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Wang Z, Peng H, Wan J, Song A. Identification of histopathological classification and establishment of prognostic indicators of gastric adenocarcinoma based on deep learning algorithm. Med Mol Morphol 2024; 57:286-298. [PMID: 39088070 PMCID: PMC11543764 DOI: 10.1007/s00795-024-00399-8] [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: 03/11/2024] [Accepted: 07/15/2024] [Indexed: 08/02/2024]
Abstract
The aim of this study is to establish a deep learning (DL) model to predict the pathological type of gastric adenocarcinoma cancer based on whole-slide images(WSIs). We downloaded 356 histopathological images of gastric adenocarcinoma (STAD) patients from The Cancer Genome Atlas database and randomly divided them into the training set, validation set and test set (8:1:1). Additionally, 80 H&E-stained WSIs of STAD were collected for external validation. The CLAM tool was used to cut the WSIs and further construct the model by DL algorithm, achieving an accuracy of over 90% in identifying and predicting histopathological subtypes. External validation results demonstrated the model had a certain generalization ability. Moreover, DL features were extracted from the model to further investigate the differences in immune infiltration and patient prognosis between the two subtypes. The DL model can accurately predict the pathological classification of STAD patients, and provide certain reference value for clinical diagnosis. The nomogram combining DL-signature, gene-signature and clinical features can be used as a prognostic classifier for clinical decision-making and treatment.
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Affiliation(s)
- Zhihui Wang
- Department of Ultrasound Imaging, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430101, Hubei, China
| | - Hui Peng
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430101, Hubei, China
| | - Jie Wan
- Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430101, Hubei, China
| | - Anping Song
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430101, Hubei, China.
- Department of Oncology, Tongji Hospital Sino-French New City Branch, Caidian District, No.288 Xintian Avenue, Wuhan, 430101, Hubei, China.
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Draškovič T, Ranković B, Zidar N, Hauptman N. Upregulation of ABLIM1 Differentiates Intrahepatic Cholangiocarcinoma from Hepatocellular Carcinoma and Both Colorectal and Pancreatic Adenocarcinoma Liver Metastases. Genes (Basel) 2024; 15:1545. [PMID: 39766812 PMCID: PMC11675665 DOI: 10.3390/genes15121545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2024] [Revised: 11/22/2024] [Accepted: 11/26/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Altered gene expression in cancers holds great potential to improve the diagnostics and differentiation of primary and metastatic liver cancers. In this study, the expression of the protein-coding genes ring finger protein 135 (RNF135), ephrin-B2 (EFNB2), ring finger protein 125 (RNF125), homeobox-C 4 (HOXC4), actin-binding LIM protein 1 (ABLIM1) and oncostatin M receptor (OSMR) and the long non-coding RNAs (lncRNA) prospero homeobox 1 antisense RNA 1 (PROX1-AS1) and leukemia inhibitory factor receptor antisense RNA 1 (LIFR-AS1) was investigated in hepatocellular carcinoma, cholangiocarcinoma, colorectal liver metastases and pancreatic ductal adenocarcinoma liver metastases. METHODS This study included 149 formalin-fixed, paraffin-embedded samples from 80 patients. After RNA isolation, quantification, reverse transcription and preamplification, real-time qPCR was performed. The gene expression between different groups was calculated relative to the expression of the reference genes using the ∆∆Cq method and statistically analyzed. The expression of the genes was additionally analyzed using the AmiCA and UCSC Xena platforms. RESULTS In primary cancers, our results showed differential expression between primary tumors and healthy tissues for all the genes and lncRNA examined. Moreover, we found downregulation of RNF135 in hepatocellular carcinoma, downregulation of OSMR in colorectal liver metastases and upregulation of HOXC4 in cholangiocarcinoma compared to primary liver cancers and metastatic cancers. The major finding is the upregulation of ABLIM1 in cholangiocarcinoma compared to hepatocellular carcinoma, colorectal liver metastases, pancreatic ductal adenocarcinoma liver metastases and healthy liver tissue. We propose ABLIM1 as a potential biomarker that differentiates cholangiocarcinoma from other cancers and healthy liver tissue. CONCLUSIONS This study emphasizes the importance of understanding the differences in gene expression between healthy tissues and primary and metastatic cancers and highlights the potential use of altered gene expression as a diagnostic biomarker in these malignancies.
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Affiliation(s)
| | | | | | - Nina Hauptman
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; (T.D.); (B.R.); (N.Z.)
