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Arakawa H, Komatsu S, Kiuchi J, Imamura T, Nishibeppu K, Kamiya H, Takashima Y, Ishida R, Hamada S, Yamauchi M, Ohashi T, Shimizu H, Arita T, Konishi H, Shiozaki A, Kubota T, Fujiwara H, Tsuda H, Otsuji E. Overexpression of SHANK2 contributes malignant outcomes as a Hippo pathway regulator in gastric cancer. Am J Cancer Res 2025; 15:363-374. [PMID: 39949934 PMCID: PMC11815361 DOI: 10.62347/nzmo2658] [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: 11/04/2024] [Accepted: 01/03/2025] [Indexed: 02/16/2025] Open
Abstract
BACKGROUND Recent studies identified that SH3 and multiple ankyrin repeat domains 2 (SHANK2) is located in a gene-amplified region 11q13 of various human cancers, and has oncogenic functions as a Hippo pathway suppressor in hepatocellular carcinoma. In this study, we tested whether SHANK2 acts as a cancer-promoting gene through its activation or overexpression in gastric cancer (GC). MATERIALS AND METHODS We analyzed 5 GC cell lines and 172 primary tumor samples of GC, which were curatively resected in our hospital. RESULTS Overexpression of SHANK2 protein was frequently detected in GC cell lines (4/5 cell lines, 80%). Knockdown of SHANK2 inhibited cell proliferation, migration and invasion of GC cells in a TP53 mutation-independent manner, and induced the overexpression of the Hippo pathway genes. Fluorescent immunostaining showed that overexpression of SHANK2 in cytoplasm was inversely correlated with Yes1-associated transcriptional regulator (YAP) expression, suggesting that SHANK2 may play a role in suppressing the Hippo pathway in GC. In primary GC samples, both overexpression of SHANK2 in cytoplasm and low expression of SHANK2 in nucleus, which are defined as high SHANK2 index, correlated with more aggressive venous invasion, advanced tumor and nodal stage. Patients with high SHANK2 index tumors had a lower overall survival rate than those with non-expressing tumors. Multivariate analysis demonstrated that high SHANK2 index was independently associated with poor outcomes. CONCLUSIONS These findings suggest that SHANK2 plays a crucial role in tumor malignant potential through the Hippo pathway suppression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.
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Affiliation(s)
- Hiroshi Arakawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Keiji Nishibeppu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Hajime Kamiya
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Yusuke Takashima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Ryo Ishida
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Satoshi Hamada
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Masateru Yamauchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Hiroki Shimizu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Takeshi Kubota
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
| | - Hitoshi Tsuda
- Department of Pathology, National Defense Medical College HospitalSaitama, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of MedicineKyoto, Japan
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Kővári B, Carneiro F, Lauwers GY. Epithelial tumours of the stomach. MORSON AND DAWSON'S GASTROINTESTINAL PATHOLOGY 2024:227-286. [DOI: 10.1002/9781119423195.ch13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Koike Y, Osakabe M, Sugimoto R, Uesugi N, Matsumoto T, Suzuki H, Yanagawa N, Sugai T. A genome-wide study of gastric intramucosal neoplasia based on somatic copy number alterations, gene mutations, and mRNA expression patterns. J Pathol Clin Res 2024; 10:e12368. [PMID: 38454538 PMCID: PMC10920940 DOI: 10.1002/2056-4538.12368] [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: 11/30/2023] [Revised: 01/20/2024] [Accepted: 02/21/2024] [Indexed: 03/09/2024]
Abstract
We performed comprehensive analyses of somatic copy number alterations (SCNAs) and gene expression profiles of gastric intramucosal neoplasia (IMN) using array-based methods in 97 intestinal-type IMNs, including 39 low-grade dysplasias (LGDs), 37 high-grade dysplasias (HGDs), and 26 intramucosal carcinomas (IMCs) with stromal invasion of the lamina propria to identify the molecular mechanism of IMN. In addition, we examined gene mutations using gene panel analyses. We used cluster analyses for exclusion of arbitrariness to identify SCNA patterns and expression profiles. IMNs were classified into two distinct subgroups (subgroups 1 and 2) based on SCNA patterns. Subgroup 1 showed a genomic stable pattern due to the low frequency of SCNAs, whereas subgroup 2 exhibited a chromosomal instability pattern due to the high frequencies of SCNAs and TP53 mutations. Interestingly, although the frequencies of LGD and HGD were significantly higher in subgroup 1 than in subgroup 2, IMC was commonly found in both types. Although the expression profiles of specific mRNAs could be used to categorise subgroups 1 and 2, no clinicopathological findings correlated with either subgroup. We examined signalling pathways specific to subgroups 1 and 2 to identify the association of each subgroup with signalling pathways based on gene ontology tree visualisation: subgroups 1 and 2 were associated with haem metabolism and chromosomal instability, respectively. These findings reveal a comprehensive genomic landscape that highlights the molecular complexity of IMNs and provide a road map to facilitate our understanding of gastric IMNs.
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Affiliation(s)
- Yoshihiko Koike
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityShiwagun'yahabachouJapan
| | - Mitsumasa Osakabe
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityShiwagun'yahabachouJapan
| | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityShiwagun'yahabachouJapan
| | - Noriyuku Uesugi
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityShiwagun'yahabachouJapan
- Diagnostic Pathology CenterSouthern Tohoku General HospitalKooriyamaJapan
| | - Takayuki Matsumoto
- Division of GastroenterologyDepartment of Internal MedicineShiwagun'yahabachouJapan
| | - Hiromu Suzuki
- Department of Molecular BiologySapporo Medical University, School of MedicineSapporoJapan
| | - Naoki Yanagawa
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityShiwagun'yahabachouJapan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityShiwagun'yahabachouJapan
- Diagnostic Pathology CenterSouthern Tohoku General HospitalKooriyamaJapan
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Ushiku T, Lauwers GY. Pathology and Clinical Relevance of Gastric Epithelial Dysplasia. Gastroenterol Clin North Am 2024; 53:39-55. [PMID: 38280750 DOI: 10.1016/j.gtc.2023.11.003] [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] [Indexed: 01/29/2024]
Abstract
Gastric dysplasia is defined as an unequivocally neoplastic epithelium. Dysplastic lesions are characterized by cellular atypia reflective of abnormal differentiation and disorganized glandular architecture. The last few years have been marked by a refinement of the prognosis and risk of progression of gastric dysplasia and the recognition of novel morphologic patterns of dysplasia. Determination of the correct diagnosis and grade of dysplasia are critical steps since it will be predicting the risk of malignant transformation and help tailor appropriate surveillance strategy. This review describes the morphologic characteristics of conventional dysplasia and nonconventional gastric dysplasia that have been more recently characterized.
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Affiliation(s)
- Tetsuo Ushiku
- Department of Pathology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Gregory Y Lauwers
- Department of Pathology, Gastrointestinal Pathology Section, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Drive, Tampa, FL 33612, USA; Departments of Pathology and Oncologic Sciences, Tampa, FL, USA.
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Kinami S, Yamada S, Takamura H. Confusion and prospects for carcinogenesis of gastric adenoma and dysplasia: What is the correct answer currently? World J Gastroenterol 2022; 28:6900-6908. [PMID: 36632315 PMCID: PMC9827587 DOI: 10.3748/wjg.v28.i48.6900] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/07/2022] [Accepted: 12/05/2022] [Indexed: 12/26/2022] Open
Abstract
There are differences in the diagnoses of superficial gastric lesions between Japan and other countries. In Japan, superficial gastric lesions are classified as adenoma or cancer. Conversely, outside Japan, the same lesion is classified as low-grade dysplasia (LGD), high-grade dysplasia, or invasive neoplasia. Gastric carcinogenesis occurs mostly de novo, and the adenoma-carcinoma sequence does not appear to be the main pathway of carcinogenesis. Superficial gastric tumors can be roughly divided into the APC mutation type and the TP53 mutation type, which are mutually exclusive. APC-type tumors have low malignancy and develop into LGD, whereas TP53-type tumors have high malignancy and are considered cancerous even if small. For lesions diagnosed as category 3 or 4 in the Vienna classification, it is desirable to perform complete en bloc resection by endoscopic submucosal dissection followed by staging. If there is lymphovascular or submucosal invasion after mucosal resection, additional surgical treatment of gastrectomy with lymph node dissection is required. In such cases, function-preserving curative gastrectomy guided by sentinel lymph node biopsy may be a good alternative.
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Affiliation(s)
- Shinichi Kinami
- Department of Surgical Oncology, Kanazawa Medical University, kahoku-gun 920-0293, Ishikawa, Japan
| | - Sohsuke Yamada
- Department of Clinical Pathology, Kanazawa Medical University, Uchinada 920-0293, Ishikawa, Japan
| | - Hiroyuki Takamura
- Department of Surgical Oncology, Kanazawa Medical University, Kahoku-gun 920-0293, Ishikawa, Japan
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Takashima Y, Komatsu S, Ohashi T, Kiuchi J, Kamiya H, Shimizu H, Arita T, Konishi H, Shiozaki A, Kubota T, Okamoto K, Fujiwara H, Tsuda H, Otsuji E. Overexpression of Tetraspanin31 contributes to malignant potential and poor outcomes in gastric cancer. Cancer Sci 2022; 113:1984-1998. [PMID: 35307915 PMCID: PMC9207375 DOI: 10.1111/cas.15342] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 03/09/2022] [Accepted: 03/12/2022] [Indexed: 12/24/2022] Open
Abstract
Tetraspanin has important functions in many cancers by aggregating with various proteins that interact with intracellular signaling proteins. The molecular function of Tetraspanin31 (TSPAN31), located in the 12q14 amplified region in various cancers, remains unclear in gastric cancer (GC). We tested whether TSPAN31 acts as a cancer‐promoting gene through its activation or overexpression in GC. We analyzed seven GC cell lines and 189 primary tumors, which were curatively resected in our hospital between 2011 and 2013. Overexpression of the TSPAN31 protein was frequently detected in three GC cell lines (42.9%) and 62 primary GC specimens (32.8%). Overexpression of TSPAN31 was significantly correlated with lymphatic invasion, venous invasion, more advanced pT and pN stages, and a higher recurrence rate. Moreover, TSPAN31 positivity was an independent factor predicting worse patient outcomes (p = 0.0283, hazard ratio 3.97). Ectopic overexpression of TSPAN31 facilitated cell proliferation of GC cells, and knockdown of TSPAN31 inhibited cell proliferation, migration, invasion, and epithelial–mesenchymal transition of GC cells through the PI3K‐Akt pathway and increased cell apoptosis in a TP53 mutation‐independent manner. In vivo analysis also revealed knockdown of TSPAN31 suppressed tumor progression. In addition, knockdown of TSPAN31 improved chemosensitivity to cisplatin through the suppression of ABCC2. These findings suggest that TSPAN31 plays a crucial role in tumor‐malignant potential through overexpression, highlighting its utility as a prognostic factor and a potential therapeutic target in GC.
