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Shaikh DH, Park M, Chen J, Huang J, Friedman MS, Dam AN, Luthra AK, Cappelle S, Pena LR, Permuth JB, Mok SRS. Differences in Gender and Overall Survival for Temperature-Sensitive TP53 Mutations in Gastroesophageal Cancer. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:1901. [PMID: 39597086 PMCID: PMC11597060 DOI: 10.3390/medicina60111901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 11/10/2024] [Accepted: 11/14/2024] [Indexed: 11/29/2024]
Abstract
Background and Objectives: Temperature-sensitive (TS) mutants of TP53 are thermally unstable, unfolded, and inactive at body temperature but can be refolded and reactivated at sub-physiological temperatures. TS TP53 may be amenable for functional rescue by hypothermia or structure-stabilizing drugs, and may retain low-level transcriptional activity at 37 °C. TP53 mutations are observed in 47% of all esophageal cancers (ECs) and 25% to 40% of gastric cancers (GCs). We aimed to investigate the trends and outcomes of EC and GC with TS TP53 mutations using cBioportal. We hypothesize that TS TP53 mutants in EC and GC present a unique prognostic profile distinct from non-TS TP53 mutants, potentially affecting overall survival and cancer progression. Materials and Methods: We identified 1924 patients from cBioportal with GC or EC, harboring any TP53 mutation. Patients were then stratified based on the TP53 temperature sensitivity according to a recently reported functional analysis of its activity. Patients were also stratified based on a history of Barrett's esophagus (BE), cancer stage, sex, and race. We then compared populations (TS vs. non-TS TP53) to assess differences and evaluated survival outcomes. Results: Males represented 77% of the cohort, and 51.6% of the samples were from patients with stage IV cancer. No association was found between TS vs. non-TS mutational status and BE, cancer stage, or race. Interestingly, a significantly higher proportion of females (22.9%) than males (14.5%) displayed a TS TP53 mutation (p = 0.012). No significant difference was seen in overall survival between the TS and non-TS mutations capable of ≥50% growth suppression at 32 °C (median = 33 vs. 28 months, p = 0.36). This trend was also observed when the patients were filtered based on cancer location. The median survival for EC was 32.5 months compared to 33 months (p = 0.67). In cases of GC, median survival times could not be determined due to the insufficient number of events. Conclusions: Although no statistical significance was observed, a decrease in overall survival for patients with TS TP53 mutations was noted. The result is counterintuitive given that TS mutants have less severe structural destabilization and suggests TS TP53 mutations may have a unique prognostic value that warrants further investigation.
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Affiliation(s)
- Danial H. Shaikh
- Department of GI Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Margaret Park
- Department of GI Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
- Department of Bioinformatics and Biostatistics, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Jiandong Chen
- Molecular Oncology Department, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Jeffrey Huang
- Department of Anesthesiology & HOB, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Mark S. Friedman
- Department of GI Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Aamir N. Dam
- Department of GI Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Anjuli K. Luthra
- Department of GI Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
| | | | - Luis R. Pena
- Department of GI Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Jennifer B. Permuth
- Department of GI Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
- Department of Bioinformatics and Biostatistics, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Shaffer R. S. Mok
- Department of GI Oncology, Moffitt Cancer Center, Tampa, FL 33612, USA
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Zhu E, Xie Q, Huang X, Zhang Z. Application of spatial omics in gastric cancer. Pathol Res Pract 2024; 262:155503. [PMID: 39128411 DOI: 10.1016/j.prp.2024.155503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 07/25/2024] [Accepted: 07/27/2024] [Indexed: 08/13/2024]
Abstract
Gastric cancer (GC), a globally prevalent and lethal malignancy, continues to be a key research focus. However, due to its considerable heterogeneity and complex pathogenesis, the treatment and diagnosis of gastric cancer still face significant challenges. With the rapid development of spatial omics technology, which provides insights into the spatial information within tumor tissues, it has emerged as a significant tool in gastric cancer research. This technology affords new insights into the pathology and molecular biology of gastric cancer for scientists. This review discusses recent advances in spatial omics technology for gastric cancer research, highlighting its applications in the tumor microenvironment (TME), tumor heterogeneity, tumor genesis and development mechanisms, and the identification of potential biomarkers and therapeutic targets. Moreover, this article highlights spatial omics' potential in precision medicine and summarizes existing challenges and future directions. It anticipates spatial omics' continuing impact on gastric cancer research, aiming to improve diagnostic and therapeutic approaches for patients. With this review, we aim to offer a comprehensive overview to scientists and clinicians in gastric cancer research, motivating further exploration and utilization of spatial omics technology. Our goal is to improve patient outcomes, including survival rates and quality of life.
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Affiliation(s)
- Erran Zhu
- Department of Clinical Medicine, Grade 20, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Qi Xie
- Department of Clinical Medicine, Grade 20, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Xinqi Huang
- Excellent Class, Clinical Medicine, Grade 20, Hengyang Medical College, University of South China, Hengyang, Hunan, 421001, China
| | - Zhiwei Zhang
- Cancer Research Institute of Hengyang Medical College, University of South China; Key Laboratory of Cancer Cellular and Molecular Pathology of Hunan; Department of Pathology, Department of Pathology of Hengyang Medical College, University of South China; The First Affiliated Hospital of University of South China, China.