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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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Song J, Yan XX, Zhang FL, Lei YY, Ke ZY, Li F, Zhang K, He YQ, Li W, Li C, Pan YM. Unveiling the secrets of gastrointestinal mucous adenocarcinoma survival after surgery with artificial intelligence: A population-based study. World J Gastrointest Oncol 2024; 16:2404-2418. [PMID: 38994138 PMCID: PMC11236227 DOI: 10.4251/wjgo.v16.i6.2404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/27/2024] [Accepted: 04/03/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Research on gastrointestinal mucosal adenocarcinoma (GMA) is limited and controversial, and there is no reference tool for predicting postoperative survival. AIM To investigate the prognosis of GMA and develop predictive model. METHODS From the Surveillance, Epidemiology, and End Results database, we collected clinical information on patients with GMA. After random sampling, the patients were divided into the discovery (70% of the total, for model training), validation (20%, for model evaluation), and completely blind test cohorts (10%, for further model evaluation). The main assessment metric was the area under the receiver operating characteristic curve (AUC). All collected clinical features were used for Cox proportional hazard regression analysis to determine factors influencing GMA's prognosis. RESULTS This model had an AUC of 0.7433 [95% confidence intervals (95%CI): 0.7424-0.7442] in the discovery cohort, 0.7244 (GMA: 0.7234-0.7254) in the validation cohort, and 0.7388 (95%CI: 0.7378-0.7398) in the test cohort. We packaged it into Windows software for doctors' use and uploaded it. Mucinous gastric adenocarcinoma had the worst prognosis, and these were protective factors of GMA: Regional nodes examined [hazard ratio (HR): 0.98, 95%CI: 0.97-0.98, P < 0.001)] and chemotherapy (HR: 0.62, 95%CI: 0.58-0.66, P < 0.001). CONCLUSION The deep learning-based tool developed can accurately predict the overall survival of patients with GMA postoperatively. Combining surgery, chemotherapy, and adequate lymph node dissection during surgery can improve patient outcomes.
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Affiliation(s)
- Jie Song
- Department of Gastroenterology, Dongying People’s Hospital, Dongying Hospital of Shandong Provincial Hospital Group, Dongying 257000, Shandong Province, China
| | - Xiang-Xiu Yan
- Department of Gastroenterology, Dongying People’s Hospital, Dongying Hospital of Shandong Provincial Hospital Group, Dongying 257000, Shandong Province, China
| | - Fang-Liang Zhang
- Gastrointestinal Surgery Department, Suining Central Hospital, Suining 629000, Sichuan Province, China
| | - Yong-Yi Lei
- Obstetrical Department, Suining Central Hospital, Suining 629000, Sichuan Province, China
| | - Zi-Yin Ke
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
| | - Fang Li
- Department of Pathology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing 100049, China
| | - Kai Zhang
- General Department, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
| | - Yu-Qi He
- Department of Gastroenterology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
| | - Wei Li
- Department of Thoracic Surgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan Province, China
| | - Chao Li
- Department of Gastroenterology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing 100049, China
| | - Yuan-Ming Pan
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
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Song J, Yan XX, Zhang FL, Lei YY, Ke ZY, Li F, Zhang K, He YQ, Li W, Li C, Pan YM. Unveiling the secrets of gastrointestinal mucous adenocarcinoma survival after surgery with artificial intelligence: A population-based study. World J Gastrointest Oncol 2024; 16:2392-2406. [DOI: 10.4251/wjgo.v16.i6.2392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Revised: 02/27/2024] [Accepted: 04/03/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Research on gastrointestinal mucosal adenocarcinoma (GMA) is limited and controversial, and there is no reference tool for predicting postoperative survival.
AIM To investigate the prognosis of GMA and develop predictive model.
METHODS From the Surveillance, Epidemiology, and End Results database, we collected clinical information on patients with GMA. After random sampling, the patients were divided into the discovery (70% of the total, for model training), validation (20%, for model evaluation), and completely blind test cohorts (10%, for further model evaluation). The main assessment metric was the area under the receiver operating characteristic curve (AUC). All collected clinical features were used for Cox proportional hazard regression analysis to determine factors influencing GMA’s prognosis.
RESULTS This model had an AUC of 0.7433 [95% confidence intervals (95%CI): 0.7424-0.7442] in the discovery cohort, 0.7244 (GMA: 0.7234-0.7254) in the validation cohort, and 0.7388 (95%CI: 0.7378-0.7398) in the test cohort. We packaged it into Windows software for doctors’ use and uploaded it. Mucinous gastric adenocarcinoma had the worst prognosis, and these were protective factors of GMA: Regional nodes examined [hazard ratio (HR): 0.98, 95%CI: 0.97-0.98, P < 0.001)] and chemotherapy (HR: 0.62, 95%CI: 0.58-0.66, P < 0.001).
CONCLUSION The deep learning-based tool developed can accurately predict the overall survival of patients with GMA postoperatively. Combining surgery, chemotherapy, and adequate lymph node dissection during surgery can improve patient outcomes.
