/06/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Epstein-Barr virus (EBV) and microsatellite instability (MSI) are associated with the carcinogenesis of many kinds of tumors, including gastric cancer (GC). However, the impact of EBV and MSI status on the prognosis of stage II and III GC is still unclear. The aim of this study was to find out the prognostic value of EBV and MSI status in a population of GC patients from Southern China. METHODS Patients were genotyped for EBV infection based on the detection of EBV DNA from the formalin-fixed paraffin-embedded (FFPE) specimens. Sequentially, MSI status was measured by direct sequencing. Clinical characteristics and overall survival (OS) were analyzed in 202 GC patients. Additionally, the association of EBV and MSI status with chemotherapy-based toxicity was analyzed in 324 GC patients. RESULTS The survival analysis revealed EBV+ patients had a poorer OS than EBV- patients (HR=1.75, 95% CI: 1.08-2.82, FDR p=0.04). This survival advantage for EBV- patients was also found in patients <60y (FDR p=0.04) and patient with stage III disease (FDR p=0.04). CONCLUSIONS EBV infection and MSI status are associated with overall survival of gastric cancer patients. However, traditional chemotherapy showed no difference on outcome of patients in EBV and MSI subgroups.
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Affiliation(s)
- Hua Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China; Gastroenterology and Urology Department, Hunan Cancer hospital, Xiangya School of Medicine, Central South University, Changsha, China
| | - Meizuo Zhong
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, China
| | - Weili Wang
- Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China
| | - Ping Liao
- Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China
| | - Xianli Yin
- Gastroenterology and Urology Department, Hunan Cancer hospital, Xiangya School of Medicine, Central South University, Changsha, China
| | - Daniel Rotroff
- Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA
| | - Todd C Knepper
- Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA
| | - Howard L Mcleod
- Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China; Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA
| | - Chengfang Zhou
- Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China
| | - Shangchen Xie
- Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China
| | - Wei Li
- Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China
| | - Biaobo Xu
- Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China.
| | - Yijing He
- Department of Clinical Pharmacology, Xiangya Hospital, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China; Moffitt Cancer Center, DeBartolo Family Personalized Medicine Institute, Tampa, FL, USA.
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Park J, Yoo HM, Jang W, Shin S, Kim M, Kim Y, Lee SW, Kim JG. Distribution of somatic mutations of cancer-related genes according to microsatellite instability status in Korean gastric cancer. Medicine (Baltimore) 2017; 96:e7224. [PMID: 28640116 PMCID: PMC5484224 DOI: 10.1097/md.0000000000007224] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
In studies of the molecular basis of gastric cancer (GC), microsatellite instability (MSI) is one of the key factors. Somatic mutations found in GC are expected to contribute to MSI-high (H) tumorigenesis. We estimated somatic mutation distribution according to MSI status in 52 matched pair GC samples using the Ion Torrent Ion S5 XL with the AmpliSeq Cancer Hotspot panel.Seventy-five (9.8%) somatic variants consisting of 34 hotspot mutations and 41 other likely pathogenic variants were identified in 34 GC samples. The TP53 mutations was most common (35%, 26/75), followed by EGFR (8%, 6/75), HNF1A (8%, 6/75), PIK3CA (8%, 6/75), and ERBB2 (5%, 4/75). To determine MSI status, 52 matched pair samples were estimated using 15 MSI markers. Thirty-nine MS stable (S), 5 MSI-low (L), and 8 MSI-H were classified. GCs with MSI-H tended to have more variants significantly compared with GCs with MS stable (MSS) and MSI-L (standardized J-T statistic = 3.161 for number of variants; P = .002). The mean number of all variants and hotspot mutations per tumor samples only in GCs with MSI-H were 3.9 (range, 1-6) and 1.1 (range, 0-3), respectively. Whereas, the mean number of all variants and hotspot mutations per tumor samples only in GCs with MSS/MSI-L were 1 (0-5)/0.8 (0-1) and 0.5 (0-3)/0.8 (0-1), respectively.In conclusion, GC with MSI-H harbored more mutations in genes that act as a tumor suppressor or oncogene compared to GC with MSS/MSI-L. This finding suggests that the accumulation of MSIs contributes to the genetic diversity and complexities of GC. In addition, targeted NGS approach allows for detection of common and also rare clinically actionable mutations and profiles of comutations in multiple patients simultaneously. Because GC shows distinctive patterns related to ethnics, further studies pertaining to different racial/ethnic groups or cancer types may reinforce our investigations.