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3
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Li F, Wang Y, Ping X, Yin JC, Wang F, Zhang X, Li X, Zhai J, Shen L. Molecular evolution of intestinal-type early gastric cancer according to Correa cascade. J Biomed Res 2024; 38:1-16. [PMID: 39314047 DOI: 10.7555/jbr.38.20240118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/25/2024] Open
Abstract
Early screening is crucial for the prevention of intestinal-type gastric cancer. The objective of the current study was to ascertain molecular evolution of intestinal-type gastric cancer according to the Correa cascade for the precise gastric cancer screening. We collected sequential lesions of the Correa cascade in the formalin-fixed and paraffin-embedded endoscopic submucosal dissection-resected specimens from 14 Chinese patients by microdissection, and subsequently determined the profiles of somatic aberrations during gastric carcinogenesis using the whole exome sequencing, identifying multiple variants at different Correa stages. The results showed that TP53, PCLO, and PRKDC were the most frequently mutated genes in the early gastric cancer (EGC). A high frequency of TP53 alterations was found in low-grade intraepithelial neoplasia (LGIN), which further increased in high-grade intraepithelial neoplasia (HGIN) and EGC. Intestinal metaplasia (IM) had no significant correlation with EGC in terms of mutational spectra, whereas both LGIN and HGIN showed higher genomic similarities to EGC, compared with IM. Based on Jaccard similarity coefficients, three evolutionary models were further constructed, and most patients showed linear progression from LGIN to HGIN, ultimately resulting in EGC. The ECM-receptor interaction pathway was revealed to be involved in the linear evolution. Additionally, the retrospective validation study of 39 patients diagnosed with LGIN indicated that PRKDC mutations, in addition to TP53 mutations, may drive LGIN progression to HGIN or EGC. In conclusion, the current study unveils the genomic evolution across the Correa cascade of intestinal-type gastric cancer, elucidates the underlying molecular mechanisms of gastric carcinogenesis, and provides some evidence for potential personalized gastric cancer surveillance.
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Affiliation(s)
- Fangyuan Li
- Digestive Endoscopy Center, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China
| | - Yaohui Wang
- Department of Pathology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China
| | - Xiaochun Ping
- Department of General Surgery, the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China
| | - Jiani C Yin
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu 210061, China
| | - Fufeng Wang
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu 210061, China
| | - Xian Zhang
- Geneseeq Research Institute, Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu 210061, China
| | - Xiang Li
- Department of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China
| | - Jing Zhai
- Department of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China
| | - Lizong Shen
- Department of General Surgery, the First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210029, China
- Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu 211166, China
- Department of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China
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4
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Li X, Tang Z, Li Z, Li Z, Zhao P, Song Y, Yang K, Xia Z, Wang Y, Guo D. Somatic mutations that affect early genetic progression and immune microenvironment in gastric carcinoma. Pathol Res Pract 2024; 257:155310. [PMID: 38663178 DOI: 10.1016/j.prp.2024.155310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 03/24/2024] [Accepted: 04/12/2024] [Indexed: 05/12/2024]
Abstract
Gastric carcinoma (GC) is a high heterogeneity and malignant tumor with a poor prognosis. The current implementation of immunotherapy in GC is limited due to the insufficient exploration of immune-related mutations and speculated early mutation events. Therefore, we performed whole-exome sequencing on 40 patients with GC to explore their genetic characteristics, shedding light on the order of genetic events, somatic mutations impacting the immune microenvironment, and potential biomarkers for immunotherapy. Regarding genetic events, TP53 disruptions were identified as frequent and early events in GC progression, often occurring alongside other gene mutations. The mutations occurring in GANS, SMAD4, and POLE were early independent events. Patients harboring CSMD3, FAT4, FLG, KMT2C, LRP1B, MUC5B, MUC16, PLEC, RNF43, SYNE1, TP53, TTN, XIRP2, and ZFHX4 mutations tended to have decreased B cells, T cells, macrophage, neutrophil, and dendritic cells infiltration, except for the ARID1A gene mutations. We also found patients with microsatellite instability-high tumors had higher homologous recombination deficiency (HRD) scores. HRD showed a positive correlation with tumor mutational burden, which might serve as indirect evidence supporting the potential of HRD as a biomarker for GC. These findings highlighted GC's high heterogeneity and complexity and provided valuable insights into the somatic mutations that affect early genetic progression and immune microenvironment.
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Affiliation(s)
- Xiaoxiao Li
- Center for GI Cancer Diagnosis and Treatment, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, China
| | - Zirui Tang
- School of Software Engineering, Northeastern University, Shenyang, Liaoning 110169, China; Shenzhen Byoryn Technology Co. Ltd, Shenzhen, China
| | - Zhaopeng Li
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China
| | - Zhao Li
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China
| | - Ping Zhao
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China
| | - Yi Song
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China
| | - Kexin Yang
- Department of Cardiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Zihan Xia
- The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China
| | - Yinan Wang
- Department of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen 518036, China.
| | - Dong Guo
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, China.
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5
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He J, Nascakova Z, Leary P, Papa G, Valenta T, Basler K, Müller A. Inactivation of the tumor suppressor gene Apc synergizes with H. pylori to induce DNA damage in murine gastric stem and progenitor cells. SCIENCE ADVANCES 2023; 9:eadh0322. [PMID: 37967175 PMCID: PMC10651120 DOI: 10.1126/sciadv.adh0322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 10/16/2023] [Indexed: 11/17/2023]
Abstract
Helicobacter pylori infection is a major risk factor for the development of gastric cancer. The bacteria reside in close proximity to gastric surface mucous as well as stem and progenitor cells. Here, we take advantage of wild-type and genetically engineered murine gastric organoids and organoid-derived monolayers to study the cellular targets of H. pylori-induced DNA damage and replication stress and to explore possible interactions with preexisting gastric cancer driver mutations. We find using alkaline comet assay, single-molecule DNA fiber assays, and immunofluorescence microscopy of DNA repair foci that H. pylori induces transcription-dependent DNA damage in actively replicating, Leucine-rich-repeat containing G-Protein-Coupled Receptor 5 (Lgr5)-positive antral stem and progenitor cells and their Troy-positive corpus counterparts, but not in other gastric epithelial lineages. Infection-dependent DNA damage is aggravated by Apc inactivation, but not by Trp53 or Smad4 loss, or Erbb2 overexpression. Our data suggest that H. pylori induces DNA damage in stem and progenitor cells, especially in settings of hyperproliferation due to constitutively active Wnt signaling.