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Affiliation(s)
- Jie Song
- Department of Gastroenterology, Dongying People’s Hospital, Dongying Hospital of Shandong Provincial Hospital Group, Dongying 257000, Shandong Province, China
| | - Xiang-Xiu Yan
- Department of Gastroenterology, Dongying People’s Hospital, Dongying Hospital of Shandong Provincial Hospital Group, Dongying 257000, Shandong Province, China
| | - Fang-Liang Zhang
- Gastrointestinal Surgery Department, Suining Central Hospital, Suining 629000, Sichuan Province, China
| | - Yong-Yi Lei
- Obstetrical Department, Suining Central Hospital, Suining 629000, Sichuan Province, China
| | - Zi-Yin Ke
- School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, Guangdong Province, China
| | - Fang Li
- Department of Pathology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing 100049, China
| | - Kai Zhang
- General Department, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
| | - Yu-Qi He
- Department of Gastroenterology, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
| | - Wei Li
- Department of Thoracic Surgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan Province, China
| | - Chao Li
- Department of Gastroenterology, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing 100049, China
| | - Yuan-Ming Pan
- Cancer Research Center, Beijing Chest Hospital, Capital Medical University/Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing 101149, China
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Rokutan H, Arai Y, Kunita A, Yamasaki S, Nakamura H, Hama N, Nakayama A, Hosoda F, Totoki Y, Fujishiro M, Seto Y, Shibata T, Ushiku T. Genomic and Pathologic Profiling of Very Well-Differentiated Gastric Adenocarcinoma of Intestinal Type: A Study With Emphasis on Diffuse-Type Transformation. Am J Surg Pathol 2024; 48:652-661. [PMID: 38584451 DOI: 10.1097/pas.0000000000002222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Very well-differentiated adenocarcinoma of intestinal type is a distinct subtype of gastric cancer characterized by anastomosing glands with a hand-in-hand pattern and low-grade cytologic atypia resembling intestinal metaplasia. This is a slow-growing neoplasm with an indolent clinical course; however, a subset demonstrates transformation into adenocarcinoma with higher-grade histology, typically diffuse-type carcinoma, and behaves aggressively. This study aimed to better characterize the genomic and pathologic features, with a focus on factors associated with diffuse-type transformation. A total of 58 cases with (n=31) and without (n=27) diffuse-type transformation were analyzed for molecular and pathologic features. First, comprehensive deep DNA sequencing was conducted in 18 cases (discovery cohort), followed by a digital droplet polymerase chain reaction of hot spot RHOA mutations in 40 cases (validation cohort). In total, RHOA mutations were the most common alteration (34%), followed by loss of ARID1A (12%), p53 alterations (10%), and CLDN18 :: ARHGAP26/6 fusions (3.4%). FGFR2 amplification was identified in an advanced case with a p53 alteration. Altered p53 expression was recognized only in higher-grade components and was significantly associated with advanced disease ( P =0.0015) and diffuse-type transformation ( P =0.026). A mixed mucin phenotype was also strongly correlated with advanced disease ( P <0.001) and diffuse-type transformation ( P <0.001). Decreased E-cadherin expression was frequently observed (74%) in poorly cohesive components. This study demonstrated that a subset of RHOA -mutant diffuse-type gastric cancers develops through the transformation of very well-differentiated adenocarcinoma of intestinal type. Our observations suggest a mixed mucin phenotype as a risk factor and alterations in p53 and E-cadherin as drivers of diffuse-type transformation.
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Affiliation(s)
| | - Yasuhito Arai
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo
| | | | - Satoshi Yamasaki
- Laboratory of Molecular Medicine, The Institute of Medical Science, The University of Tokyo
| | - Hiromi Nakamura
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo
| | - Natsuko Hama
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo
| | | | - Fumie Hosoda
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo
| | - Yasushi Totoki
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo
- Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, Osaka, Tokyo, Japan
| | | | | | - Tatsuhiro Shibata
- Laboratory of Molecular Medicine, The Institute of Medical Science, The University of Tokyo
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo
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Lu S, Duan R, Cong L, Song Y. The effects of ARID1A mutation in gastric cancer and its significance for treatment. Cancer Cell Int 2023; 23:296. [PMID: 38008753 PMCID: PMC10676575 DOI: 10.1186/s12935-023-03154-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 11/21/2023] [Indexed: 11/28/2023] Open
Abstract
Gastric cancer (GC) has emerged as a significant issue in public health all worldwide as a result of its high mortality rate and dismal prognosis. AT-rich interactive domain 1 A (ARID1A) is a vital component of the switch/sucrose-non-fermentable (SWI/SNF) chromatin remodeling complex, and ARID1A mutations occur in various tumors, leading to protein loss and decreased expression; it then affects the tumor biological behavior or prognosis. More significantly, ARID1A mutations will likely be biological markers for immune checkpoint blockade (ICB) treatment and selective targeted therapy. To provide theoretical support for future research on the stratification of individuals with gastric cancer with ARID1A as a biomarker to achieve precision therapy, we have focused on the clinical significance, predictive value, underlying mechanisms, and possible treatment strategies for ARID1A mutations in gastric cancer in this review.