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Affiliation(s)
- Yusuke Takashima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hajime Kamiya
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hiroki Shimizu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takeshi Kubota
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Hitoshi Tsuda
- Department of Pathology, National Cancer Center Hospital, Tokyo, Japan.,Department of Basic Pathology, National Defense Medical College, Tokorozawa, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
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7
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Molecular Landscapes of Gastric Pre-Neoplastic and Pre-Invasive Lesions. Int J Mol Sci 2021; 22:ijms22189950. [PMID: 34576114 PMCID: PMC8468646 DOI: 10.3390/ijms22189950] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/03/2021] [Accepted: 09/11/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric carcinoma (GC) represents one of the most common and most lethal malignancies worldwide. The histopathological characterization of GC precursor lesions has provided great knowledge about gastric carcinogenesis, with the consequent introduction of effective strategies of primary and secondary prevention. In recent years, a large amount of data about the molecular events in GC development is emerging, flanking the histomorphological descriptions. In this review, we describe the landscape of molecular alterations in gastric pre-invasive lesions with a glance at their potential use in the diagnostic and therapeutic decision-making process.
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Bhaskar Rao D, Devanandan HJ, Ganesan K. Identification of kinases and kinase inhibitors for the differential targeting of Wnt/β-catenin signaling in gastric cancer subtypes. Drug Dev Res 2021; 82:1182-1192. [PMID: 34002415 DOI: 10.1002/ddr.21833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 05/04/2021] [Accepted: 05/07/2021] [Indexed: 01/21/2023]
Abstract
The oncogenic signaling pathway Wnt is often activated in many cancers including gastric cancer. Wnt signaling pathway is considered as a potential target for developing new targeted therapeutics. Kinase inhibitors are the promising class of drugs for many diseases including cancers. Toward identifying the potent inhibitors targeting Wnt signaling pathway, a kinase inhibitor library with 82 inhibitors were screened using Wnt pathway reporter assay in gastric cancer cells. Notably, 34 kinase inhibitors were identified to inhibit Wnt mediated reporter activity to the extent of more than 50%. The corresponding kinase genes, which are known targets of these kinase inhibitors, were investigated for their expression in the available mRNA profiles of gastric tumors. A major group of the kinase genes showed higher expression in intestinal subtype gastric tumors. Another group of kinase genes were found expressed in diffuse type gastric tumors. The kinase genes expressed in intestinal type gastric tumors were found associated with varying survival of gastric cancer patients whereas those expressed in diffuse type tumors were found associated with the poor survival. Thus, the kinase genes specifically expressed in intestinal and diffuse type gastric tumors and the kinase inhibitors to target Wnt signaling pathway in gastric cancer subtypes have been identified.
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Affiliation(s)
- Divya Bhaskar Rao
- Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, India
| | - Helen Jemimah Devanandan
- Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, India
| | - Kumaresan Ganesan
- Unit of Excellence in Cancer Genetics, Department of Genetics, Centre for Excellence in Genomic Sciences, School of Biological Sciences, Madurai Kamaraj University, Madurai, India
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Lee SW, Lee T, Sul HJ, Park KC, Park J. Differences in Somatic Mutation Profiles between Korean Gastric Cancer and Gastric Adenoma Patients. J Clin Med 2021; 10:jcm10092038. [PMID: 34068652 PMCID: PMC8126162 DOI: 10.3390/jcm10092038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 05/06/2021] [Accepted: 05/07/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND We aimed to investigate molecular factors potentially related to the progression of gastric adenoma (GA) to gastric cancer (GC) and compare the mutation characteristics between GC and GA. METHODS We conducted custom gene panel sequencing for 135 GC-related genes and estimated the difference in somatic mutation profiles between 20 GC and 20 GA cases. RESULTS A total of 31 somatic mutations, including 22 missense, 3 nonsense, and 6 frameshift mutations, were detected in 17 samples. We estimated an average of 1.8 mutations per sample (range, 1 to 3 mutations), with 12 in GC and 5 in GA. GC tended to have one or more mutated genes (p = 0.0217), as well as higher allele frequencies of mutated genes (p = 0.0003), compared to GA. Likewise, known driver mutations associated with GC tumorigenesis (TP53, ERBB2, PIK3CA, and RNF43) were identified in half of the GC cases (50%, 10/20; p = 0.0002). Only the mutant burden, regardless of gene type, was retained, with an odds ratio of 1.8392 (95% confidence interval (CI), 1.0071 to 3.3588; p = 0.0474). CONCLUSION Our study demonstrates that the accumulation of mutant burden contributes to tumorigenesis progression from GA to GC in Korean patients, regardless of the kind of genes. These findings may elucidate the molecular pathogenesis of gastric carcinogenesis and malignant progression.
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Affiliation(s)
- Seung Woo Lee
- Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Taekyu Lee
- Thermo Fisher Scientific Solutions, Seoul 06349, Korea;
| | - Hae Jung Sul
- Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Ki Cheol Park
- Clinical Research Institute, Daejeon St. Mary’s Hospital, The Catholic University of Korea, Daejeon 34943, Korea;
| | - Joonhong Park
- Department of Laboratory Medicine, Jeonbuk National University Medical School and Hospital, Jeonju 54907, Korea
- Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Korea
- Correspondence: ; Tel.: +82-63-250-1218
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10
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Tanaka K, Maekawa S, Yoshida T, Yamaguchi T, Takano S, Matsuda S, Hayakawa H, Ishida Y, Muraoka M, Kawakami S, Fukasawa Y, Kuno T, Iwamoto F, Tsukui Y, Kobayashi S, Asakawa Y, Shindo H, Fukasawa M, Nakayama Y, Inoue T, Uetake T, Ohtaka M, Sato T, Mochizuki K, Enomoto N. Role of magnifying endoscopy with narrow-band imaging in the diagnosis of noninvasive gastric neoplasia. JGH OPEN 2021; 5:446-453. [PMID: 33860094 PMCID: PMC8035442 DOI: 10.1002/jgh3.12513] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 01/21/2021] [Accepted: 02/12/2021] [Indexed: 11/12/2022]
Abstract
Background and Aim There are no globally approved, distinguishing criteria enabling the classification of gastric adenomas and intramucosal carcinomas for differential diagnosis of noninvasive neoplasia (NIN). Methods Next‐generation sequencing of 50 cancer‐related genes was undertaken on 68 pathologically diagnosed microdissected gastric neoplasms (25 adenomas, 27 intramucosal carcinomas, and 16 submucosal carcinomas) obtained during endoscopic submucosal dissection. Findings from magnifying endoscopy with narrow‐band imaging (M‐NBI) of 52 NINs (the 25 adenomas and 27 intramucosal carcinomas) were compared with these data. Results Among all 68 neoplasms, the most frequently mutated genes were APC (76% in adenoma, 11.1% in intramucosal carcinoma, and 0% in submucosal carcinoma; P < 0.001) and TP53 in intramucosal and submucosal carcinomas (8% in adenoma, 48.1% in intramucosal carcinoma, and 75% in submucosal carcinoma; P < 0.001). Dividing the NIN neoplasms into five groups according to their mutational status (A1: APC mutation, A2: APC + α mutation, B: APC + TP53 mutation, C: TP53 mutation, D: no mutation in either APC or TP53) resulted in almost identical diagnoses by pathology and M‐NBI for groups A1 (12/13, 92%), C (12/13, 92%), and D (16/17, 94%) but not for groups A2 (3/7, 43%) or B (0/2, 0%). This finding implies that NINs with the APC + α mutation have carcinoma‐like endoscopic features despite most being judged as adenomas by pathology. Conclusion A diagnosis of NINs by pathology or M‐NBI in the subset of gastric tumors classified by cancer‐related mutations is not completely identical, suggesting the possible additional role of M‐NBI in diagnosing NINs. Further studies are needed to confirm this.
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Affiliation(s)
- Keisuke Tanaka
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Shinya Maekawa
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Takashi Yoshida
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Tatsuya Yamaguchi
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Shinichi Takano
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Shuya Matsuda
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Hiroshi Hayakawa
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Yasuaki Ishida
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Masaru Muraoka
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Satoshi Kawakami
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Yoshimitsu Fukasawa
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Toru Kuno
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Fumihiko Iwamoto
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Yuya Tsukui
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Shoji Kobayashi
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Yukiko Asakawa
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Hiroko Shindo
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Mitsuharu Fukasawa
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Yasuhiro Nakayama
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Taisuke Inoue
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Tomoyoshi Uetake
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Masahiko Ohtaka
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Tadashi Sato
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Kunio Mochizuki
- Department of Pathology, Faculty of Medicine University of Yamanashi Yamanashi Japan
| | - Nobuyuki Enomoto
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Yamanashi Japan
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Nishibeppu K, Komatsu S, Kiuchi J, Kishimoto T, Takashima Y, Shoda K, Arita T, Kosuga T, Konishi H, Shiozaki A, Kubota T, Okamoto K, Fujiwara H, Tsuda H, Otsuji E. TRIM37 contributes to malignant outcomes and CDDP resistance in gastric cancer. J Cancer 2021; 12:316-325. [PMID: 33391428 PMCID: PMC7739001 DOI: 10.7150/jca.47577] [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: 04/29/2020] [Accepted: 10/25/2020] [Indexed: 12/12/2022] Open
Abstract
Background: TRIM37 (Tripartite Motif Containing 37) is an E3 ubiquitin ligase for histone H2A and inhibits transcription in several genes. However, it is not known whether it plays a role in gastric cancer (GC). In this study, we tested whether TRIM37 acts as a cancer-promoting factor by being overexpressed in GC. Methods: We analyzed GC cell lines and 124 primary tumors, which were curatively resected in our hospital between 2001 and 2003. Results: Overexpression of the TRIM37 protein was detected in almost all GC cell lines and GC samples (76 out of 124 cases) and was significantly correlated with lymphatic and venous invasion, advanced T-Stage, N-Stage, histology and high recurrence rate. Patients with TRIM37 overexpressing tumors had a worse survival rate than those with non-expressing tumors (P=0.0057). Moreover, TRIM37 positivity was identified as an independent factor predicting worse outcomes (P=0.018, Hazard ratio 3.41). The apoptotic cell analysis showed that the knockdown of TRIM37 increased apoptosis in comparison with the control. In TRIM37 overexpressing GC cells, knockdown of TRIM37 suppressed the migration and invasion. Conclusions: TRIM37 plays a crucial role in tumor malignant potential through its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.
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Affiliation(s)
- Keiji Nishibeppu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Takuma Kishimoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Yusuke Takashima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Katsutoshi Shoda
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Toshiyuki Kosuga
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Takeshi Kubota
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Hitoshi Tsuda
- Department of Pathology, National Cancer Center Hospital, Tokyo, Japan.,Department of Basic Pathology, National Defense Medical College, Tokorozawa, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
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12
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Kővári B, Kim BH, Lauwers GY. The pathology of gastric and duodenal polyps: current concepts. Histopathology 2020; 78:106-124. [PMID: 33382489 DOI: 10.1111/his.14275] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/25/2020] [Accepted: 10/01/2020] [Indexed: 12/26/2022]
Abstract
The liberal use of upper endoscopy has led to an increased detection of gastric and duodenal polyps, which are identified in as many as 6 and 4.6% of patient examinations, respectively. Gastroduodenal polyps are a heterogeneous group of lesions that can be neoplastic or non-neoplastic (e.g. hyperplastic or heterotopical). Most polyps present characteristic topographical features, as well as endoscopic appearance and size. Evaluation of the surrounding mucosa is essential in assessing the underlying pathology (e.g. Helicobacter pylori, autoimmune gastritis or inherited polyposis syndromes). Phylogenetically, gastric and duodenal polyps can be classified according to the epithelial compartment from which they derive. Polyps that arise from the surface epithelium can either be of foveolar or intestinal type, and they can develop from either the native mucosa or the metaplastic epithelium (gastric intestinal metaplasia or duodenal foveolar metaplasia). Other polyps develop from the deeper glandular component, such as pyloric/oxyntic gland derived subtypes. In this review we focus upon epithelial polyps, with an emphasis on the most common and clinically relevant lesions, and present recently described entities.