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Affiliation(s)
- Jiazhuo He
- Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland
| | - Zuzana Nascakova
- Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland
| | - Peter Leary
- Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland
- Functional Genomics Center Zürich, University of Zürich/ETHZ, Zürich, Switzerland
| | - Giovanni Papa
- Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland
| | - Tomas Valenta
- Department of Molecular Life Sciences, University of Zürich, Zürich, Switzerland
- Laboratory of Cell and Developmental Biology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
| | - Konrad Basler
- Department of Molecular Life Sciences, University of Zürich, Zürich, Switzerland
- Comprehensive Cancer Center Zürich, Zürich, Switzerland
| | - Anne Müller
- Institute of Molecular Cancer Research, University of Zürich, Zürich, Switzerland
- Comprehensive Cancer Center Zürich, Zürich, Switzerland
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6
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Qiu MZ, Chen Q, Zheng DY, Zhao Q, Wu QN, Zhou ZW, Yang LQ, Luo QY, Sun YT, Lai MY, Yuan SS, Wang FH, Luo HY, Wang F, Li YH, Zhang HZ, Xu RH. Precise microdissection of gastric mixed adeno-neuroendocrine carcinoma dissects its genomic landscape and evolutionary clonal origins. Cell Rep 2023; 42:112576. [PMID: 37285266 DOI: 10.1016/j.celrep.2023.112576] [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: 09/22/2022] [Revised: 03/02/2023] [Accepted: 05/15/2023] [Indexed: 06/09/2023] Open
Abstract
Gastric mixed adenoneuroendocrine carcinoma (MANEC) is a clinically aggressive and heterogeneous tumor composed of adenocarcinoma (ACA) and neuroendocrine carcinoma (NEC). The genomic properties and evolutionary clonal origins of MANEC remain unclear. We conduct whole-exome and multiregional sequencing on 101 samples from 33 patients to elucidate their evolutionary paths. We identify four significantly mutated genes, TP53, RB1, APC, and CTNNB1. MANEC resembles chromosomal instability stomach adenocarcinoma in that whole-genome doubling in MANEC is predominant and occurs earlier than most copy-number losses. All tumors are of monoclonal origin, and NEC components show more aggressive genomic properties than their ACA counterparts. The phylogenetic trees show two tumor divergence patterns, including sequential and parallel divergence. Furthermore, ACA-to-NEC rather than NEC-to-ACA transition is confirmed by immunohistochemistry on 6 biomarkers in ACA- and NEC-dominant regions. These results provide insights into the clonal origin and tumor differentiation of MANEC.
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Affiliation(s)
- Miao-Zhen Qiu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - Qingjian Chen
- Department of Basic Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China; State Key Laboratory of Systems Medicine for Cancer, Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Dan-Yang Zheng
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China; Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong
| | - Qi Zhao
- Department of Basic Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - Qi-Nian Wu
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - Zhi-Wei Zhou
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - Li-Qiong Yang
- Department of Basic Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - Qiu-Yun Luo
- Department of Basic Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - Yu-Ting Sun
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - Ming-Yu Lai
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - Sha-Sha Yuan
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - Feng-Hua Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - Hui-Yan Luo
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - Feng Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - Yu-Hong Li
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - Hui-Zhong Zhang
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China
| | - Rui-Hua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou 510060, P.R. China; Research Unit of Precision Diagnosis and Treatment for Gastrointestinal Cancer, Chinese Academy of Medical Sciences, Guangzhou 510060, P.R. China.
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7
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Akazawa Y, Ueyama H, Hayashi T, Utsunomiya H, Uchida R, Abe D, Oki S, Suzuki N, Ikeda A, Yatagai N, Komori H, Takeda T, Matsumoto K, Ueda K, Matsumoto K, Asaoka D, Hojo M, Saito T, Yao T, Nagahara A. Clinicopathological and molecular characterization of early gastric adenocarcinoma in Helicobacter pylori-uninfected patients: emphasis on differentiated gastric adenocarcinoma. J Gastroenterol 2022; 57:725-734. [PMID: 35939123 DOI: 10.1007/s00535-022-01906-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 07/19/2022] [Indexed: 02/04/2023]
Abstract
BACKGROUND Recently, Helicobacter pylori (HP)-uninfected gastric mucosal cancer has been reported; however, the clinicopathological and molecular features of HP-uninfected gastric cancer have not been elucidated. METHODS We evaluated the clinicopathological, immunohistochemical, and genetic alterations in HP-uninfected early gastric adenocarcinoma using next-generation sequencing (NGS). RESULTS Among 968 primary early gastric carcinomas, 64 (6.6%) were HP-uninfected gastric adenocarcinoma and were pathologically classified as gastric adenocarcinoma of fundic-gland type (GA-FG, n = 39), differentiated gastric adenocarcinoma (DGA, n = 16), and signet-ring cell carcinoma (SRCC, n = 9). Based on the expression profile of the mucin core protein, DGAs were classified into a gastrointestinal phenotype showing either MUC5AC or MUC6 expression and MUC2 or CD10 expression simultaneously (n = 5), and a gastric phenotype (n = 11) showing either MUC5AC or MUC6 expression. All DGAs with a gastrointestinal phenotype shared similar endoscopic characteristics, such as reddish depressed lesions in the antrum. In contrast, DGAs with a gastric phenotype exhibited several distinct endoscopic features, including a raspberry-shaped appearance and whitish flat-elevated appearance; the former expressed only MUC5AC and the latter exhibited co-expression of MUC5AC and MUC6. Among 16 HP-uninfected DGAs, seven were subjected to NGS. APC was recurrently mutated in DGA (42.9%) and was enriched in DGAs with a gastrointestinal phenotype (75%). CONCLUSIONS Overall, HP-uninfected gastric adenocarcinomas showed distinct clinicopathologic and endoscopic characteristics. Furthermore, HP-uninfected DGAs, especially those with a gastrointestinal phenotype, may be characterized by recurrent APC mutations.