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Affiliation(s)
- Shan Lu
- Gastroenteric Medicine and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China
| | - Ruifeng Duan
- Gastroenteric Medicine and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China
| | - Liang Cong
- Gastroenteric Medicine and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China
| | - Ying Song
- Gastroenteric Medicine and Digestive Endoscopy Center, The Second Hospital of Jilin University, Changchun, China.
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Liang H, Li Q, Wang N, Wang C, Shi S, Yang H, Cao Y, Shi R, Jin L, Zhang C. KDM4D enhances osteo/dentinogenic differentiation and migration of SCAPs via binding to RPS5. Oral Dis 2023; 29:2827-2836. [PMID: 36579641 DOI: 10.1111/odi.14479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2022] [Revised: 10/21/2022] [Accepted: 12/19/2022] [Indexed: 12/30/2022]
Abstract
OBJECTIVES Stem cells of the apical papilla (SCAPs) provide promising candidates for dental pulp regeneration. Despite great advances in the transcriptional controls of the SCAPs fate, little is known about the regulation of SCAP differentiation. MATERIALS AND METHODS Short hairpin RNAs and full-length RNA were used to deplete or overexpress lysine demethylase 4D (KDM4D) gene expression. Western blotting, real-time RT-PCR, alizarin red staining, and scratch migration assays were used to study the role of KDM4D and the ribosomal protein encoded by RPS5 in SCAPs. RNA microarray, chromatin Immunoprecipitation (ChIP), and co-immunoprecipitation (Co-IP) assays were performed to explore the underlying molecular mechanisms. RESULTS KDM4D enhanced the osteo/dentinogenic differentiation, migration, and chemotaxis of SCAPs. The microarray results revealed that 88 mRNAs were differentially expressed in KDM4D-overexpressed SCAPs. ChIP results showed knock-down of KDM4D increased the level of H3K9me2 and H3K9me3 in CNR1 promoter region. There were 37 possible binding partners of KDM4D. KDM4D was found to combine with RPS5, which also promoted the osteo/dentinogenic differentiation, migration, and chemotaxis of SCAPs. CONCLUSIONS KDM4D promoted the osteo/dentinogenic differentiation and migration potential of SCAPs in combination with RPS5, which provides a therapeutic clue for improving SCAPs-based dental tissue regeneration.
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Affiliation(s)
- Hanbing Liang
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
- Department of Endodontics, Capital Medical University School of Stomatology, Beijing, China
| | - Qian Li
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
- Department of Endodontics, Capital Medical University School of Stomatology, Beijing, China
| | - Ning Wang
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
| | - Chunxiong Wang
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
- Department of Endodontics, Capital Medical University School of Stomatology, Beijing, China
| | - Shaojing Shi
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
- Department of Endodontics, Capital Medical University School of Stomatology, Beijing, China
| | - Haoqing Yang
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
| | - Yangyang Cao
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
| | - Ruitang Shi
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
- Department of Endodontics, Capital Medical University School of Stomatology, Beijing, China
| | - Luyuan Jin
- Department of General Dentistry and Integrated Emergency Dental Care, Capital Medical University School of Stomatology, Beijing, China
| | - Chen Zhang
- Department of Endodontics, Capital Medical University School of Stomatology, Beijing, China
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Feng Z, Ding H, Peng Z, Hu K. Downregulated KDM6A mediates gastric carcinogenesis via Wnt/β-catenin signaling pathway mediated epithelial-to-mesenchymal transition. Pathol Res Pract 2023; 245:154461. [PMID: 37060821 DOI: 10.1016/j.prp.2023.154461] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 03/29/2023] [Accepted: 04/10/2023] [Indexed: 04/17/2023]
Abstract
This study explored the connection between KDM6A expression and patient prognosis and the mechanism of KDM6A's role in developing GC (GC). From the immunohistochemical Analysis of 107 GC patients' tumors, we discovered that patients with reduced KDM6A expression had a shorter survival time. There was a correlation between KDM6A expression and the degree of differentiation of tumor tissue, T stage, N stage, and TNM stage. KDM6A gene expression was positively connected with the expression level of E-cadherin and negatively connected with the expression level of N-cadherin and vimentin in vitro tests. KDM6A gene suppression prevented GC cell proliferation, migration, and invasion, whereas high KDM6A gene expression promoted these processes. Second, low expression of KDM6A down-regulates GSK3β, p-GSK3β, up-regulates C-Myc, CyclinD1, and promotes β-catenin protein expression in the nucleus, while the high expression does the opposite. Then, we used ICG001 to block the Wnt/β-catenin signal transduction pathway, and the results revealed that ICG001 could reduce the promoting effect of low KDM6A expression on aggressiveness and EMT in GC cells. KDM6A down-regulation stimulates the proliferation of GC cells, while ICG001 reverses this action in vivo tests. Patients whose KDM6A expression was found to be low had a poor prognosis, as this study found. The EMT is inhibited by regulating theWnt/β-catenin signaling by KDM6A, which reduces GC cell proliferation, migration, and invasion. KDM6A may be a viable target for GC in clinical therapy.