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Affiliation(s)
- Bence Kővári
- Department of Pathology, University of Szeged and Albert Szent-Györgyi Health Center, Szeged, Hungary.,Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute and Departments of Pathology and Oncologic Sciences, University of South Florida, Tampa, FL, USA
| | - Baek H Kim
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute and Departments of Pathology and Oncologic Sciences, University of South Florida, Tampa, FL, USA.,Department of Pathology, Korea University Guro Hospital, Seoul, Korea
| | - Gregory Y Lauwers
- Department of Pathology, H. Lee Moffitt Cancer Center and Research Institute and Departments of Pathology and Oncologic Sciences, University of South Florida, Tampa, FL, USA
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13
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Taggart MW, Foo WC, Lee SM. Tumors of the Gastrointestinal System Including the Pancreas. ONCOLOGICAL SURGICAL PATHOLOGY 2020:691-870. [DOI: 10.1007/978-3-319-96681-6_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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14
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Komatsu S, Otsuji E. Essential updates 2017/2018: Recent topics in the treatment and research of gastric cancer in Japan. Ann Gastroenterol Surg 2019; 3:581-591. [PMID: 31788646 PMCID: PMC6875932 DOI: 10.1002/ags3.12284] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 07/28/2019] [Accepted: 08/06/2019] [Indexed: 12/12/2022] Open
Abstract
Recent developments in diagnostic technology, accumulated clinical effort and established evidence have boosted early detection and drastically improved early and long-term outcomes of gastric cancer. However, gastric cancer continues to be one of the most aggressive and life-threatening malignancies among all cancers and is a global health problem. Between January 2017 and December 2018, various fascinating reports of managements and research were published, including the new 15th Japanese Classification of Gastric Carcinoma reflecting the 8th American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) tumor, node and metastasis (TNM) classification (October 2017) and the new Gastric Cancer Treatment Guidelines version 5 (January 2018). Moreover, pivotal molecular features of gastric cancer were clarified by the worldwide cancer genome project, and various treatment targets and biomarkers such as circulating DNAs and microRNAs were detected. Novel treatment options using programmed cell death protein 1 immune checkpoint inhibitors have been started. In this review, we summarize the recent topics of classification, guidelines, and clinical and basic research in order to bring new insights to gastric cancer treatment.
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Affiliation(s)
- Shuhei Komatsu
- Division of Digestive SurgeryDepartment of SurgeryKyoto Prefectural University of MedicineKyotoJapan
- Department of SurgeryKyoto First Red Cross HospitalKyotoJapan
| | - Eigo Otsuji
- Division of Digestive SurgeryDepartment of SurgeryKyoto Prefectural University of MedicineKyotoJapan
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15
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Ryu WJ, Lee JE, Cho YH, Lee G, Seo MK, Lee SK, Hwang JH, Min DS, Noh SH, Paik S, Kim S, Cheong JH, Choi KY. A Therapeutic Strategy for Chemotherapy-Resistant Gastric Cancer via Destabilization of Both β-Catenin and RAS. Cancers (Basel) 2019; 11:cancers11040496. [PMID: 30965636 PMCID: PMC6521309 DOI: 10.3390/cancers11040496] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 04/04/2019] [Accepted: 04/04/2019] [Indexed: 01/14/2023] Open
Abstract
Treatment of advanced gastric cancer patients with current standard chemotherapeutic agents frequently results in resistance, leading to poor overall survival. However, there has been no success in developing strategies to overcome it. We showed the expression levels of both β-catenin and RAS were significantly increased and correlated in tissues of 756 gastric cancer (GC) patients and tissues of primary- and acquired-resistance patient-derived xenograft tumors treated with 5-fluorouracil and oxaliplatin modulated with leucovorin (FOLFOX). On the basis of our previous studies, where small molecules to suppress colorectal cancer (CRC) via degrading both β-catenin and RAS were developed, we tested the effectiveness of KYA1797K, a representative compound functioning by binding axin, in the growth of GC cells. The efficacy test of the drugs using gastric tumor organoids of Apc1638N mice showed that the CD44 and ALDH1A3 cancer stem cell markers were induced by FOLFOX, but not by KYA1797K. KYA1797K also efficiently suppressed tumors generated by re-engrafting the FOLFOX-resistant patient-derived xenograft (PDX) tumors, which also showed resistance to paclitaxel. Overall, the small-molecule approach degrading both β-catenin and RAS has potential as a therapeutic strategy for treating GC patients resistant to current standard chemotherapies.
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Affiliation(s)
- Won-Ji Ryu
- Translational Research Center for Protein Function Control, Yonsei University, Seoul 03722, Korea.
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
| | - Jae Eun Lee
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea.
| | - Yong-Hee Cho
- Translational Research Center for Protein Function Control, Yonsei University, Seoul 03722, Korea.
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
| | - Gunho Lee
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul 03722, Korea.
- Graduate Program for Nanomedical Science, Yonsei University, Seoul 03722, Korea.
| | - Mi-Kyoung Seo
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul 03722, Korea.
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea.
| | - Sang-Kyu Lee
- Translational Research Center for Protein Function Control, Yonsei University, Seoul 03722, Korea.
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
| | - Jeong-Ha Hwang
- Translational Research Center for Protein Function Control, Yonsei University, Seoul 03722, Korea.
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
| | - Do Sik Min
- Translational Research Center for Protein Function Control, Yonsei University, Seoul 03722, Korea.
- Department of Molecular Biology, College of Natural Science, Pusan National University, Pusan 46241, Korea.
| | - Sung Hoon Noh
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea.
| | - Soonmyung Paik
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Korea.
| | - Sangwoo Kim
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul 03722, Korea.
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea.
| | - Jae-Ho Cheong
- Department of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea.
- Department of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul 03722, Korea.
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul 03722, Korea.
| | - Kang-Yell Choi
- Translational Research Center for Protein Function Control, Yonsei University, Seoul 03722, Korea.
- Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea.
- CK Biotechnology Inc., Rm 417, Engineering Research Park, 50 Yonsei Ro, Seodaemun-Gu, Seoul 03722, Korea.
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16
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Rokutan H, Abe H, Nakamura H, Ushiku T, Arakawa E, Hosoda F, Yachida S, Tsuji Y, Fujishiro M, Koike K, Totoki Y, Fukayama M, Shibata T. Initial and crucial genetic events in intestinal-type gastric intramucosal neoplasia. J Pathol 2019; 247:494-504. [PMID: 30474112 DOI: 10.1002/path.5208] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 11/18/2018] [Accepted: 11/22/2018] [Indexed: 12/23/2022]
Abstract
Gastric cancer (GC) is one of the most common and life-threatening malignancies. The course of disease and tumor aggressiveness vary among GCs, although how early fate is determined and by what factors remains elusive. To solve this question, we collected 43 gastric intramucosal neoplasias (GINs), comprising dysplasia/intraepithelial neoplasia (D/IEN; a premalignant lesion) and minute GC (miGC; ≤10 mm) of intestinal histotype and performed targeted deep DNA sequencing of 67 GC-related genes derived from large-scale data. Gastric D/IEN was classified into low or high grade (LG-D/IEN or HG-D/IEN). The most frequent mutations in D/IENs included APC (19/25; 76%), ARID2 (6/25; 24%) and MUC6 (5/25; 20%). All LG-D/IENs had APC mutation (12/12) and APC hotspot mutations affecting R1450 and E1554 were noted in both LG-D/IEN and HG-D/IEN. ARID2 mutation always co-occurred with APC mutation, whose tumor variant allele frequency (TVAF) was higher than that of ARID2 in D/IEN. APC and TP53 mutations were mutually exclusive in D/IEN (p = 0.031 [main cohort], p = 0.025 [expanding cohort]) and TP53-mutated D/IEN was exclusively HG-D/IEN (4/4). TP53 mutations were highly recurrent (11/14; 79%) in MLH1-positive miGCs and were detected even in two microscopic lesions measuring 1 and 3 mm, respectively. Furthermore, TVAF analyses suggested that TP53 mutation is the initial event in the TP53-mutated miGCs. In contrast, TP53 mutation was absent (0/4) in MLH1-negative small intramucosal carcinoma (8-24 mm). Advanced GC data suggested that early mutations (APC and TP53) may affect the potential of cancerous progression from D/IEN. This study revealed somatic mutational landscape and initial mutations of GINs, and we report for the first time that TP53 mutations precede other mutations in intestinal-type GC. Our results also indicate that molecular subtyping based on APC/TP53 mutations would be a high-priority approach for determining and predicting the malignant potential of GIN, including D/IEN. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Hirofumi Rokutan
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Hiroyuki Abe
- Department of Pathology, The University of Tokyo, Tokyo, Japan
| | - Hiromi Nakamura
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, The University of Tokyo, Tokyo, Japan
| | - Erika Arakawa
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Fumie Hosoda
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Shinichi Yachida
- Laboratory of Clinical Genomics, National Cancer Center Research Institute, Tokyo, Japan.,Department of Cancer Genome Informatics, Graduate School of Medicine, Faculty of Medicine, Osaka University, Osaka, Japan
| | - Yosuke Tsuji
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan.,Department of Endoscopy & Endoscopic Surgery, The University of Tokyo, Tokyo, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, The University of Tokyo, Tokyo, Japan
| | - Yasushi Totoki
- Division of Cancer Genomics, National Cancer Center Research Institute, 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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17
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Kiuchi J, Komatsu S, Imamura T, Nishibeppu K, Shoda K, Arita T, Kosuga T, Konishi H, Shiozaki A, Kubota T, Okamoto K, Fujiwara H, Ichikawa D, Tsuda H, Otsuji E. Overexpression of YEATS4 contributes to malignant outcomes in gastric carcinoma. Am J Cancer Res 2018; 8:2436-2452. [PMID: 30662802 PMCID: PMC6325477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Accepted: 11/29/2018] [Indexed: 06/09/2023] Open
Abstract
YEATS domain containing 4 (YEATS4) has functions of chromatin modification and transcriptional regulation and is in a gene-amplified region (12q13) in various human cancers. In this study, we tested whether YEATS4 acts as a cancer-promoting gene through its activation/overexpression in gastric cancer (GC). We analyzed 5 GC cell lines and 135 primary tumor samples of GC, which were curatively resected in our hospital. Overexpression of the YEATS4 protein was frequently detected in GC cell lines (5/5 cell lines, 100%) and primary GC tumor tissues (32/135 cases, 23.7%). Knockdown of YEATS4 inhibited proliferation, migration and invasion of GC cells through NOTCH2 down-regulation in a TP53 mutation-independent manner, and induced apoptosis in wild-type TP53 GC cells. Moreover, knockdown of YEATS4 improved chemosensitivity for CDDP and L-OHP. Overexpression of YEATS4 protein significantly correlated with more aggressive lymphatic invasion, larger tumor size, deeper tumor depth, positive lymph node metastasis and recurrence. Patients with YEATS4-overexpressing tumors had a lower overall survival rate than those with non-expressing tumors. Multivariate analysis demonstrated that YEATS4 was independently associated with poor outcomes. These findings suggest that YEATS4 plays a pivotal role in tumor malignant potential through its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.