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Affiliation(s)
| | - Han Mo Yoo
- Division of Gastrointestinal Surgery, Department of Surgery
| | | | | | | | | | - Seung-Woo Lee
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jeong Goo Kim
- Division of Gastrointestinal Surgery, Department of Surgery
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Schumacher SE, Shim BY, Corso G, Ryu MH, Kang YK, Roviello F, Saksena G, Peng S, Shivdasani RA, Bass AJ, Beroukhim R. Somatic copy number alterations in gastric adenocarcinomas among Asian and Western patients. PLoS One 2017; 12:e0176045. [PMID: 28426752 PMCID: PMC5398631 DOI: 10.1371/journal.pone.0176045] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Accepted: 04/04/2017] [Indexed: 12/20/2022] Open
Abstract
Gastric cancer, a leading worldwide cause of cancer mortality, shows high geographic and ethnic variation in incidence rates, which are highest in East Asia. The anatomic locations and clinical behavior also differ by geography, leading to the controversial idea that Eastern and Western forms of the disease are distinct. In view of these differences, we investigated whether gastric cancers from Eastern and Western patients show distinct genomic profiles. We used high-density profiling of somatic copy-number aberrations to analyze the largest collection to date of gastric adenocarcinomas and utilized genotyping data to rigorously annotate ethnic status. The size of this collection allowed us to accurately identify regions of significant copy-number alteration and separately to evaluate tumors arising in Eastern and Western patients. Among molecular subtypes classified by The Cancer Genome Atlas, the frequency of gastric cancers showing chromosomal instability was modestly higher in Western patients. After accounting for this difference, however, gastric cancers arising in Easterners and Westerners have highly similar somatic copy-number patterns. Only one genomic event, focal deletion of the phosphatase gene PTPRD, was significantly enriched in Western cases, though also detected in Eastern cases. Thus, despite the different risk factors and clinical features, gastric cancer appears to be a fundamentally similar disease in both populations and the divergent clinical outcomes cannot be ascribed to different underlying structural somatic genetic aberrations.
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Affiliation(s)
- Steven E. Schumacher
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
| | - Byoung Yong Shim
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - Giovanni Corso
- Department of Human Pathology, University Hospital, Siena, Italy
| | - Min-Hee Ryu
- Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Yoon-Koo Kang
- Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea
| | - Franco Roviello
- Department of Human Pathology, University Hospital, Siena, Italy
| | - Gordon Saksena
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
| | - Shouyong Peng
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - Ramesh A. Shivdasani
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
- Departments of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail: (RB); (AJB); (RAS)
| | - Adam J. Bass
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
- Departments of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail: (RB); (AJB); (RAS)
| | - Rameen Beroukhim
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
- Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
- Departments of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail: (RB); (AJB); (RAS)
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45
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Patel TN, Roy S, Ravi R. Gastric cancer and related epigenetic alterations. Ecancermedicalscience 2017; 11:714. [PMID: 28144288 PMCID: PMC5243136 DOI: 10.3332/ecancer.2017.714] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2016] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer, a malignant and highly proliferative condition, has significantly affected a large population around the globe and is known to be caused by various factors including genetic, epigenetic, and environmental influences. Though the global trend of these cancers is declining, an increase in its frequency is still a threat because of changing lifestyles and dietary habits. However, genetic and epigenetic alterations related to gastric cancers also have an equivalent contribution towards carcinogenic development. DNA methylation is one of the major forms of epigenetic modification which plays a significant role in gastric carcinogenesis. Methylation leads to inactivation of some of the most important genes like DNA repair genes, cell cycle regulators, apoptotic genes, transcriptional regulators, and signalling pathway regulators; which subsequently cause uncontrolled proliferation of cells. Mutations in these genes can be used as suitable prognostic markers for early diagnosis of the disease, since late diagnosis of gastric cancers has a huge negative impact on overall patient survival. In this review, we focus on the important epigenetic mutations that contribute to the development of gastric cancer and the molecular pathogenesis underlying each of them. Methylation, acetylation, and histone modifications play an integral role in the onset of genomic instability, one of the many contributory factors to gastric cancer. This article also covers the constraints of incomplete knowledge of epigenetic factors influencing gastric cancer, thus throwing light on our understanding of the disease.