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Affiliation(s)
- Zhenyou Feng
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Huiming Ding
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Zhiwei Peng
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Kongwang Hu
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei 230032, China; Fuyang Hospital Affiliated to Anhui Medical University, Fuyang 236000, China.
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Li D, Li X, Li S, Qi M, Sun X, Hu G. Relationship between the deep features of the full-scan pathological map of mucinous gastric carcinoma and related genes based on deep learning. Heliyon 2023; 9:e14374. [PMID: 36942252 PMCID: PMC10023952 DOI: 10.1016/j.heliyon.2023.e14374] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 02/28/2023] [Accepted: 03/02/2023] [Indexed: 03/11/2023] Open
Abstract
Background Long-term differential expression of disease-associated genes is a crucial driver of pathological changes in mucinous gastric carcinoma. Therefore, there should be a correlation between depth features extracted from pathology-based full-scan images using deep learning and disease-associated gene expression. This study tried to provides preliminary evidence that long-term differentially expressed (disease-associated) genes lead to subtle changes in disease pathology by exploring their correlation, and offer a new ideas for precise analysis of pathomics and combined analysis of pathomics and genomics. Methods Full pathological scans, gene sequencing data, and clinical data of patients with mucinous gastric carcinoma were downloaded from TCGA data. The VGG-16 network architecture was used to construct a binary classification model to explore the potential of VGG-16 applications and extract the deep features of the pathology-based full-scan map. Differential gene expression analysis was performed and a protein-protein interaction network was constructed to screen disease-related core genes. Differential, Lasso regression, and extensive correlation analyses were used to screen for valuable deep features. Finally, a correlation analysis was used to determine whether there was a correlation between valuable deep features and disease-related core genes. Result The accuracy of the binary classification model was 0.775 ± 0.129. A total of 24 disease-related core genes were screened, including ASPM, AURKA, AURKB, BUB1, BUB1B, CCNA2, CCNB1, CCNB2, CDCA8, CDK1, CENPF, DLGAP5, KIF11, KIF20A, KIF2C, KIF4A, MELK, PBK, RRM2, TOP2A, TPX2, TTK, UBE2C, and ZWINT. In addition, differential, Lasso regression, and extensive correlation analyses were used to screen eight valuable deep features, including features 51, 106, 109, 118, 257, 282, 326, and 487. Finally, the results of the correlation analysis suggested that valuable deep features were either positively or negatively correlated with core gene expression. Conclusion The preliminary results of this study support our hypotheses. Deep learning may be an important bridge for the joint analysis of pathomics and genomics and provides preliminary evidence for long-term abnormal expression of genes leading to subtle changes in pathology.
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Affiliation(s)
- Ding Li
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Xiaoyuan Li
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Shifang Li
- Department of Neurosurgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Mengmeng Qi
- Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Xiaowei Sun
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
| | - Guojie Hu
- Department of Traditional Chinese Medicine, The Affiliated Hospital of Qingdao University, Qingdao, Shandong, China
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Wu S, Xu P, Zhang F. Advances in targeted therapy for gastric cancer based on tumor driver genes. Zhejiang Da Xue Xue Bao Yi Xue Ban 2023; 53:73-83. [PMID: 38413217 PMCID: PMC10938109 DOI: 10.3724/zdxbyxb-2023-0522] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 01/23/2024] [Indexed: 02/29/2024]
Abstract
As the understanding of the pathogenic mechanisms of gastric cancer deepens and the identification of gastric cancer driver genes advances, drugs targeting gastric cancer driver genes have been applied in clinical practice. Among them, trastuzumab, as the first targeted drug for gastric cancer, effectively inhibits the proliferation and metastasis of tumor cells by targeting overexpressed human epidermal growth factor receptor 2 (HER2). Trastuzumab has become the standard treatment for HER2-positive gastric cancer patients. Ramucirumab, on the other hand, inhibits tumor angiogenesis by targeting vascular endothelial growth factor receptor 2 (VEGFR2) and has been used as second-line therapy for advanced gastric cancer patients. In addition, bemarituzumab targets overexpressed fibroblast growth factor receptor 2 (FGFR2), while zolbetuximab targets overexpressed claudin 18.2 (CLDN18.2), significantly extending progression-free survival and overall survival in patients with gastric cancer in clinical trials. This article reviews the roles of tumor driver genes in the progression of gastric cancer, and the treatment strategies for gastric cancer primarily based on targeting HER2, VEGF, FGFR2, CLDN18.2 and MET. This provides a reference for clinical application of targeted therapy for gastric cancer.
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Affiliation(s)
- Shiying Wu
- College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China.
- Key Laboratory of Biosystems Homeostasis and Protection, Ministry of Education, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou 310058, China.
| | - Pinglong Xu
- Key Laboratory of Biosystems Homeostasis and Protection, Ministry of Education, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou 310058, China.