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Affiliation(s)
- Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Keiji Nishibeppu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Katsutoshi Shoda
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Toshiyuki Kosuga
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Takeshi Kubota
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
| | - Daisuke Ichikawa
- First Department of Surgery, Faculty of Medicine, University of YamanashiYamanashi, Japan
| | - Hitoshi Tsuda
- Department of Pathology, National Cancer Center HospitalTokyo, Japan
- Department of Basic Pathology, National Defense Medical CollegeTokorozawa, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine465 Kajii-Cho, Kawaramachihirokoji, Kamigyo-Ku, Kyoto, Japan
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18
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Imamura T, Komatsu S, Ichikawa D, Miyamae M, Okajima W, Ohashi T, Kiuchi J, Nishibeppu K, Kosuga T, Konishi H, Shiozaki A, Fujiwara H, Okamoto K, Tsuda H, Otsuji E. Overexpression of ZRF1 is related to tumor malignant potential and a poor outcome of gastric carcinoma. Carcinogenesis 2018; 39:263-271. [PMID: 29228320 DOI: 10.1093/carcin/bgx139] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Accepted: 11/29/2017] [Indexed: 12/13/2022] Open
Abstract
Zuotin-related factor 1 (ZRF1) is a recently characterized epigenetic factor involved in transcriptional regulation and is highly overexpressed in several malignancies, but it is not known whether it plays a role in gastric cancer (GC). In this study, we investigated whether ZRF1 acts as a cancer-promoting gene through its activation/overexpression in GC. We analyzed five GC cell lines and 133 primary tumors, which had been curatively resected in our hospital between 2001 and 2003. Overexpression of ZRF1 was detected in GC cell lines (four out of five lines, 80.0%) and was detected in primary tumor samples of GC (52 out of 133 cases, 39.1%) and significantly correlated with differentiated histological type, venous invasion, lymphatic invasion, advanced stage and a higher recurrence rate. ZRF1-overexpressing tumors had a worse survival rate than those with non-expressing tumors (P < 0.01, log-rank test). ZRF1 positivity was independently associated with a worse outcome in the multivariate analysis (P < 0.01; hazard ratio 4.92; 95% confidence interval: 1.6-21.1). In ZRF1-overexpressing GC cells, knockdown of ZRF1 using specific siRNAs inhibited the cell proliferation, migration and invasion and induced apoptosis in a p53-dependent manner. These findings suggest that ZRF1 plays a crucial role in tumor malignant potential through its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.
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Affiliation(s)
- Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Daisuke Ichikawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Mahito Miyamae
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Wataru Okajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Keiji Nishibeppu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Toshiyuki Kosuga
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Hitoshi Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
| | - Hitoshi Tsuda
- Department of Pathology, National Cancer Center Hospital, Tokyo, Japan.,Department of Basic Pathology, National Defense Medical College, Tokorozawa, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, Japan
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19
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Oh JH, Rhyu MG, Kim SI, Yun MR, Shin JH, Hong SJ. Gastric Mucosal Atrophy Impedes Housekeeping Gene Methylation in Gastric Cancer Patients. Cancer Res Treat 2018; 51:267-279. [PMID: 29747491 PMCID: PMC6334004 DOI: 10.4143/crt.2018.085] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Accepted: 04/27/2018] [Indexed: 12/15/2022] Open
Abstract
PURPOSE Helicobacter pylori infection induces phenotype-stabilizing methylation and promotes gastric mucosal atrophy that can inhibit CpG-island methylation. Relationship between the progression of gastric mucosal atrophy and the initiation of CpG-island methylation was analyzed to delineate epigenetic period for neoplastic transformation. Materials and Methods Normal-appearing gastric mucosa was biopsied from 110 H. pylori-positive controls, 95 H. pylori-negative controls, 99 gastric cancer patients, and 118 gastric dysplasia patients. Gastric atrophy was assessed using endoscopic-atrophic-border score. Methylation-variable sites of eight CpG-island genes adjacent to Alu (CDH1, ARRDC4, PPARG, and TRAPPC2L) or LTR (MMP2, CDKN2A, RUNX2, and RUNX3) retroelements and stomach-specific TFF3 gene were analyzed using radioisotope-labeled methylation-specific polymerase chain reaction. RESULTS Mean ages of H. pylori-positive controls with mild, moderate, and severe atrophy were 51, 54, and 65 years and those of H. pylori-associated TFF3 overmethylation at the three atrophic levels (51, 58, and 63 years) tended to be periodic. Alu-adjacent overmethylation (50 years) was earlier than TFF3 overmethylation (58 years) in H. pylori-positive controls with moderate atrophy. Cancer patients with moderate atrophy showed late Alu-adjacent (58 years) overmethylation and frequent LTR-adjacent overmethylation. LTR-adjacent overmethylation was frequent in cancer (66 years) and dysplasia (68 years) patients with severe atrophy. CONCLUSION Atrophic progression is associated with gastric cancer at moderate level by impeding the initiation of Alu-adjacent methylation. LTR-adjacent methylation is increased in cancer patients and subsequently in dysplasia patients.
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Affiliation(s)
- Jung-Hwan Oh
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Mun-Gan Rhyu
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Suk-Il Kim
- Department of Preventive Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Mi-Ri Yun
- Department of Preventive Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jung-Ha Shin
- Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Seung-Jin Hong
- Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea
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20
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Lee SK, Hwang JH, Choi KY. Interaction of the Wnt/β-catenin and RAS-ERK pathways involving co-stabilization of both β-catenin and RAS plays important roles in the colorectal tumorigenesis. Adv Biol Regul 2018; 68:46-54. [PMID: 29449169 DOI: 10.1016/j.jbior.2018.01.001] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Revised: 01/08/2018] [Accepted: 01/08/2018] [Indexed: 12/21/2022]
Abstract
Cancer development is usually driven by multiple genetic and molecular alterations rather than by a single defect. In the human colorectal cancer (CRC), series of mutations of genes are involved in the different stages of tumorigenesis. For example, adenomatous polyposis coli (APC) and KRAS mutations have been known to play roles in the initiation and progression of the tumorigenesis, respectively. However, many studies indicate that mutations of these two genes, which play roles in the Wnt/β-catenin and RAS-extra-cellular signal regulated kinase (ERK) pathways, respectively, cooperatively interact in the tumorigenesis in several different cancer types including CRC. Both Apc and Kras mutations critically increase number and growth rate of tumors although single mutation of these genes does not significantly enhance the small intestinal tumorigenesis of mice. Both APC and KRAS mutations even result in the liver metastasis with inductions of the cancer stem cells (CSCs) markers in a mice xenograft model. In this review, we are going to describe the history for interaction between the Wnt/β-catenin and RAS/ERK pathways especially related with CRC, and provide the mechanical basis for the cross-talk between the two pathways. The highlight of the crosstalk involving the stability regulation of RAS protein via the Wnt/β-catenin signaling which is directly related with the cellular proliferation and transformation will be discussed. Activation status of GSK3β, a key enzyme involving both β-catenin and RAS degradations, is regulated by the status of the Wnt/β-catenin signaling dependent upon extracellular stimuli or intracellular abnormalities of the signaling components. The levels of both β-catenin and RAS proteins are co-regulated by the Wnt/β-catenin signaling, and these proteins are overexpressed with a positive correlation in the tumor tissues of CRC patients. These results indicate that the elevation of both β-catenin and RAS proteins is pathologically significant in CRC. In this review, we also will discuss further involvement of the increments of both β-catenin and RAS especially mutant KRAS in the activation of CSCs and metastasis. Overall, the increments of β-catenin and RAS especially mutant KRAS by APC loss play important roles in the cooperative tumorigenesis of CRC.
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Affiliation(s)
- Sang-Kyu Lee
- Translational Research Center for Protein Function Control, Yonsei University, Seoul, South Korea; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Jeong-Ha Hwang
- Translational Research Center for Protein Function Control, Yonsei University, Seoul, South Korea; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea
| | - Kang-Yell Choi
- Translational Research Center for Protein Function Control, Yonsei University, Seoul, South Korea; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul, South Korea.
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Sepulveda AR, J. Del Portillo A. Molecular Basis of Diseases of the Gastrointestinal Tract. MOLECULAR PATHOLOGY 2018:387-415. [DOI: 10.1016/b978-0-12-802761-5.00019-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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22
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Youssef O, Sarhadi V, Ehsan H, Böhling T, Carpelan-Holmström M, Koskensalo S, Puolakkainen P, Kokkola A, Knuutila S. Gene mutations in stool from gastric and colorectal neoplasia patients by next-generation sequencing. World J Gastroenterol 2017; 23:8291-8299. [PMID: 29307989 PMCID: PMC5743500 DOI: 10.3748/wjg.v23.i47.8291] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 11/01/2017] [Accepted: 11/14/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To study cancer hotspot mutations by next-generation sequencing (NGS) in stool DNA from patients with different gastrointestinal tract (GIT) neoplasms.
METHODS Stool samples were collected from 87 Finnish patients diagnosed with various gastric and colorectal neoplasms, including benign tumors, and from 14 healthy controls. DNA was isolated from stools by using the PSP® Spin Stool DNA Plus Kit. For each sample, 20 ng of DNA was used to construct sequencing libraries using the Ion AmpliSeq Cancer Hotspot Panel v2 or Ion AmpliSeq Colon and Lung Cancer panel v2. Sequencing was performed on Ion PGM. Torrent Suite Software v.5.2.2 was used for variant calling and data analysis.
RESULTS NGS was successful in assaying 72 GIT samples and 13 healthy controls, with success rates of the assay being 78% for stomach neoplasia and 87% for colorectal tumors. In stool specimens from patients with gastric neoplasia, five hotspot mutations were found in APC, CDKN2A and EGFR genes, in addition to seven novel mutations. From colorectal patients, 20 mutations were detected in AKT1, APC, ERBB2, FBXW7, KIT, KRAS, NRAS, SMARCB1, SMO, STK11 and TP53. Healthy controls did not exhibit any hotspot mutations, except for two novel ones. APC and TP53 were the most frequently mutated genes in colorectal neoplasms, with five mutations, followed by KRAS with two mutations. APC was the most commonly mutated gene in stools of patients with premalignant/benign GIT lesions.
CONCLUSION Our results show that in addition to colorectal neoplasms, mutations can also be assayed from stool specimens of patients with gastric neoplasms.