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Affiliation(s)
- Yoichi Akazawa
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hiroya Ueyama
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Takuo Hayashi
- Department of Human Pathology, Juntendo University School of Medicine, 1-1-19 Hongo, Bunkyo-Ku, Tokyo, Japan.
| | - Hisanori Utsunomiya
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Ryota Uchida
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Daiki Abe
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Shotaro Oki
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Nobuyuki Suzuki
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Atsushi Ikeda
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Noboru Yatagai
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hiroyuki Komori
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tsutomu Takeda
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Kohei Matsumoto
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Kumiko Ueda
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Kenshi Matsumoto
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Daisuke Asaoka
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Mariko Hojo
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tsuyoshi Saito
- Department of Human Pathology, Juntendo University School of Medicine, 1-1-19 Hongo, Bunkyo-Ku, Tokyo, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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8
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Ghojazadeh M, Somi MH, Naseri A, Salehi-Pourmehr H, Hassannezhad S, Hajikamanaj Olia A, Kafshdouz L, Nikniaz Z. Systematic Review and Meta-analysis of TP53, HER2/ERBB2, KRAS, APC, and PIK3CA Genes Expression Pattern in Gastric Cancer. Middle East J Dig Dis 2022; 14:335-345. [PMID: 36619267 PMCID: PMC9489438 DOI: 10.34172/mejdd.2022.292] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2021] [Accepted: 05/19/2022] [Indexed: 11/06/2022] Open
Abstract
Background: With a global prevalence of about 10%, gastric cancer is among the most prevalent cancers. Currently, there has been an ongoing trend toward investigating genetic disruptions in different cancers because they can be used as a target-specific therapy. We aimed to systemically review some gene expression patterns in gastric cancer. Methods: The current systematic review was designed and executed in 2020. Scopus, PubMed, Cochrane Library, Google Scholar, web of knowledge, and Science Direct were searched for relevant studies. A manual search of articles (hand searching), reference exploring, checking for grey literature, and seeking expert opinion were also done. Results: In this review, 65 studies were included, and the expression pattern of HER2/ ERBB2, ER1/Erb1/EGFR, PIK3CA, APC, KRAS, ARID1A, TP53, FGFR2 and MET was investigated. TP53, APC, KRAS, and PIK3CA mutation cumulative frequency were 24.8 (I2=95.05, Q value=525.53, df=26, P<0.001), 7.2 (I2=89.79, Q value=48.99, df=5, P<0.001), 7.8 (I2=93.60, Q value=140.71, df=9, P=0.001) and 8.6 (I2=80.78, Q value=525.53, df=9, P<0.001) percent, respectively. Overexpression was investigated for HER1/ Erb1/EGFR, PIK3CA, APC, KRAS, ARID1A, TP53, CCND1, FGFR2, MET and MYC. The frequency of TP53 and HER2/ERBB2 were 43.1 (I2=84.06, Q value=58.09, df=9, P<0.001) and 20.8 (I2=93.61, Q value=234.89, df=15, P<0.001) percent, respectively. Conclusion: More research is encouraged to investigate the genes for which we could not perform a meta-analysis.
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Affiliation(s)
- Morteza Ghojazadeh
- Research Center for Evidence-based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hossein Somi
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirreza Naseri
- Aging Research Institute, Tabriz University of Medical Sciences, Tabriz, Iran,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hanieh Salehi-Pourmehr
- Research Center for Evidence-based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sina Hassannezhad
- Research Center for Evidence-based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Arash Hajikamanaj Olia
- Research Center for Evidence-based Medicine, Iranian EBM Centre: A Joanna Briggs Institute (JBI) Center of Excellence, Tabriz University of Medical Sciences, Tabriz, Iran,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Leila Kafshdouz
- Genetic Department, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Zeinab Nikniaz
- Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran,Corresponding Author: Zeinab Nikniaz, PhD Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Tel:+98 4133367473 Fax:+984133367473
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9
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Zhang J, Xiao X, Guo Q, Wei Z, Hua W. Identification of Four Metabolic Subtypes of Glioma Based on Glycolysis-Cholesterol Synthesis Genes. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:9448144. [PMID: 35242216 PMCID: PMC8886743 DOI: 10.1155/2022/9448144] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 01/06/2022] [Accepted: 01/17/2022] [Indexed: 12/21/2022]
Abstract
Based on alterations in gene expression associated with the production of glycolysis and cholesterol, this research classified glioma into prognostic metabolic subgroups. In this study, data from the CGGA325 and The Cancer Genome Atlas (TCGA) datasets were utilized to extract single nucleotide variants (SNVs), RNA-seq expression data, copy number variation data, short insertions and deletions (InDel) mutation data, and clinical follow-up information from glioma patients. Glioma metabolic subtypes were classified using the ConsensusClusterPlus algorithm. This study determined four metabolic subgroups (glycolytic, cholesterogenic, quiescent, and mixed). Cholesterogenic patients had a higher survival chance. Genome-wide investigation revealed that inappropriate amplification of MYC and TERT was associated with improper cholesterol anabolic metabolism. In glioma metabolic subtypes, the mRNA levels of mitochondrial pyruvate carriers 1 and 2 (MPC1/2) presented deletion and amplification, respectively. Differentially upregulated genes in the glycolysis group were related to pathways, including IL-17, HIF-1, and TNF signaling pathways and carbon metabolism. Downregulated genes in the glycolysis group were enriched in terpenoid backbone biosynthesis, nitrogen metabolism, butanoate metabolism, and fatty acid metabolism pathway. Cox analysis of univariate and multivariate survival showed that risks of glycolysis subtypes were significantly higher than other subtypes. Those results were validated in the CGGA325 dataset. The current findings greatly contribute to a comprehensive understanding of glioma and personalized treatment.