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Affiliation(s)
- Trupti N Patel
- Department of Medical Biotechnology, VIT University, Vellore 632014, Tamil Nadu, India
| | - Soumyadipta Roy
- Department of Medical Biotechnology, VIT University, Vellore 632014, Tamil Nadu, India
| | - Revathi Ravi
- Department of Medical Biotechnology, VIT University, Vellore 632014, Tamil Nadu, India
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46
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Figueiredo C, Camargo MC, Leite M, Fuentes-Pananá EM, Rabkin CS, Machado JC. Pathogenesis of Gastric Cancer: Genetics and Molecular Classification. Curr Top Microbiol Immunol 2017. [PMID: 28124158 DOI: 10.1007/978-3-319-50520-6_12.erratum.in:currtopmicrobiolimmunol.2017;400:e1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/14/2023]
Abstract
Gastric cancer is the fifth most incident and the third most common cause of cancer-related death in the world. Infection with Helicobacter pylori is the major risk factor for this disease. Gastric cancer is the final outcome of a cascade of events that takes decades to occur and results from the accumulation of multiple genetic and epigenetic alterations. These changes are crucial for tumor cells to expedite and sustain the array of pathways involved in the cancer development, such as cell cycle, DNA repair, metabolism, cell-to-cell and cell-to-matrix interactions, apoptosis, angiogenesis, and immune surveillance. Comprehensive molecular analyses of gastric cancer have disclosed the complex heterogeneity of this disease. In particular, these analyses have confirmed that Epstein-Barr virus (EBV)-positive gastric cancer is a distinct entity. The identification of gastric cancer subtypes characterized by recognizable molecular profiles may pave the way for a more personalized clinical management and to the identification of novel therapeutic targets and biomarkers for screening, prognosis, prediction of response to treatment, and monitoring of gastric cancer progression.
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Affiliation(s)
- Ceu Figueiredo
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal.,Faculty of Medicine of the University of Porto, Porto, Portugal
| | - M C Camargo
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, ML, USA
| | - Marina Leite
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal
| | - Ezequiel M Fuentes-Pananá
- Research Unit of Cancer and Virology, Children's Hospital of Mexico "Federico Gomez", Mexico City, Mexico
| | - Charles S Rabkin
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, ML, USA
| | - José C Machado
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal. .,Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Júlio Amaral de Carvalho 45, 4200-135, Porto, Portugal. .,Faculty of Medicine of the University of Porto, Porto, Portugal.