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Affiliation(s)
- Omar Youssef
- Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland
| | - Virinder Sarhadi
- Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland
| | - Homa Ehsan
- Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland
| | - Tom Böhling
- Department of Pathology, University of Helsinki and HUSLAB, Helsinki University Hospital, Helsinki 00014, Finland
| | | | - Selja Koskensalo
- The HUCH Gastrointestinal Clinic, University Central Hospital of Helsinki, Helsinki 00290, Finland
| | - Pauli Puolakkainen
- The HUCH Gastrointestinal Clinic, University Central Hospital of Helsinki, Helsinki 00290, Finland
| | - Arto Kokkola
- The HUCH Gastrointestinal Clinic, University Central Hospital of Helsinki, Helsinki 00290, Finland
| | - Sakari Knuutila
- Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland
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23
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Tafrihi M, Nakhaei Sistani R. E-Cadherin/β-Catenin Complex: A Target for Anticancer and Antimetastasis Plants/Plant-derived Compounds. Nutr Cancer 2017; 69:702-722. [PMID: 28524727 DOI: 10.1080/01635581.2017.1320415] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Plants reputed to have cancer-inhibiting potential and putative active components derived from those plants have emerged as an exciting new field in cancer study. Some of these compounds have cancer-inhibiting potential in different clinical staging levels, especially metastasis. A few of them which stabilize cell-cell adhesions are controversial topics. This review article introduces some effective herbal compounds that target E-cadherin/β-catenin protein complex. In this article, at first, we briefly review the structure and function of E-cadherin and β-catenin proteins, Wnt signaling pathway, and its target genes. Then, effective compounds of the Teucrium persicum, Teucrium polium, Allium sativum (garlic), Glycine max (soy), and Brassica oleracea (broccoli) plants, which influence stability and cellular localization of E-cadherin/β-catenin complex, were studied. Based on literature review, there are some compounds in these plants, including genistein of soy, sulforaphane of broccoli, organosulfur compounds of garlic, and the total extract of Teucrium genus that change the expression of variety of Wnt target genes such as MMPs, E-cadherin, p21, p53, c-myc, and cyclin D1. So they may induce cell-cycle arrest, apoptosis and/or inhibition of Epithelial-Mesenchymal Transition (EMT) and metastasis.
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Affiliation(s)
- Majid Tafrihi
- a Molecular and Cell Biology Research Laboratory, Department of Molecular and Cell Biology, Faculty of Basic Sciences , University of Mazandaran , Babolsar , Mazandaran , Iran
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24
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Yang JY, Li D, Zhang Y, Guan BX, Gao P, Zhou XC, Zhou CJ. The Expression of MCM7 is a Useful Biomarker in the Early Diagnostic of Gastric Cancer. Pathol Oncol Res 2017; 24:367-372. [PMID: 28540486 DOI: 10.1007/s12253-017-0251-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 05/04/2017] [Indexed: 12/15/2022]
Abstract
The aim of this study was to investigate the expression of minichromosome maintenance complex component 7 (MCM7) in gastric mucosal lesions, further to find its potential effect as a biomarker to distinguish intraepithelial neoplasia from gastric mucosal lesions. MCM7 and Ki67 were detected in 93 cases of gastric mucosal lesions by immunohistochemistry. MCM7 and Ki67 expression in GT were lowest compared with other groups (P<0.001), meanwhile there were significant differences compared with Group IM and other groups in MCM7 and Ki67 expression (P<0.001). MCM7 and Ki67 expression in GSC were highest (P<0.05). Groups of LGN, HGN and GIC had no significant differences in MCM7 expression (P>0.05), but there was significant difference compared with Group LGN and Group GIC in Ki67 expression (P<0.05). MCM7 expression elevated with tumor grade increasing and had positive correlation with Ki67 significantly (r=0.940, P<0.001). Furthermore, in some cases, some tumor cells were immunoreactive to MCM7 but negative to Ki67. So we concluded that MCM7 is helpful for us to make differential diagnosis in pathological grade, MCM7 combination of Ki67 may serve as more sensitive proliferation markers for evaluation of gastric carcinoma and precancerous lesions.
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Affiliation(s)
- Jing-Yan Yang
- Department of Pathology, The Second Hospital of Shandong University, 247#, BeiYuan Street, Jinan, Shandong, 250033, People's Republic of China
| | - Dong Li
- Department of Orthopedics, Shandong Provincial Hospital Affiliated to Shandong University, 324#, Jing 5 Road, Jinan, Shandong, 250021, People's Republic of China
| | - Yuan Zhang
- Center of Evidence-based Medicine, The Second Hospital of Shandong University, 247#, BeiYuan Street, Jinan, Shandong, 250033, People's Republic of China
| | - Bing-Xin Guan
- Department of Pathology, The Second Hospital of Shandong University, 247#, BeiYuan Street, Jinan, Shandong, 250033, People's Republic of China
| | - Ping Gao
- Yantai Affiliated Hospital of Binzhou Medical University, 717#, Jinbu Road, Muping District, Yantai, Shandong, 264100, People's Republic of China
| | - Xing-Chen Zhou
- Department of Pathology, The Second Hospital of Shandong University, 247#, BeiYuan Street, Jinan, Shandong, 250033, People's Republic of China
| | - Cheng-Jun Zhou
- Department of Pathology, The Second Hospital of Shandong University, 247#, BeiYuan Street, Jinan, Shandong, 250033, People's Republic of China.
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25
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McKnight TFP, Noffsinger AE, Landry KK, Ahmed O, Wilcox R. Early gastric adenocarcinoma arising within foveolar-type dysplasia in a patient with Muir-Torre variant Lynch syndrome. Virchows Arch 2017; 471:129-132. [PMID: 28501935 DOI: 10.1007/s00428-017-2146-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Revised: 04/27/2017] [Accepted: 05/08/2017] [Indexed: 01/05/2023]
Affiliation(s)
- Tristan F P McKnight
- Department of Pathology and Laboratory Medicine, University of Vermont Medical Center/University of Vermont College of Medicine, Burlington, VT, USA.
| | - Amy E Noffsinger
- Department of Gastrointestinal Pathology, Miraca Life Sciences, Irving, TX, USA
| | - Kara K Landry
- Department of Pathology and Laboratory Medicine, University of Vermont Medical Center/University of Vermont College of Medicine, Burlington, VT, USA
| | - Ovais Ahmed
- Department of Gastroenterology and Hepatology, University of Vermont Medical Center/University of Vermont College of Medicine, Burlington, VT, USA
| | - Rebecca Wilcox
- Department of Pathology and Laboratory Medicine, University of Vermont Medical Center/University of Vermont College of Medicine, Burlington, VT, USA
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26
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Overexpression of denticleless E3 ubiquitin protein ligase homolog (DTL) is related to poor outcome in gastric carcinoma. Oncotarget 2017; 6:36615-24. [PMID: 26472028 PMCID: PMC4742199 DOI: 10.18632/oncotarget.5620] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 10/02/2015] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Denticleless E3 ubiquitin protein ligase homolog (DTL) has been identified in amplified region (1q32) of several cancers and has an oncogenic function. In this study, we tested whether DTL acts as a cancer-promoting gene through its activation/overexpression in gastric cancer (GC). METHODS We analyzed 7 GC cell lines and 100 primary tumors that were curatively resected in our hospital between 2001 and 2003. RESULTS Overexpression of the DTL protein was detected in GC cell lines (4/7 cell lines; 57%) and primary GC tumor samples (42/100 cases; 42%). Knockdown of DTL using several specific siRNAs inhibited the proliferation, migration and invasion in a TP53 mutation-independent manner. Overexpression of the DTL was significantly correlated with lymphatic invasion, deeper tumor depth and higher recurrence rate. Patients with DTL-overexpressing tumors had a worse survival rate than those with non-expressing tumors in overall survival (P = 0.0498, log-rank test) and disease-free survival (P = 0.0324, log-rank test). In a multivariate analysis, DTL positivity was independently associated with a worse overall survival (P = 0.0104, hazard ratio 3.7 [1.36-10.1]) and disease-free survival (P = 0.0070 (hazard ratio, 3.9 (1.45-10.46)) following radical gastrectomy. CONCLUSIONS These findings suggest that DTL overexpression plays a crucial role in tumor cell proliferation and highlights its usefulness as a prognosticator and potential therapeutic target in gastric cancer.
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27
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Yantiss RK. Immunohistochemical and Molecular Features of Gastric Hyperplastic Polyps. ACTA ACUST UNITED AC 2017. [DOI: 10.15406/acp.2017.02.00012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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28
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Jiang Y, Yu Y. Transgenic and gene knockout mice in gastric cancer research. Oncotarget 2017; 8:3696-3710. [PMID: 27713138 PMCID: PMC5356912 DOI: 10.18632/oncotarget.12467] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 09/28/2016] [Indexed: 12/19/2022] Open
Abstract
Mouse models are useful tool for carcinogenic study. They will greatly enrich the understanding of pathogenesis and molecular mechanisms for gastric cancer. However, only few of mice could develop gastric cancer spontaneously. With the development and improvement of gene transfer technology, investigators created a variety of transgenic and knockout/knockin mouse models of gastric cancer, such as INS-GAS mice and gastrin knockout mice. Combined with helicobacter infection and carcinogens treatment, these transgenic/knockout/knockin mice developed precancerous or cancerous lesions, which are proper for gene function study or experimental therapy. Here we review the progression of genetically engineered mouse models on gastric cancer research, and emphasize the effects of chemical carcinogens or infectious factors on carcinogenesis of genetically modified mouse. We also emphasize the histological examination on mouse stomach. We expect to provide researchers with some inspirations on this field.
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Affiliation(s)
- Yannan Jiang
- Department of Surgery of Ruijin Hospital and Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingyan Yu
- Department of Surgery of Ruijin Hospital and Shanghai Institute of Digestive Surgery, Shanghai Key Laboratory for Gastric Neoplasms, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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29
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Overexpression of PBK/TOPK relates to tumour malignant potential and poor outcome of gastric carcinoma. Br J Cancer 2016; 116:218-226. [PMID: 27898655 PMCID: PMC5243986 DOI: 10.1038/bjc.2016.394] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Revised: 09/26/2016] [Accepted: 11/03/2016] [Indexed: 01/07/2023] Open
Abstract
Background: PDZ-binding kinase/T-LAK cell-originated protein kinase (PBK/TOPK) is a serine–threonine kinase and overexpressed in various types of cancer by inhibiting the transactivation activities of p53 and PTEN. We tested whether PBK/TOPK acts as a cancer-promoting gene through its activation/overexpression in gastric cancer (GC). Methods: We analysed five GC cell lines and 144 primary tumours, which were curatively resected in our hospital between 2001 and 2003. Results: Overexpression of the PBK/TOPK protein was frequently detected in GC cell lines (4 out of 5 lines, 80.0%) was detected in primary tumour samples of GC (24 out of 144 cases, 16.6%) and was significantly correlated with venous invasion, tumour depth and recurrence rate. PDZ-binding kinase/T-LAK cell-originated protein kinase-overexpressing tumours had a worse survival rate than those with non-expressing tumours (P=0.0009, log-rank test). PDZ-binding kinase/T-LAK cell-originated protein kinase positivity was independently associated with a worse outcome in multivariate analysis (P<0.0001, hazard ratio 6.40 (2.71–14.49)). In PBK/TOPK-overexpressing GC cells, knockdown of PBK/TOPK inhibited the cell proliferation through the p53 activation in a TP53 mutation-dependent manner and inhibited the migration/invasion through the PTEN upregulation in a TP53 mutation-independent manner. Conclusions: These findings suggest PBK/TOPK plays a crucial role in tumour malignant potential through its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.