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Affiliation(s)
- Jinsen Zhang
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
- Neurosurgical Institute of Fudan University, Shanghai 200040, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
- Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China
| | - Xing Xiao
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
- Neurosurgical Institute of Fudan University, Shanghai 200040, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
- Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China
| | - Qinglong Guo
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
- Neurosurgical Institute of Fudan University, Shanghai 200040, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
- Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China
| | - Zixuan Wei
- Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China
| | - Wei Hua
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai 200040, China
- Neurosurgical Institute of Fudan University, Shanghai 200040, China
- Shanghai Clinical Medical Center of Neurosurgery, Shanghai 200040, China
- Shanghai Key Laboratory of Brain Function and Restoration and Neural Regeneration, Shanghai 200040, China
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10
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Zhu Z, Qin J, Dong C, Yang J, Yang M, Tian J, Zhong X. Identification of four gastric cancer subtypes based on genetic analysis of cholesterogenic and glycolytic pathways. Bioengineered 2021; 12:4780-4793. [PMID: 34346836 PMCID: PMC8806458 DOI: 10.1080/21655979.2021.1956247] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Warburg phenomenon refers to the development of unique metabolic patterns during the growth of tumor cells. This study stratified gastric cancer into prognostic metabolic subgroups according to changes in gene expressions related to glycolysis and cholesterol synthesis. The RNA-seq expression data, single nucleotide variants (SNV), short insertions and deletions (InDel) mutation data, copy number variation (CNV) data and clinical follow-up information data of gastric cancer tissues were downloaded from The Cancer Genome Atlas (TCGA) database. ConsensusClusterPlus was used to stratify the metabolic subtypes of gastric cancer. Four metabolic subtypes (Cholesterogenic, Glycolytic, Mixed and Quiescent) of gastric cancer were identified, and patients with cholesterogenic tumors had the longest disease-specific survival (DSS). Genome-wide analysis showed that aberrant amplification of TP53 and MYC in gastric cancer was associated with abnormal cholesterol anabolic metabolism. The mRNA levels of mitochondrial pyruvate carriers 1 and 2 (MPC1/2) differed among the four subtypes. Tumors in the glycolytic group showed a higher PDCD1. A genomic signature based on tumor metabolism of different cancer types was established. This study showed that genes related to glucose and lipid metabolism play an important role in gastric cancer and facilitate a personalized treatment of gastric cancer.
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Affiliation(s)
- Zhou Zhu
- Department of Gastrointestinal Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Jian Qin
- Department of Radiation Oncology of Clinical Cancer Center, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Chencheng Dong
- Department of Gastrointestinal Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
| | - Jin Yang
- Strategic Operations Department, YuceBio Technology Co., Ltd, Guangzhou, China
| | - Maughan Yang
- Strategy DevelopmentDepartment, Meta Health Sector of Yuanzhi Technology Group, Beijing, China
| | - Jana Tian
- Strategy DevelopmentDepartment, Meta Health Sector of Yuanzhi Technology Group, Beijing, China
| | - Xiaogang Zhong
- Department of Gastrointestinal Surgery, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning, China
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11
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Mortalin/glucose-regulated protein 75 promotes the cisplatin-resistance of gastric cancer via regulating anti-oxidation/apoptosis and metabolic reprogramming. Cell Death Discov 2021; 7:140. [PMID: 34117210 PMCID: PMC8196146 DOI: 10.1038/s41420-021-00517-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 04/19/2021] [Accepted: 05/14/2021] [Indexed: 12/15/2022] Open
Abstract
Platinum drug treatment is one of the most predominant chemotherapeutic strategies for patients with gastric cancer (GC). However, the therapeutic effect is less than satisfactory, largely due to the acquired resistance to platinum drugs. Therefore, a better understanding of the underlying mechanisms can greatly improve the therapeutic efficacy of GC. In this study, we aimed to investigate the chemo-resistance related functions/mechanisms and clinical significance of glucose-regulated protein 75 (GRP75) in GC. Here, our data showed that compared with SGC7901 cells, the expression of GRP75 was markedly higher in cisplatin-resistance cells (SGC7901CR). Knockdown of GRP75 abolished the maintenance of mitochondrial membrane potential (MMP) and inhibited the nuclear factor erythroid-2-related factor 2 (NRF2), phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT), hypoxia-inducible factor 1α (HIF-1α), and c-myc, which resulted in blocking the activation of their downstream targets. These processes attenuated the anti-oxidation/apoptosis abilities and altered the metabolic reprogramming in SGC7901CR cells, leading to re-sensitizing these cells to cisplatin. However, overexpression of GRP75 in SGC7901 cells caused the opposite effects. A xenografts model confirmed the abovementioned results. In GC patients receiving platinum chemotherapy and a meta-analysis, a high level of GRP75 was positively associated with aggressive characteristics and poor prognosis including but not limited to gastrointestinal cancers, and was an independent predictor for overall survival. Collectively, our study indicated that GRP75 was involved in the cisplatin-resistance of GC and that GRP75 could be a potential therapeutic target for restoring the drug response in platinum-resistance cells and a useful additive prognostic tool in guiding clinical management of GC patients.