- Institute of Intelligent Medicine, Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311200, China.
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
- Cancer Center, Zhejiang University, Hangzhou 310058, China.
| | - Fei Zhang
- Key Laboratory of Biosystems Homeostasis and Protection, Ministry of Education, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou 310058, China.
- Institute of Intelligent Medicine, Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311200, China.
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12
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Glycosphingolipids are mediators of cancer plasticity through independent signaling pathways. Cell Rep 2022; 40:111181. [PMID: 35977490 DOI: 10.1016/j.celrep.2022.111181] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 06/01/2022] [Accepted: 07/19/2022] [Indexed: 11/23/2022] Open
Abstract
The molecular repertoire promoting cancer cell plasticity is not fully elucidated. Here, we propose that glycosphingolipids (GSLs), specifically the globo and ganglio series, correlate and promote the transition between epithelial and mesenchymal cells. The epithelial character of ovarian cancer remains stable throughout disease progression, and spatial glycosphingolipidomics reveals elevated globosides in the tumor compartment compared with the ganglioside-rich stroma. CRISPR-Cas9 knockin mediated truncation of endogenous E-cadherin induces epithelial-to-mesenchymal transition (EMT) and decreases globosides. The transcriptomics analysis identifies the ganglioside-synthesizing enzyme ST8SIA1 to be consistently elevated in mesenchymal-like samples, predicting poor outcome. Subsequent deletion of ST8SIA1 induces epithelial cell features through mTORS2448 phosphorylation, whereas loss of globosides in ΔA4GALT cells, resulting in EMT, is accompanied by increased ERKY202/T204 and AKTS124. The GSL composition dynamics corroborate cancer cell plasticity, and further evidence suggests that mesenchymal cells are maintained through ganglioside-dependent, calcium-mediated mechanisms.
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13
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Satoh H, Arai Y, Furukawa E, Moriguchi T, Hama N, Urushidate T, Totoki Y, Kato M, Ohe Y, Yamamoto M, Shibata T. Genomic landscape of chemical-induced lung tumors under Nrf2 different expression levels. Carcinogenesis 2022; 43:613-623. [PMID: 35561328 DOI: 10.1093/carcin/bgac041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 04/19/2022] [Accepted: 05/12/2022] [Indexed: 11/14/2022] Open
Abstract
The transcription factor Nrf2 plays a crucial role in the anti-oxidative stress response, protection of DNA from injury, and DNA repair mechanisms. Nrf2 activity reduces cancer initiation, but how Nrf2 affects whole-genome alterations upon carcinogenic stimulus remains unexplored. Although recent genome-wide analysis using next-generation sequencing revealed landscapes of nucleotide mutations and copy number alterations in various human cancers, genomic changes in murine cancer models have not been thoroughly examined. We elucidated the relationship between Nrf2 expression levels and whole exon mutation patterns using an ethyl-carbamate (urethane)-induced lung carcinogenesis model employing Nrf2-deficient and Keap1-kd mice, the latter of which express high levels of Nrf2. Exome analysis demonstrated that single nucleotide and trinucleotide mutation patterns and the Kras mutational signature differed significantly and were dependent on the expression level of Nrf2. The Nrf2-deficient tumors exhibited fewer copy number alterations relative to the Nrf2-wt and Keap1-kd tumors. The observed trend in genomic alterations likely prevented the Nrf2-deficient tumors from progressing into malignancy. For the first time, we present whole-exome sequencing results for chemically-induced lung tumors in the Nrf2 gain or loss of function mouse models. Our results demonstrate that different Nrf2 expression levels lead to distinct gene mutation patterns that underly different oncogenic mechanisms in each tumor genotype.