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30
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Min BH, Hwang J, Kim NKD, Park G, Kang SY, Ahn S, Ahn S, Ha SY, Lee YK, Kushima R, Van Vrancken M, Kim MJ, Park C, Park HY, Chae J, Jang SS, Kim SJ, Kim YH, Kim JI, Kim KM. Dysregulated Wnt signalling and recurrent mutations of the tumour suppressorRNF43in early gastric carcinogenesis. J Pathol 2016; 240:304-314. [DOI: 10.1002/path.4777] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Revised: 07/06/2016] [Accepted: 08/03/2016] [Indexed: 12/15/2022]
Affiliation(s)
- Byung-Hoon Min
- Department of Medicine, Samsung Medical Centre; Sungkyunkwan University School of Medicine; Seoul Korea
| | - Jinha Hwang
- Department of Biomedical Science; Seoul National University Graduate School; Seoul Korea
| | - Nayoung KD Kim
- Samsung Genome Institute; Samsung Medical Centre; Seoul Korea
| | - Gibeom Park
- Department of Biomedical Science; Seoul National University Graduate School; Seoul Korea
| | - So Young Kang
- Department of Pathology and Translational Genomics, Samsung Medical Centre; Sungkyunkwan University School of Medicine; Seoul Korea
| | - Sangjeong Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Centre; Sungkyunkwan University School of Medicine; Seoul Korea
| | - Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Centre; Sungkyunkwan University School of Medicine; Seoul Korea
| | - Sang Yun Ha
- Department of Pathology and Translational Genomics, Samsung Medical Centre; Sungkyunkwan University School of Medicine; Seoul Korea
| | - Yun Kyung Lee
- Department of Pathology and Translational Genomics, Samsung Medical Centre; Sungkyunkwan University School of Medicine; Seoul Korea
| | - Ryoji Kushima
- Department of Pathology, Undergraduate School of Medicine; Shiga University of Medical Science; Shiga Japan
| | - Michael Van Vrancken
- Department of Pathology and Laboratory Medicine; Tulane University School of Medicine; New Orleans LA USA
| | - Min Jung Kim
- Cancer Research Institute; Seoul National University College of Medicine; Seoul Korea
| | - Changho Park
- Department of Biomedical Science; Seoul National University Graduate School; Seoul Korea
| | - Ha Young Park
- Department of Biomedical Science; Seoul National University Graduate School; Seoul Korea
- Department of Pathology and Translational Genomics, Samsung Medical Centre; Sungkyunkwan University School of Medicine; Seoul Korea
| | - Jeesoo Chae
- Department of Biomedical Science; Seoul National University Graduate School; Seoul Korea
| | - Se Song Jang
- Department of Biomedical Science; Seoul National University Graduate School; Seoul Korea
| | - Sung Jin Kim
- Samsung Biomedical Research Institute; Samsung Medical Centre; Seoul Korea
| | - Young-Ho Kim
- Department of Medicine, Samsung Medical Centre; Sungkyunkwan University School of Medicine; Seoul Korea
| | - Jong-Il Kim
- Department of Biomedical Science; Seoul National University Graduate School; Seoul Korea
- Cancer Research Institute; Seoul National University College of Medicine; Seoul Korea
- Genomic Medicine Institute, Medical Research Centre; Seoul National University; Seoul Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Centre; Sungkyunkwan University School of Medicine; Seoul Korea
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Zauber P, Marotta SP, Sabbath-Solitare M. GNAS gene mutation may be present only transiently during colorectal tumorigenesis. INTERNATIONAL JOURNAL OF MOLECULAR EPIDEMIOLOGY AND GENETICS 2016; 7:24-31. [PMID: 27186325 PMCID: PMC4858613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Accepted: 02/29/2016] [Indexed: 06/05/2023]
Abstract
Mutations of the gene GNAS have been shown to activate the adenylate cyclase gene and lead to constitutive cAMP signaling. Several preliminary reports have suggested a role for GNAS gene mutations during colorectal carcinogenesis, particularly mucinous carcinomas. The aim of this study was to clarify the incidence of GNAS mutations in adenomas (tubular, tubulovillous, and villous), carcinomas with residual adenoma, and carcinomas, and to relate these findings to mutations of the KRAS gene and to the mucinous status of the tumors. We used standard PCR techniques and direct gene sequencing to evaluate tumors for gene mutations. No GNAS mutations were identified in 25 tubular adenomas, but were present in 6.4% of tubulovillous adenomas and 11.2% of villous adenomas. A GNAS mutation was found in 9.7% of the benign portion of carcinoma with residual adenoma, but in none of 86 carcinomas. A similar trend was seen for KRAS mutation across the five groups of tumors. GNAS mutations may function as an important driver mutation during certain phases of colorectal carcinogenesis, but may then be lost once the biological advantage gained by the mutated gene is no longer necessary to sustain or advance tumor development.
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Affiliation(s)
- Peter Zauber
- Department of Medicine, Saint Barnabas Medical Center100 Old Short Hills Road, Livingston, NJ 07039, USA
| | - Stephen P Marotta
- Department of Pathology, Saint Barnabas Medical Center100 Old Short Hills Road, Livingston, NJ 07039, USA
| | - Marlene Sabbath-Solitare
- Department of Pathology, Saint Barnabas Medical Center100 Old Short Hills Road, Livingston, NJ 07039, USA
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32
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Fu DG. Epigenetic alterations in gastric cancer (Review). Mol Med Rep 2015; 12:3223-3230. [PMID: 25997695 PMCID: PMC4526033 DOI: 10.3892/mmr.2015.3816] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Accepted: 05/22/2015] [Indexed: 12/21/2022] Open
Abstract
Gastric cancer is one of the most common types of cancer and the second most common cause of cancer-related mortality worldwide. An increasing number of recent studies have confirmed that gastric cancer is a multistage pathological state that arises from environmental factors; dietary factors in particulary are considered to play an important role in the etiology of gastric cancer. Improper dietary habits are one of the primary concerns as they influence key molecular events associated with the onset of gastric carcinogenesis. In the field of genetics, anticancer research has mainly focused on the various genetic markers and genetic molecular mechanisms responsible for the development of this of this disease. Some of this research has proven to be very fruitful, providing insight into the possible mechamisms repsonsible for this disease and into possible treatment modalities. However, the mortality rate associated with gastric cancer remains relatively high. Thus, epigenetics has become a hot topic for research, whereby genetic markers are bypassed and this research is directed towards reversible epigenetic events, such as methylation and histone modifications that play a crucial role in carcinogenesis. The present review focuses on the epigenetic events which play an important role in the development and progression of this deadly disease, gastric cancer.
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Affiliation(s)
- Du-Guan Fu
- Department of Cardiology, Xiangyang Hospital Affiliated to Hubei University of Medicine, Xiangyang, Hubei 441000, P.R. China
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33
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Hashimoto T, Ogawa R, Matsubara A, Taniguchi H, Sugano K, Ushiama M, Yoshida T, Kanai Y, Sekine S. Familial adenomatous polyposis-associated and sporadic pyloric gland adenomas of the upper gastrointestinal tract share common genetic features. Histopathology 2015; 67:689-98. [PMID: 25832318 DOI: 10.1111/his.12705] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2015] [Accepted: 03/27/2015] [Indexed: 12/29/2022]
Abstract
AIMS Familial adenomatous polyposis (FAP) is a hereditary cancer predisposition syndrome caused by a germline APC mutation. A recent study showed the enrichment of pyloric gland adenomas (PGAs) of the stomach, in addition to fundic gland polyps (FGPs) and foveolar-type adenomas (FAs), in patients with FAP. In the present study, we analysed the genetic alterations in these FAP-associated gastric lesions. METHODS AND RESULTS Mutational statuses of GNAS and KRAS, which are frequently mutated in sporadic PGAs, as well as those of APC, were examined in PGAs, FAs and FGPs in patients with FAP using Sanger sequencing. Our analysis identified GNAS mutations in five of six PGAs (83%), but in none of the three FAs or the 40 FGPs examined. KRAS mutations were identified in four PGAs (67%), one FA (33%) and one FGP (3%). Somatic truncating APC mutations were found in all PGAs (100%), two FAs (67%) and 14 FGPs (47%). We additionally analysed sporadic PGAs of the stomach and duodenum and identified truncating APC mutations in 11 of 25 lesions (44%). CONCLUSIONS FAP-associated and sporadic PGAs not only show similar morphologies, but also share common genetic aberrations, including mutations of GNAS, KRAS and APC.
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Affiliation(s)
- Taiki Hashimoto
- Division of Pathology and Clinical Laboratory, National Cancer Center Hospital, Tokyo, Japan
| | - Reiko Ogawa
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Akiko Matsubara
- Division of Pathology and Clinical Laboratory, National Cancer Center Hospital, Tokyo, Japan
| | - Hirokazu Taniguchi
- Division of Pathology and Clinical Laboratory, National Cancer Center Hospital, Tokyo, Japan
| | - Kokichi Sugano
- Oncogene Research Unit/Cancer Prevention Unit, Tochigi Cancer Center Research Institute, Tochigi, Japan
| | - Mineko Ushiama
- Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan
| | - Teruhiko Yoshida
- Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan
| | - Yae Kanai
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Shigeki Sekine
- Division of Pathology and Clinical Laboratory, National Cancer Center Hospital, Tokyo, Japan.,Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
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Inada R, Sekine S, Taniguchi H, Tsuda H, Katai H, Fujiwara T, Kushima R. ARID1A expression in gastric adenocarcinoma: Clinicopathological significance and correlation with DNA mismatch repair status. World J Gastroenterol 2015; 21:2159-2168. [PMID: 25717252 PMCID: PMC4326154 DOI: 10.3748/wjg.v21.i7.2159] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2014] [Revised: 08/30/2014] [Accepted: 09/30/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To analyze the mismatch repair (MMR) status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.
METHODS: We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas. The results were further correlated with clinicopathological variables.
RESULTS: The loss of any MMR protein expression, indicative of MMR deficiency, was observed in 38 cases (7.8%) and was significantly associated with an older age (68.6 ± 9.2 vs 60.4 ± 11.7, P < 0.001), a female sex (55.3% vs 31.3%, P = 0.004), an antral location (44.7% vs 25.7%, P = 0.021), and a differentiated histology (57.9% vs 39.7%, P = 0.023). Abnormal ARID1A expression, including reduced or loss of ARID1A expression, was observed in 109 cases (22.3%) and was significantly correlated with lymphatic invasion (80.7% vs 69.5%, P = 0.022) and lymph node metastasis (83.5% vs 73.7%, P = 0.042). The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency (47.4% vs 20.2%, P < 0.001). A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor (HR = 1.36, 95%CI: 1.01-1.84; P = 0.040).
CONCLUSION: Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion, lymph node metastasis, poor prognosis, and MMR deficiency in gastric adenocarcinomas.