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12
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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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13
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Zhang L, Wang Y, Li Z, Lin D, Liu Y, Zhou L, Wang D, Wu A, Li Z. Clinicopathological features of tumor mutation burden, Epstein-Barr virus infection, microsatellite instability and PD-L1 status in Chinese patients with gastric cancer. Diagn Pathol 2021; 16:38. [PMID: 33933102 PMCID: PMC8088709 DOI: 10.1186/s13000-021-01099-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 04/15/2021] [Indexed: 01/10/2023] Open
Abstract
Objectives Gastric cancer (GC) is the 4th most common type of cancer worldwide. Different GC subtypes have unique molecular features that may have different therapeutic methods. The aim of the present study was to investigate Epstein-Barr virus (EBV) infection, microsatellite instability (MSI) status, the expression of programmed death-ligand 1 (PD-L1) and gene mutations in GC patients. Methods The data of 2504 GC patients, who underwent curative gastrectomy with lymphadenectomy at Peking University Cancer Hospital between 2013 and 2018, were reviewed. We analyzed the clinicopathological factors associated with the immunohistochemistry (IHC) profiles of these patients, and genetic alterations were analyzed using next generation sequencing (NGS). Results Mismatch repair-deficient (d-MMR) GC patients were found to have a higher probability of expressing PD-L1 (p = 0.000, PD-L1 cutoff value = 1%). In addition, 4 and 6.9% of the 2504 gastric cancer patients were EBV-positive and d-MMR, respectively. The number of MLH1/PMS2-negative cases was 126 (6%), and the number of MSH2/MSH6-negative cases was 14 (0.9%). d-MMR status was associated with a intestinal group (p = 0.012), but not with tumor differentiation. Furthermore, MSI and d-MMR GC status (detected by NGS and IHC, respectively) were consistently high, and the rate of MSI was higher in patients with d-MMR GC. A number of genes associated with DNA damage repair were detected in GC patients with MSI, including POLE, ETV6, BRCA and RNF43. In patients with a high tumor mutation burden, the most significantly mutated genes were LRP1B (79.07%), ARID1A (74.42%), RNF43 (69.77%), ZFHX3 (65.12%), TP53 (58.14%), GANS (51.16%), BRCA2 (51.16%), PIK3CA (51.16%), NOTCH1 (51.16%), SMARCA4 (48.84%), ATR (46.51%), POLE (41.86%) and ATM (39.53%). Conclusions Using IHC and NGS, MSI status, protein expression, tumor mutation burden (TMB) and genetic alterations were identified in patients with GC, which provides a theoretical basis for the future clinical treatment of GC.
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Affiliation(s)
- Li Zhang
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, No.52 Fucheng Road Haidian District, Beijing, 100142, People's Republic of China
| | - Yinkui Wang
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, No.52 Fucheng Road Haidian District, Beijing, 100142, People's Republic of China
| | - Zhongwu Li
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, No.52 Fucheng Road Haidian District, Beijing, 100142, People's Republic of China
| | - Dongmei Lin
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, No.52 Fucheng Road Haidian District, Beijing, 100142, People's Republic of China
| | - Yiqiang Liu
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, No.52 Fucheng Road Haidian District, Beijing, 100142, People's Republic of China.,Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, No.52 Fucheng Road Haidian District, Beijing, 100142, People's Republic of China
| | - Linxin Zhou
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, No.52 Fucheng Road Haidian District, Beijing, 100142, People's Republic of China
| | - Dongliang Wang
- ChosenMed, Beijing Economic-Technological Development Area, Beijing, 100176, People's Republic of China
| | - Aiwen Wu
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, No.52 Fucheng Road Haidian District, Beijing, 100142, People's Republic of China.
| | - Ziyu Li
- Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, No.52 Fucheng Road Haidian District, Beijing, 100142, People's Republic of China.