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Affiliation(s)
- Hironori Satoh
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.,Department of Respiratory Medicine, Pulmonary Center, National Cancer Center Hospital, Tokyo, Japan.,Division of Cancer Pathophysiology, National Cancer Center Research Institute, Tokyo, Japan
| | - Yasuhito Arai
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Eisaku Furukawa
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.,Division of Bioinformatics, National Cancer Center Research Institute, Tokyo, Japan
| | - Takashi Moriguchi
- Division of Medical Biochemistry, Tohoku Medical Pharmaceutical University, Sendai, Japan
| | - Natuko Hama
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Tomoko Urushidate
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Yasushi Totoki
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Mamoru Kato
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.,Division of Bioinformatics, National Cancer Center Research Institute, Tokyo, Japan
| | - Yuichiro Ohe
- Department of Respiratory Medicine, Pulmonary Center, National Cancer Center Hospital, Tokyo, Japan
| | - Masayuki Yamamoto
- Department of Medical Biochemistry, Graduate School of Medicine, Tohoku University, Sendai, Japan.,Department of Integrative Genomics, Tohoku Medical Megabank, Tohoku University, Sendai, Japan
| | - Tatsuhiro Shibata
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
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14
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Xiao JF, Kua LF, Ding LW, Sun QY, Myint KN, Chia XR, Venkatachalam N, Loh X, Duex JE, Neang V, Zhou S, Li Y, Yang H, Koeffler HP, Theodorescu D. KDM6A Depletion in Breast Epithelial Cells Leads to Reduced Sensitivity to Anticancer Agents and Increased TGFβ Activity. Mol Cancer Res 2022; 20:637-649. [PMID: 35022315 PMCID: PMC10030164 DOI: 10.1158/1541-7786.mcr-21-0402] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 09/29/2021] [Accepted: 01/05/2022] [Indexed: 11/16/2022]
Abstract
KDM6A, an X chromosome-linked histone lysine demethylase, was reported to be frequently mutated in many tumor types including breast and bladder cancer. However, the functional role of KDM6A is not fully understood. Using MCF10A as a model of non-tumorigenic epithelial breast cells, we found that silencing KDM6A promoted cell migration and transformation demonstrated by the formation of tumor-like acini in three-dimensional culture. KDM6A loss reduced the sensitivity of MCF10A cells to therapeutic agents commonly used to treat patients with triple-negative breast cancer and also induced TGFβ extracellular secretion leading to suppressed expression of cytotoxic genes in normal human CD8+ T cells in vitro. Interestingly, when cells were treated with TGFβ, de novo synthesis of KDM6A protein was suppressed while TGFB1 transcription was enhanced, indicating a TGFβ/KDM6A-negative regulatory axis. Furthermore, both KDM6A deficiency and TGFβ treatment promoted disorganized acinar structures in three-dimensional culture, as well as transcriptional profiles associated with epithelial-to-mesenchymal transition and metastasis, suggesting KDM6A depletion and TGFβ drive tumor progression. IMPLICATIONS Our study provides the preclinical rationale for evaluating KDM6A and TGFβ in breast tumor samples as predictors for response to chemo and immunotherapy, informing personalized therapy based on these findings.
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Affiliation(s)
- Jin-Fen Xiao
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Division of Medical Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Surgery (Urology), Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Corresponding authors: Dan Theodorescu, Address: 8700 Beverly Blvd, NT-Plaza Level 2429C, Los Angeles, CA 90048; , Phone: +1(310)-423-8431; Jin-Fen Xiao, Address: Davis Research Building RM3057, 110 N George Burns Rd, Los Angeles, CA 90048; ; Phone: 1(310)423-1326
| | - Ley-Fang Kua
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Ling-Wen Ding
- Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Qiao-Yang Sun
- Department of Hematology, Singapore General Hospital, Singapore
| | - Khine Nyein Myint
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Xiu-Rong Chia
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | | | - Xinyi Loh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Jason E. Duex
- Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA
| | - Vanessa Neang
- Division of Medical Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Siqin Zhou
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Ying Li
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Henry Yang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - H. Phillip Koeffler
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Division of Medical Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Dan Theodorescu
- Department of Surgery (Urology), Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Corresponding authors: Dan Theodorescu, Address: 8700 Beverly Blvd, NT-Plaza Level 2429C, Los Angeles, CA 90048; , Phone: +1(310)-423-8431; Jin-Fen Xiao, Address: Davis Research Building RM3057, 110 N George Burns Rd, Los Angeles, CA 90048; ; Phone: 1(310)423-1326
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15
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Ma L, Xiao J, Guan Y, Wu D, Gu T, Wang J. SDK1-ALK Fusion in a Lung Adenocarcinoma Patient With Excellent Response to ALK Inhibitor Treatment: A Case Report. Front Oncol 2022; 12:860060. [PMID: 35311071 PMCID: PMC8931607 DOI: 10.3389/fonc.2022.860060] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 02/14/2022] [Indexed: 12/30/2022] Open
Abstract
BackgroundRearrangements of Anaplastic lymphoma kinase (ALK) have been discovered as a novel driver mutation in patients with non–small-cell lung cancer (NSCLC). Patients’ responses to ALK tyrosine kinase inhibitors (TKIs) may vary depending on the variations of ALK rearrangements they have. It is imperative for clinicians to identify druggable ALK fusions in routine practice.Case PresentationIn this study, we discovered a rare ALK rearrangement type (SDK1–ALK) in a Chinese lung adenocarcinoma patient who responded well to ALK inhibitor SAF-189s. The positive expression of ALK in lung biopsy tissue was verified by IHC analysis. A new SDK1-ALK fusion was discovered using NGS. The patient was treated with SAF-189s (160 mg per day) as a first-line therapy and went into continuous remission, with a 12 months progression-free survival at the last follow-up.ConclusionThis is the first case of SDK1-ALK fusion with an excellent response to an ALK inhibitor, which will provide better understanding of ALK-TKI applications for NSCLC patients with ALK fusion in the future.