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47
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Park JH, Kim EK, Kim YH, Kim JH, Bae YS, Lee YC, Cheong JH, Noh SH, Kim H. Epstein-Barr virus positivity, not mismatch repair-deficiency, is a favorable risk factor for lymph node metastasis in submucosa-invasive early gastric cancer. Gastric Cancer 2016; 19:1041-1051. [PMID: 26573601 DOI: 10.1007/s10120-015-0565-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 11/02/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Epstein-Barr virus (EBV)-associated gastric cancer (GC) and microsatellite-instability-high GC are associated with a low prevalence of regional lymph node metastasis (LNM). To evaluate the feasibility of endoscopic treatment of EBV-associated and/or microsatellite-instability-high early GC (EGC), we analyzed the risk factors for LNM using a large series (n = 756) of submucosa-invasive (SM) EGC. METHODS EBV-encoded RNA in situ hybridization (EBER ISH) and immunohistochemistry for four mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, and MSH6) were performed. The clinicopathologic features and results of EBER ISH and immunohistochemistry were compared according to the LNM status. RESULTS Among the cases, 146 EGCs (19.3 %) showed LNM. EBV negativity, larger tumor size (greater than 2 cm), deeper level of submucosal invasion, submucosal invasion depth greater than 500 µm, presence of ulceration, and presence of lymphovascular invasion (LVI) were associated with LNM. However, the MMR deficiency was not correlated with LNM. On multivariate regression analysis, larger tumor size (greater than 2 cm; odds ratio 1.6, p = 0.030), deeper level of submucosal invasion (odds ratio 2.9, p = 0.001), LVI (odds ratio 7.4, p < 0.001), and EBV negativity (p = 0.020) were independent risk factors for LNM in SM EGCs. CONCLUSIONS EBV positivity was a favorable risk factor for LNM in SM EGC. However, MMR deficiency was not associated with the status of LNM. Thus, we suggest that examination with EBER ISH could be considered for endoscopic resected specimens, especially in cases of SM EGC showing no LVI and clear resection margins.
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Affiliation(s)
- Ji Hye Park
- Department of Pathology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Eun Kyung Kim
- Department of Pathology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Yon Hee Kim
- Department of Pathology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Jie-Hyun Kim
- Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Yoon Sung Bae
- Department of Pathology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Yong Chan Lee
- Department of Internal Medicine, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Jae-Ho Cheong
- Department of Surgery, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Sung Hoon Noh
- Department of Surgery, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea
| | - Hyunki Kim
- Department of Pathology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea.
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48
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Goode EF, Smyth EC. Immunotherapy for Gastroesophageal Cancer. J Clin Med 2016; 5:jcm5100084. [PMID: 27669318 PMCID: PMC5086586 DOI: 10.3390/jcm5100084] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 09/07/2016] [Accepted: 09/14/2016] [Indexed: 12/29/2022] Open
Abstract
Survival for patients with advanced oesophageal and stomach cancer is poor; together these cancers are responsible for more than a million deaths per year globally. As chemotherapy and targeted therapies such as trastuzumab and ramucirumab result in modest improvements in survival but not long-term cure for such patients, development of alternative treatment approaches is warranted. Novel immunotherapy drugs such as checkpoint inhibitors have been paradigm changing in melanoma, non-small cell lung cancer and urothelial cancers. In this review, we assess the early evidence for efficacy of immunotherapy in patients with gastroesophageal cancer in addition to considering biomarkers associated with response to these treatments. Early results of Anti- Programmed Cell Death Protein-1 (anti-PD-1), anti-PD-L1 and anti-Cytotoxic T-lymphocyte assosciated protein-4 (anti-CTLA4) trials are examined, and we conclude with a discussion on the future direction for immunotherapy for gastroesophageal cancer patients.
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Affiliation(s)
- Emily F Goode
- The Royal Marsden Hospital, NHS Foundation Trust, London SW3 6JJ, UK.
| | - Elizabeth C Smyth
- The Royal Marsden Hospital, NHS Foundation Trust, London SW3 6JJ, UK.