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Lee JH, Kim DK. Microsatellite Instability of Nuclear and Mitochondrial DNAs in Gastric Carcinogenesis. Asian Pac J Cancer Prev 2014. [DOI: 10.7314/apjcp.2014.15.19.8027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
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Komatsu S, Ichikawa D, Hirajima S, Nagata H, Nishimura Y, Kawaguchi T, Miyamae M, Okajima W, Ohashi T, Konishi H, Shiozaki A, Fujiwara H, Okamoto K, Tsuda H, Imoto I, Inazawa J, Otsuji E. Overexpression of SMYD2 contributes to malignant outcome in gastric cancer. Br J Cancer 2014; 112:357-64. [PMID: 25321194 PMCID: PMC4453442 DOI: 10.1038/bjc.2014.543] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Revised: 09/01/2014] [Accepted: 09/18/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND SET and MYND domain-containing protein 2 (SMYD2) is a lysine methyltransferase for histone H3, p53 and Rb and inhibits their transactivation activities. In this study, we tested whether SMYD2 (1q42) acts as a cancer-promoting factor by being overexpressed in gastric cancer. METHODS We analysed 7 gastric cancer cell lines and 147 primary tumor samples of gastric cancer, which were curatively resected in our hospital. RESULTS SET and MYND domain-containing protein 2 was detected in these cell lines (five out of seven cell lines; 71.4%) and primary tumor samples (fifty-six out of one hundred and forty-seven cases; 38.1%). Knockdown of SMYD2 using specific small interfering RNA inhibited proliferation, migration and invasion of SMYD2-overexpressing cells in a TP53 mutation-independent manner. Overexpression of SMYD2 protein correlated with larger tumor size, more aggressive lymphatic invasion, deeper tumor invasion and higher rates of lymph node metastasis and recurrence. Patients with SMYD2-overexpressing tumours had a worse overall rate of survival than those with non-expressing tumours (P=0.0073, log-rank test) in an intensity and proportion score-dependent manner. Moreover, multivariate analysis demonstrated that SMYD2 was independently associated with worse outcome (P=0.0021, hazard ratio 4.25 (1.69-10.7)). CONCLUSIONS These findings suggest that SMYD2 has a crucial role in tumor cell proliferation by its overexpression and highlight its usefulness as a prognostic factor and potential therapeutic target in gastric cancer.
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Affiliation(s)
- S Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - D Ichikawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - S Hirajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - H Nagata
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - Y Nishimura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - T Kawaguchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - M Miyamae
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - W Okajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - T Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - H Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - A Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - H Fujiwara
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - K Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
| | - H Tsuda
- Department of Pathology, National Cancer Center Hospital, Tokyo 104-0045, Japan
| | - I Imoto
- Department of Human Genetics, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8505, Japan
| | - J Inazawa
- Department of Molecular Cytogenetics, Medical Research Institute and School of Biomedical Science, Tokyo Medical and Dental University, Tokyo 113-5810, Japan
| | - E Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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Shi J, Qu YP, Hou P. Pathogenetic mechanisms in gastric cancer. World J Gastroenterol 2014; 20:13804-13819. [PMID: 25320518 PMCID: PMC4194564 DOI: 10.3748/wjg.v20.i38.13804] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 01/15/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is a major public health issue as the fourth most common cancer and the second leading cause of cancer-related death. Recent advances have improved our understanding of its molecular pathogenesis, as best exemplified by elucidating the fundamental role of several major signaling pathways and related molecular derangements. Central to these mechanisms are the genetic and epigenetic alterations in these signaling pathways, such as gene mutations, copy number variants, aberrant gene methylation and histone modification, nucleosome positioning, and microRNAs. Some of these genetic/epigenetic alterations represent effective diagnostic and prognostic biomarkers and therapeutic targets for GC. This information has now opened unprecedented opportunities for better understanding of the molecular mechanisms of gastric carcinogenesis and the development of novel therapeutic strategies for this cancer. The pathogenetic mechanisms of GC are the focus of this review.
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Palacio-Rúa KA, Isaza-Jiménez LF, Ahumada-Rodríguez E, Muñetón-Peña CM. Genetic analysis in APC, KRAS, and TP53 in patients with stomach and colon cancer. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2014; 79:79-89. [PMID: 24861525 DOI: 10.1016/j.rgmx.2014.05.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2013] [Accepted: 03/10/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND Stomach cancer (SC) and colorectal cancer (CRC) present with high rates of incidence and mortality in the worldwide population. These 2 tumors are characterized by great genetic heterogeneity. Up to now, there have been no molecular studies that analyze the mutations in the APC, KRAS, and TP53 genes in the Colombian/Latin American population. OBJECTIVES To analyze mutations in the APC, KRAS, and TP53 genes through direct sequencing in 59 patients with SC and CRC. PATIENTS AND METHODS Twenty-nine patients with SC and 30 with CRC were studied. An analysis of the mutations of the 3 genes was carried out using polymerase chain reaction and direct sequencing techniques. RESULTS A 30.5% total mutation frequency was found. The most frequently mutated gene was APC (15.3%), followed by KRAS (10.1%) and TP53 (5.1%). The CRC samples had a mutation frequency of 46.7% and it was 13.3% in the SC samples (P=.006). No mutations occurred simultaneously in the 3 genes. Mutations in 2 genes were found in only 6 tumor samples (10%). There was also a high frequency of polymorphisms in both types of cancer, the most common of which was the rs41115 polymorphism, located on the APC gene. CONCLUSION The APC, KRAS, and TP53 gene mutations were more common in CRC than in SC. Our results suggest the existence of different genetic pathways in the carcinogenesis of SC and CRC and they also reveal a particular mutation frequency in the Colombian patients studied; this could be influenced by factors related to the environment, ethnicity, and lifestyle of this population.
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Affiliation(s)
- K A Palacio-Rúa
- Unidad de Genética Médica, Departamento de Pediatría, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
| | - L F Isaza-Jiménez
- Departamento de Cirugía, Facultad de Medicina, Universidad de Antioquia, Hospital San Vicente de Paúl, Medellín, Colombia
| | - E Ahumada-Rodríguez
- Departamento de Patología, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
| | - C M Muñetón-Peña
- Unidad de Genética Médica, Departamento de Pediatría, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.
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Genetic analysis in APC, KRAS, and TP53 in patients with stomach and colon cancer. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2014. [DOI: 10.1016/j.rgmxen.2014.06.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Farinati F, Cardin R, Piciocchi M, Rodríguez-Castro K, Maddalo G, Rugge M. Helicobacter pylori Infection – The Link Between Oxidative Damage, Cell Proliferation, Apoptosis, and Gastric Cancer. SYSTEMS BIOLOGY OF FREE RADICALS AND ANTIOXIDANTS 2014:1871-1891. [DOI: 10.1007/978-3-642-30018-9_211] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Jang BG, Lee BL, Kim WH. Distribution of LGR5+ cells and associated implications during the early stage of gastric tumorigenesis. PLoS One 2013; 8:e82390. [PMID: 24340024 PMCID: PMC3858308 DOI: 10.1371/journal.pone.0082390] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2013] [Accepted: 11/01/2013] [Indexed: 12/30/2022] Open
Abstract
Lgr5 was identified as a promising gastrointestinal tract stem cell marker in mice. Lineage tracing indicates that Lgr5+ cells may not only be the cells responsible for the origin of tumors; they may also be the so-called cancer stem cells. In the present study, we investigated the presence of Lgr5+ cells and their biological significance in normal human gastric mucosa and gastric tumors. RNAscope, a newly developed RNA in situ hybridization technique, specifically labeled Lgr5+ cells at the basal glands of the gastric antrum. Notably, the number of Lgr5+ cells was remarkably increased in intestinal metaplasia. In total, 76% of gastric adenomas and 43% of early gastric carcinomas were positive for LGR5. Lgr5+ cells were found more frequently in low-grade tumors with active Wnt signaling and an intestinal gland type, suggesting that LGR5 is likely involved in the very early stages of Wnt-driven tumorigenesis in the stomach. Interestingly, similar to stem cells in normal tissues, Lgr5+ cells were often restricted to the base of the tumor glands, and such Lgr5+ restriction was associated with high levels of intestinal stem cell markers such as EPHB2, OLFM4, and ASCL2. Thus, our findings show that Lgr5+ cells are present at the base of the antral glands in the human stomach and that this cell population significantly expands in intestinal metaplasias. Furthermore, Lgr5+ cells are seen in a large number of gastric tumors ; their frequent basal arrangements and coexpression of ISC markers support the idea that Lgr5+ cells act as stem cells during the early stage of intestinal-type gastric tumorigenesis.
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Affiliation(s)
- Bo Gun Jang
- Department of Pathology, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea
| | - Byung Lan Lee
- Department of Anatomy, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea
| | - Woo Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Jongno-gu, Seoul, Korea
- * E-mail:
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Hidaka Y, Mitomi H, Saito T, Takahashi M, Lee SY, Matsumoto K, Yao T, Watanabe S. Alteration in the Wnt/β-catenin signaling pathway in gastric neoplasias of fundic gland (chief cell predominant) type. Hum Pathol 2013; 44:2438-48. [PMID: 24011952 DOI: 10.1016/j.humpath.2013.06.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 06/04/2013] [Accepted: 06/12/2013] [Indexed: 12/13/2022]
Abstract
Gastric neoplasia of chief cell-predominant type (GN-CCP) has been reported as a new, rare variant of gastric tumor. GN-CCPs were defined as tumors consisting of irregular anastomosing glands of columnar cells mimicking chief cells of fundic gland with nuclear atypia and prolapse-type submucosal involvement. We comparatively evaluated clinicopathologic features between 31 GN-CCPs and 130 cases of conventional gastric adenocarcinoma invading into submucosa (CGA-SM) in addition to nuclear β-catenin immunolabeling and direct sequencing of members of the Wnt/β-catenin pathway, CTNNB1, APC, and AXIN, in a subset of these tumors. GN-CCP presented as small protruded lesions located in the upper third of the stomach, with minimal involvement into the submucosa and rare lymphovascular invasion. None of the lesions have demonstrated a recurrence of disease or metastasis on follow-up. Nuclear β-catenin immunolabeling was higher in GN-CCP (labeling index [LI]: median, 19.3%; high expresser [LI >30%], 7/27 cases [26%]) than CGA-SM (median LI, 14.7%; high expresser, 1/19 cases [6%]). Missense mutation of APC was observed in 1 GN-CCP but not CGA-SM. Missense or nonsense mutations of CTNNB1 and AXIN1 were higher in GN-CCPs (14.8%, both) than CGA-SMs (5.3%, both). Missense mutations of AXIN2 were higher in GN-CCPs (25.9%) than in CGA-SMs (10.5%). Overall, 14 (51.9%) of 27 GN-CCPs and 5 (26.3%) of 19 CGA-SM cases harbored at least 1 of these gene mutations. In conclusion, GN-CCPs as a unique variant of nonaggressive tumor are characterized by nuclear β-catenin accumulation and mutation of CTNNB1 or AXIN gene, suggesting activation of the Wnt/β-catenin pathway.