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14
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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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15
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Identification and Construction of a Long Noncoding RNA Prognostic Risk Model for Stomach Adenocarcinoma Patients. DISEASE MARKERS 2021; 2021:8895723. [PMID: 33680217 PMCID: PMC7929674 DOI: 10.1155/2021/8895723] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 12/11/2020] [Accepted: 02/09/2021] [Indexed: 02/08/2023]
Abstract
Background Long noncoding RNA-based prognostic biomarkers have demonstrated great potential in the diagnosis and prognosis of cancer patients. However, systematic assessment of a multiple lncRNA-composed prognostic risk model is lacking in stomach adenocarcinoma (STAD). This study is aimed at constructing a lncRNA-based prognostic risk model for STAD patients. Methods RNA sequencing data and clinical information of STAD patients were retrieved from The Cancer Genome Atlas (TCGA) database. Differentially expressed lncRNAs (DElncRNAs) were identified using the R software. Univariate and multivariate Cox regression analyses were performed to construct a prognostic risk model. The survival analysis, C-index, and receiver operating characteristic (ROC) curve were employed to assess the sensitivity and specificity of the model. The results were verified using the GEPIA online tool and our clinical samples. Pearson correlation coefficient analysis, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed to indicate the potential biological functions of the selected lncRNA. Results A total of 1917 DElncRNAs were identified from 343 cases of STAD tissues and 30 cases of noncancerous tissues. According to univariate and multivariable Cox regression analyses, four DElncRNAs (AC129507.1, LINC02407, AL022316.1, and AP000695.2) were selected to establish a prognostic risk model. There was a significant difference in the overall survival between high-risk patients and low-risk patients based on this risk model. The C-index of the model was 0.652. The area under the curve (AUC) for the ROC curve was 0.769. GEPIA results confirmed the expression and prognostic significance of AP000695.2 in STAD. Our clinical data confirmed that upregulated expression of AP000695.2 was correlated with the T stage, distant metastasis, and TNM stage in STAD. GO and KEGG analyses demonstrated that AP000695.2 was closely related to the tumorigenesis process. Conclusions In this study, we constructed a lncRNA-based prognostic risk model for STAD patients. Our study will provide novel insight into the diagnosis and prognosis of STAD patients.
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Guo F, Xu Q, Lv Z, Ding HX, Sun LP, Zheng ZD, Yuan Y. Correlation Between TNFAIP2 Gene Polymorphism and Prediction/Prognosis for Gastric Cancer and Its Effect on TNFAIP2 Protein Expression. Front Oncol 2020; 10:1127. [PMID: 32793480 PMCID: PMC7394262 DOI: 10.3389/fonc.2020.01127] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 06/04/2020] [Indexed: 01/26/2023] Open
Abstract
Objective: TNFAIP2 is a novel gene induced by TNF-α and participates in inflammatory reaction and tumor angiogenesis. This study aims to understand the correlation between TNFAIP2 gene polymorphism and prediction as well as prognosis of gastric cancer (GC) in a Chinese population. Methods: One thousand two hundred seventy-nine cases were enrolled, including 640 GC and 639 non-cancer cases. The functional tagSNPs of the TNFAIP2 gene were screened by Haploview software and NIH Snpinfo website. Human whole-blood genomic DNA was extracted by phenol chloroform method and analyzed by KASP SNP typing and sequencing method. ELISA was used to determine the expression of TNFAIP2 protein in serum samples. The miRNAs bound to TNFAIP2 3′ UTR rs8126 were predicted by MirSNP and TargetScan database. SPSS 22.0 software was used for statistical analysis, and P < 0.05 showed statistical difference. Results: Four functional TNFAIP2 tagSNPs were found by bioinformatics analysis. TNFAIP2 rs8126 T>C polymorphism increased GC risk, and the risk in TC genotype cases was higher than that in TT genotype cases (P = 0.001, OR = 1.557). In the dominant model, the TNFAIP2 rs8126 polymorphic carrier was 1.419 times higher (P = 0.007). TNFAIP2 rs710100 C>T polymorphism, TNFAIP2 rs3759571 G>A polymorphism, and TNFAIP2 rs3759573 A>G polymorphism were not correlated with GC risk. In the subgroup analysis, TNFAIP2 rs8126 TC genotype cases had a higher GC risk in male, aged 60 years or older, Helicobacter pylori-negative, non-smoking, and non-drinking. However, there was no correlation between TNFAIP2 SNPs and GC prognosis. The TNFAIP2 protein concentration in GC patients was significantly different from that in healthy persons (P = 0.029), but it was not associated with GC prognosis. The high or low expression of TNFAIP2 protein had no significant difference with gender, age, H. pylori infection, smoking, and drinking in GC patients. The serum TNFAIP2 protein expression in rs8126 TT genotype carriers was significantly higher than that in rs8126 CC genotype carriers (P < 0.001). Conclusion: TNFAIP2 3′ UTR rs8126 T>C polymorphism was associated with GC risk in a Chinese population, especially in cases with males aged 60 years or older, H. pylori negative, non-smoking and non-drinking. Compared with healthy persons, serum TNFAIP2 protein expression was higher in Chinese GC patients, and TNFAIP2 3′ UTR rs8126 T>C polymorphism might affect TNFAIP2 protein expression.