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49
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Rokutan H, Hosoda F, Hama N, Nakamura H, Totoki Y, Furukawa E, Arakawa E, Ohashi S, Urushidate T, Satoh H, Shimizu H, Igarashi K, Yachida S, Katai H, Taniguchi H, Fukayama M, Shibata T. Comprehensive mutation profiling of mucinous gastric carcinoma. J Pathol 2016; 240:137-48. [DOI: 10.1002/path.4761] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Revised: 05/16/2016] [Accepted: 06/07/2016] [Indexed: 02/05/2023]
Affiliation(s)
- Hirofumi Rokutan
- Division of Cancer Genomics; National Cancer Center Research Institute; Tokyo Japan
- Department of Pathology, Graduate School of Medicine; The University of Tokyo; Tokyo Japan
| | - Fumie Hosoda
- Division of Cancer Genomics; National Cancer Center Research Institute; Tokyo Japan
| | - Natsuko Hama
- Division of Cancer Genomics; National Cancer Center Research Institute; Tokyo Japan
| | - Hiromi Nakamura
- Division of Cancer Genomics; National Cancer Center Research Institute; Tokyo Japan
| | - Yasushi Totoki
- Division of Cancer Genomics; National Cancer Center Research Institute; Tokyo Japan
| | - Eisaku Furukawa
- Division of Cancer Genomics; National Cancer Center Research Institute; Tokyo Japan
| | - Erika Arakawa
- Division of Cancer Genomics; National Cancer Center Research Institute; Tokyo Japan
| | - Shoko Ohashi
- Division of Cancer Genomics; National Cancer Center Research Institute; Tokyo Japan
| | - Tomoko Urushidate
- Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science; The University of Tokyo; Tokyo Japan
| | - Hironori Satoh
- Division of Cancer Genomics; National Cancer Center Research Institute; Tokyo Japan
| | - Hiroko Shimizu
- Division of Cancer Genomics; National Cancer Center Research Institute; Tokyo Japan
| | - Keiko Igarashi
- Division of Cancer Genomics; National Cancer Center Research Institute; Tokyo Japan
| | - Shinichi Yachida
- Division of Cancer Genomics; National Cancer Center Research Institute; Tokyo Japan
| | - Hitoshi Katai
- Gastric Surgery Division; National Cancer Center Hospital; Tokyo Japan
| | | | - Masashi Fukayama
- Department of Pathology, Graduate School of Medicine; The University of Tokyo; Tokyo Japan
| | - Tatsuhiro Shibata
- Division of Cancer Genomics; National Cancer Center Research Institute; Tokyo Japan
- Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science; The University of Tokyo; Tokyo Japan
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50
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Karpińska-Kaczmarczyk K, Lewandowska M, Ławniczak M, Białek A, Urasińska E. Expression of Mismatch Repair Proteins in Early and Advanced Gastric Cancer in Poland. Med Sci Monit 2016; 22:2886-92. [PMID: 27527654 PMCID: PMC4996049 DOI: 10.12659/msm.897150] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 01/05/2016] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Mutations in DNA of mismatch repair (MMR) genes result in failure to repair errors that occur during DNA replication in microsatellites, resulting in accumulation of frameshift mutations in these genes and leading to DNA mismatch replication errors and microsatellite instability. Gastric cancers (GCs) with high MSI (MSI-H) are a well-defined subset of carcinomas showing distinctive clinicopathological features. In this study we investigated the rate of MSI and the correlation between MSI status and clinicopathological features of GC. MATERIAL AND METHODS The study included 107 patients with GCs: 61 with advanced gastric cancers (AGC) and 46 with early gastric cancer (EGC). MSI deficiency in GCs was assessed by the immunohistochemical analysis of expression of MMR proteins - MLH1, MSH2, MSH6, and PMS2 - using formalin-fixed and paraffin-embedded tissue. RESULTS A total of 6 (5.6%) MSI-H were observed. The loss of MMR proteins expression was associated with the intestinal type of GC in Lauren classification, and tubular and papillary architecture in WHO classification. There was no statistically significant association between negative MMR expression and other selected clinical parameters: age, sex, tumor location, depth of invasion (EGC and AGC), lymph nodes status, presence of the ulceration, and lymphocytic infiltrate. CONCLUSIONS In the present era of personalized medicine, the histological type of GC and MMR proteins status in cancer cells are very important for the proper surveillance of patients with familial GC and sporadic GCs, as well as for selecting the proper follow-up and treatment. Larger collaborative studies are needed to verify the features of MSI-H GCs in Poland.
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Affiliation(s)
| | | | | | - Andrzej Białek
- Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland
| | - Elżbieta Urasińska
- Department of Pathology, Pomeranian Medical University, Szczecin, Poland
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