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Affiliation(s)
- Yasuhiro Hidaka
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Department of Human Pathology, Juntendo University School of Medicine, 1-1-19 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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Rugge M, Capelle LG, Cappellesso R, Nitti D, Kuipers EJ. Precancerous lesions in the stomach: from biology to clinical patient management. Best Pract Res Clin Gastroenterol 2013; 27:205-23. [PMID: 23809241 DOI: 10.1016/j.bpg.2012.12.007] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Accepted: 12/27/2012] [Indexed: 02/07/2023]
Abstract
Gastric cancer is the final step in a multi-stage cascade triggered by long-standing inflammatory conditions (particularly Helicobacter pylori infection) resulting in atrophic gastritis and intestinal metaplasia: these lesions represent the cancerization field in which (intestinal-type) gastric cancer develops. Intraepithelial neoplasia is consistently recognized as the phenotypic bridge between atrophic/metaplastic lesions and invasive cancer. This paper addresses the epidemiology, pathology, molecular profiling, and clinical management of advanced precancerous gastric lesions.
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Affiliation(s)
- Massimo Rugge
- Department of Medicine - DIMED, Surgical Pathology & Cytopathology Unit, University of Padova, Padova, Italy.
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Abstract
Helicobacter pylori infection leads to long-lasting chronic inflammation and represents the most common risk factor underlying gastric cancer. Recently, new insights into the mechanisms through which H. pylori and mucosal inflammation lead to cancer development have emerged. H. pylori virulence factors, in particular specific CagA genotypes, represent main factors in gastric cancer, inducing altered intracellular signaling in epithelial cells. The chronic nature of H. pylori infection appears to relate to the VacA virulence factor and Th17/Treg mechanisms. A role of H. pylori infection in epigenetic and microRNA deregulation has been shown. Mutation of the epithelial cell genome, a hallmark of cancer, was demonstrated to accumulate in H. pylori infected stomach partly due to inadequate DNA repair. Gastric stem cells were shown to be targets of oxidative injury in the Helicobacter-inflammatory milieu. Recent advances emphasizing the contribution of bacterial factors, inflammatory mediators, and the host epithelial response in gastric carcinogenesis are reviewed.
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45
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Nishimura Y, Komatsu S, Ichikawa D, Nagata H, Hirajima S, Takeshita H, Kawaguchi T, Arita T, Konishi H, Kashimoto K, Shiozaki A, Fujiwara H, Okamoto K, Tsuda H, Otsuji E. Overexpression of YWHAZ relates to tumor cell proliferation and malignant outcome of gastric carcinoma. Br J Cancer 2013; 108:1324-31. [PMID: 23422756 PMCID: PMC3619260 DOI: 10.1038/bjc.2013.65] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Several studies have demonstrated that YWHAZ (14-3-3ζ), included in the 14-3-3 family of proteins, has been implicated in the initiation and progression of cancers. We tested whether YWHAZ acted as a cancer-promoting gene through its activation/overexpression in gastric cancer (GC). METHODS We analysed 7 GC cell lines and 141 primary tumours, which were curatively resected in our hospital between 2001 and 2003. RESULTS Overexpression of the YWHAZ protein was frequently detected in GC cell lines (six out of seven lines, 85.7%) and primary tumour samples of GC (72 out of 141 cases, 51%), and significantly correlated with larger tumour size, venous and lymphatic invasion, deeper tumour depth, and higher pathological stage and recurrence rate. Patients with YWHAZ-overexpressing tumours had worse overall survival rates than those with non-expressing tumours in both intensity and proportion expression-dependent manner. YWHAZ positivity was independently associated with a worse outcome in multivariate analysis (P=0.0491, hazard ratio 2.3 (1.003-5.304)). Knockdown of YWHAZ expression using several specific siRNAs inhibited the proliferation, migration, and invasion of YWHAZ-overexpressing GC cells. Higher expression of the YWHAZ protein was significantly associated with the lower expression of miR-375 in primary GC tissues (P=0.0047). CONCLUSION These findings suggest that YWHAZ has a pivotal role in tumour cell proliferation through its overexpression, and highlight its usefulness as a prognostic factor and potential therapeutic target in GC.
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Affiliation(s)
- Y Nishimura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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Matsubara A, Sekine S, Kushima R, Ogawa R, Taniguchi H, Tsuda H, Kanai Y. Frequent GNAS and KRAS mutations in pyloric gland adenoma of the stomach and duodenum. J Pathol 2013. [PMID: 23208952 DOI: 10.1002/path.4153] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Gastric and duodenal adenomas exhibit a significant morphological and phenotypical diversity and are classified into intestinal-type, foveolar-type and pyloric gland adenomas. We analysed the mutations in GNAS, KRAS, BRAF and CTNNB1 and the expressions of mismatch repair (MMR) proteins in 80 gastric and 32 duodenal adenomas with histologically distinct subtypes, as well as in 71 gastric adenocarcinomas. Activating GNAS mutations were found in 22 of the 35 pyloric gland adenomas (PGAs; 63%) but in none of the foveolar-type or intestinal-type adenomas or the adenocarcinomas. Fourteen PGAs (41%), two foveolar-type adenomas (9%), five intestinal-type adenomas (9%) and one adenocarcinoma (1%) had KRAS mutations. BRAF mutations were absent in all the adenomas and adenocarcinomas that were examined. CTNNB1 mutations were only found in two intestinal-type adenomas (4%). Notably, 13 of the 14 KRAS-mutated gastric and duodenal PGAs had concurrent GNAS mutations. The loss of the MMR proteins, which is indicative of microsatellite instability, was observed in one PGA (3%), 12 foveolar-type adenomas (52%), one intestinal-type adenoma (2%) and five adenocarcinomas (7%). These observations indicate that each histological subtype of gastric and duodenal adenomas has a distinct genetic background. In particular, the present study identified the frequent presence of activating GNAS mutations, which are often associated with KRAS mutations, as a characteristic genetic feature of PGAs of the stomach and duodenum.
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Affiliation(s)
- Akiko Matsubara
- Pathology and Clinical Laboratories, National Cancer Centre Hospital, Tokyo, Japan
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Park JS, Hong SJ, Han JP, Kang MS, Kim HK, Kwak JJ, Ko BM, Cho JY, Lee JS, Lee MS. Early-stage gastric cancers represented as dysplasia in a previous forceps biopsy: the importance of clinical management. Dig Liver Dis 2013; 45:170-5. [PMID: 23102499 DOI: 10.1016/j.dld.2012.09.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2012] [Revised: 08/21/2012] [Accepted: 09/23/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Because histological examination of gastric lesions by forceps biopsy is of limited accuracy, management on the basis of histological results is occasionally controversial. We examined the characteristics of early gastric cancers that presented as dysplasia resulting from a previous forceps biopsy. PATIENTS AND METHODS Between April 2007 and December 2010, 341 gastric adenocarcinoma lesions from 330 patients previously diagnosed histologically via endoscopic submucosal dissection were examined. We retrospectively assessed the characteristics of early gastric cancer according to their initial forceps biopsy results. RESULTS In total, 183 EGCs were diagnosed as dysplasia (53.7%; 89 low-grade and 94 high-grade) and 158 (46.3%) as carcinoma by forceps biopsy before endoscopic submucosal dissection. Significant differences were noted with respect to histologic differentiation of carcinomas, Lauren histologic type, depth of invasion, lymphovascular invasion, and en bloc resection between the dysplastic group and carcinoma group, based on forceps biopsy results. CONCLUSION A forceps biopsy result is not fully representative of the entire lesion and, thus, endoscopic submucosal dissection should be considered for lesions diagnosed as dysplasia via forceps biopsy in order to avoid the risk of missed carcinomas.
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Affiliation(s)
- Jin Seok Park
- Digestive Disease Center, Soonchunhyang University College of Medicine, Bucheon and Seoul, Republic of Korea
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Carneiro F, Lauwers GY. Epithelial Tumours of the Stomach. MORSON AND DAWSON'S GASTROINTESTINAL PATHOLOGY 2013:180-222. [DOI: 10.1002/9781118399668.ch13] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Kashimoto K, Komatsu S, Ichikawa D, Arita T, Konishi H, Nagata H, Takeshita H, Nishimura Y, Hirajima S, Kawaguchi T, Shiozaki A, Fujiwara H, Okamoto K, Tsuda H, Otsuji E. Overexpression of TRIM44 contributes to malignant outcome in gastric carcinoma. Cancer Sci 2012; 103:2021-6. [PMID: 22862969 DOI: 10.1111/j.1349-7006.2012.02407.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2012] [Revised: 07/30/2012] [Accepted: 07/31/2012] [Indexed: 12/21/2022] Open
Abstract
Recent studies have shown that some members of the tripartite motif-containing protein (TRIM) family, which is characterized by a conserved RING finger, B-box, and coiled-coil domains, function as important regulators for carcinogenesis. In this study, we tested whether TRIM44 (11p13) acts as a cancer-promoting gene through overexpression in gastric cancer. We analyzed seven gastric cancer cell lines and 112 primary tumors, which were curatively resected in our hospital between 2001 and 2003. Expression of the TRIM44 protein was detected in gastric cancer cell lines (2/7 cell lines; 29%) and primary tumor samples of gastric cancer (29/112 cases; 25%). Knockdown of TRIM44 expression using several specific siRNAs inhibited the proliferation, migration, and invasion of TRIM44-overexpressing cells. Overexpression of the TRIM44 protein was significantly correlated with an advanced type of macroscopic appearance, lymphatic invasion, and higher recurrence rate. TRIM44-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors (P = 0.0038, log-rank test) in both intensity and proportion expression-dependent manner. TRIM44 positivity was independently associated with worse outcome in multivariate analysis (P = 0.0233, hazard ratio 3.37 [1.18-9.64]). These findings suggest that TRIM44 plays a crucial role in tumor cell proliferation through its overexpression, and highlight its usefulness as a predictor and potential therapeutic target in gastric cancer.
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Affiliation(s)
- Kingo Kashimoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Nozaki I, Nasu J, Kubo Y, Tanada M, Nishimura R, Kurita A. Risk factors for metachronous gastric cancer in the remnant stomach after early cancer surgery. World J Surg 2011; 34:1548-54. [PMID: 20217411 DOI: 10.1007/s00268-010-0518-0] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Early gastric cancer patients have a good prognosis after radical resection. However, if the patients have a gastric remnant after the surgery, the risk of metachronous gastric cancer remains. The aim of this study was to clarify the risk factors for metachronous gastric cancer after partial gastrectomy for early gastric cancer. METHODS Data on a series of 1281 consecutive gastrectomy patients with pathologically confirmed early gastric cancer from 1991 to 2007 in Shikoku Cancer Center were analyzed retrospectively. RESULTS The gastric remnants of 868 patients were periodically surveyed by endoscopic examination. Among those surveyed cases, 26 patients were diagnosed as having metachronous gastric cancer in the gastric remnant. They underwent curative resection by remnant gastrectomy (n = 13 patients) or endoscopic mucosal resection (n = 13 patients). Multivariate analysis showed that male sex, older age, submucosal invasion, and proximal gastrectomy were independent risk factors. CONCLUSIONS Our data suggested that more intensive endoscopic follow-up is needed for the remnant stomach in patients with these risk factors to detect metachronous gastric cancer at its early stage.
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Affiliation(s)
- Isao Nozaki
- Department of Surgery, Division of Gastroenterology, National Hospital Organization, Shikoku Cancer Center, 160 Minami-umemoto, Matsuyama, 791-0280, Japan.
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