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Affiliation(s)
- Fang Guo
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Department of Oncology, PLA Cancer Center, General Hospital of Northern Theater Command, Shenyang, China
| | - Qian Xu
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Zhi Lv
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Han-Xi Ding
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Li-Ping Sun
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
| | - Zhen-Dong Zheng
- Department of Oncology, PLA Cancer Center, General Hospital of Northern Theater Command, Shenyang, China
| | - Yuan Yuan
- Tumor Etiology and Screening Department of Cancer Institute and General Surgery, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of Cancer Etiology and Prevention in Liaoning Education Department, The First Hospital of China Medical University, Shenyang, China.,Key Laboratory of GI Cancer Etiology and Prevention in Liaoning Province, The First Hospital of China Medical University, Shenyang, China
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Oshima Y, Suzuki T, Yajima S, Nanami T, Shiratori F, Funahashi K, Shimada H. Serum p53 antibody: useful for detecting gastric cancer but not for predicting prognosis after surgery. Surg Today 2020; 50:1402-1408. [PMID: 32458231 DOI: 10.1007/s00595-020-02030-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 04/19/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE To establish the clinicopathological importance of serum p53 autoantibody (s-p53-Ab) titrations in patients with gastric cancer. METHODS Preoperative s-p53-Ab titers were analyzed in 448 gastric cancer patients between 2010 and 2017. Seropositive patients were divided into three groups based on their antibody titers: 1.31-10.0 U/mL (low group); 10.1-100 U/mL (medium group); and > 100 U/mL (high group). We evaluated the associations between the s-p53-Abs and clinicopathological factors, carcinoembryonic antigen (CEA) levels, and cancer antigen 19-9 (CA19-9) levels. Overall survival was analyzed by multivariate analyses. RESULTS A total of 72 patients (16%) were positive for s-p53-Abs. The rate of positivity for s-p53-Abs + CEA + CA19-9 was significantly higher than that for CEA + CA19-9, even in stage I gastric cancers. Gender, tumor depth, lymphatic node metastases, and distant metastases were all significantly associated with the presence of s-p53-Abs; however, overall survival was not associated with the antibodies. The patients in the high titer group (> 100 U/mL) had a relatively worse survival than those in the other groups. CONCLUSIONS Based on our findings, s-p53-Abs improve the overall rate of positivity for detecting gastric cancer, but the prognostic value of a high s-p53-Ab titer for predicting overall survival is limited.
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Affiliation(s)
- Yoko Oshima
- Department of Surgery, Toho University School of Medicine, Tokyo, Japan
| | - Takashi Suzuki
- Department of Surgery, Toho University School of Medicine, Tokyo, Japan
| | - Satoshi Yajima
- Department of Surgery, Toho University School of Medicine, Tokyo, Japan
| | - Tatsuki Nanami
- Department of Surgery, Toho University School of Medicine, Tokyo, Japan
| | - Fumiaki Shiratori
- Department of Surgery, Toho University School of Medicine, Tokyo, Japan
| | | | - Hideaki Shimada
- Department of Surgery, Toho University School of Medicine, Tokyo, Japan.
- Department of Gastroenterological Surgery and Clinical Oncology, Graduate School of Medicine, 6-11-1 Omori-nishi, Ota-ku, Tokyo, 143-8541, Japan.
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Genomic Characterization of Non-Invasive Differentiated-Type Gastric Cancer in the Japanese Population. Cancers (Basel) 2020; 12:cancers12020510. [PMID: 32098350 PMCID: PMC7072322 DOI: 10.3390/cancers12020510] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 02/17/2020] [Accepted: 02/19/2020] [Indexed: 12/24/2022] Open
Abstract
Background and aims: Recent genomic characterization of gastric cancer (GC) by sequencing has revealed a large number of cancer-related genes. Research to characterize the genomic landscape of cancer has focused on established invasive cancer to develop biomarkers for therapeutic or diagnostic targets, and nearly all GC reports have been about advanced GC. The aim of this study is to identify recurrently mutated genes in non-invasive GC and, in particular, the driver mutations that are associated with the development of GC. Methods and results: We performed whole-exome sequencing of 19 fresh frozen specimens of differentiated-type non-invasive GC and targeted sequencing for 168 genes of 30 formalin-fixed paraffin-embedded archival specimens of differentiated-type non-invasive GC. We found that TP53 and LRP1 are significantly associated with non-invasive GC. It has been reported that LPR1 is associated with CagA autophagy in gastric mucosa. Therefore, we downloaded RNA sequence data for gastric cancer from the The Cancer Genome Atlas (TCGA) Genomic Data Commons Data Portal and examined the differences in LRP1 gene expression levels. The expression level was significantly lower in cases without LRP1 mutation than in cases with LRP1 mutation. Based on these results, fluorescent immunostaining for CagA was performed for 49 of the above samples to evaluate CagA accumulation within the cancerous tissue. Accumulation of CagA was significantly greater when an LRP1 mutation was present than without a mutation. Conclusion: These data suggest that LRP1 mutation is an important change promoting the transformation of gastric mucosa to GC early in the carcinogenesis of cancer.
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Matsuoka T, Yashiro M. Precision medicine for gastrointestinal cancer: Recent progress and future perspective. World J Gastrointest Oncol 2020; 12:1-20. [PMID: 31966910 PMCID: PMC6960076 DOI: 10.4251/wjgo.v12.i1.1] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 10/12/2019] [Accepted: 11/04/2019] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal (GI) cancer has a high tumor incidence and mortality rate worldwide. Despite significant improvements in radiotherapy, chemotherapy, and targeted therapy for GI cancer over the last decade, GI cancer is characterized by high recurrence rates and a dismal prognosis. There is an urgent need for new diagnostic and therapeutic approaches. Recent technological advances and the accumulation of clinical data are moving toward the use of precision medicine in GI cancer. Here we review the application and status of precision medicine in GI cancer. Analyses of liquid biopsy specimens provide comprehensive real-time data of the tumor-associated changes in an individual GI cancer patient with malignancy. With the introduction of gene panels including next-generation sequencing, it has become possible to identify a variety of mutations and genetic biomarkers in GI cancer. Although the genomic aberration of GI cancer is apparently less actionable compared to other solid tumors, novel informative analyses derived from comprehensive gene profiling may lead to the discovery of precise molecular targeted drugs. These progressions will make it feasible to incorporate clinical, genome-based, and phenotype-based diagnostic and therapeutic approaches and apply them to individual GI cancer patients for precision medicine.
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Affiliation(s)
- Tasuku Matsuoka
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
| | - Masakazu Yashiro
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
- Oncology Institute of Geriatrics and Medical Science, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
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