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Affiliation(s)
- Lin Ma
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shandong Lung Cancer Institute, Jinan, China
- Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, China
| | - Junjuan Xiao
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shandong Lung Cancer Institute, Jinan, China
- Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, China
| | - Yaping Guan
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shandong Lung Cancer Institute, Jinan, China
- Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, China
| | - Dongfang Wu
- YuceBio Technology Co., Ltd, Shenzhen, China
| | - Tiantian Gu
- YuceBio Technology Co., Ltd, Shenzhen, China
| | - Jun Wang
- Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
- Shandong Lung Cancer Institute, Jinan, China
- Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, China
- *Correspondence: Jun Wang,
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16
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Meng NL, Wang YK, Wang HL, Zhou JL, Wang SN. Research on the Histological Features and Pathological Types of Gastric Adenocarcinoma With Mucinous Differentiation. Front Med (Lausanne) 2022; 9:829702. [PMID: 35308509 PMCID: PMC8931263 DOI: 10.3389/fmed.2022.829702] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 01/25/2022] [Indexed: 12/20/2022] Open
Abstract
ObjectiveTo discuss the histological features, pathological types, and prognosis of gastric adenocarcinoma with mucinous differentiation.MethodsSpecimens of 189 cases of gastric adenocarcinoma with mucinous differentiation were collected for detailed histomorphology, immunohistochemistry, fluorescence in situ hybridization, and follow-up.ResultsIn accordance with the morphological and histological structural features of the cancer cells as well as the area ratio of the mucus, gastric adenocarcinoma with mucinous differentiation was divided into four types, namely pure mucinous carcinoma, intraductal papillary mucinous carcinoma, signet ring cell type mucinous carcinoma, and mixed cell type mucinous carcinoma. Based on the macroscopic types according to Bormann's classification, pure mucinous carcinoma was mostly Type I, intraductal papillary mucinous carcinoma was mostly Type II, signet ring cell type mucinous carcinoma was mostly Type IV, and mixed cell type mucinous carcinoma was mostly Type III. The 5-year survival rate was 69.2, 64.2, 0, and 31.5%, respectively. There was a statistical difference in the lymph node metastasis rate and survival rate of the four carcinoma types. The invasion features of pure mucinous carcinoma entailed penetrating corrosively in a push-in form, without blood vessel or lymphatic metastasis and with few lymphocytes and lymphatic nodules in the marginal area. Thus, there was little lymph node metastasis and invasion of nerves. The HER2 protein expression rate was 40.2% (76/189), the HER2 gene amplification detected by FISH technology was 16.9% (32/189).ConclusionThe independent histological type, four subtypes, and histopathological classification of gastric mucinous adenocarcinoma are important for the prognosis evaluation and precise treatment of this disease.
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Affiliation(s)
- Nian-Long Meng
- Department of Pathology, 989th Hospital of the Joint Logistic Support Force of the PLA, Luoyang, China
| | - Yang-kun Wang
- Department of Pathology, Foresea Life Insurance Guangzhou General Hospital, Guangzhou, China
| | - Hai-Li Wang
- Department of Pathology, 989th Hospital of the Joint Logistic Support Force of the PLA, Luoyang, China
| | - Jun-Ling Zhou
- Shenzhen Nanshan District People's Hospital, Shenzhen, China
| | - Su-nan Wang
- Shenzhen Polytechnic, Shenzhen, China
- *Correspondence: Su-nan Wang
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17
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Lifestyles, genetics, and future perspectives on gastric cancer in east Asian populations. J Hum Genet 2021; 66:887-899. [PMID: 34267306 PMCID: PMC8384627 DOI: 10.1038/s10038-021-00960-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 06/08/2021] [Accepted: 07/05/2021] [Indexed: 12/17/2022]
Abstract
The prevalence of gastric cancer (GC) differs among regions worldwide, with the highest occurrence in east Asia. Thus, its etiology, with respect to ethnic background, environmental factors, and lifestyles, is also thought to differ essentially. In addition, etiology of GC is speculated to be changing due to the recent decrease in the Helicobacter pylori (H. pylori) infection in Japan. State-of-the-art somatic/germline cancer genomics has clarified the etiologies of gastric carcinogenesis. In this review article, we summarize past and present milestones in our understanding of GC achieved through genomic approaches, including a recent report that revealed higher-than-expected frequencies of GCs attributed to east Asian-specific germline variants in ALDH2 or CDH1 in combination with lifestyles. Based on this updated knowledge, we also discuss the possible impact of and high-risk approaches for GCs in the upcoming "H. pylori-negative era."
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18
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Numakura S, Uozaki H. Low MLL2 Protein Expression Is Associated With Fibrosis in Early Stage Gastric Cancer. In Vivo 2021; 35:603-609. [PMID: 33402515 DOI: 10.21873/invivo.12297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/19/2020] [Accepted: 11/20/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND/AIM Myeloid/lymphoid or mixed lineage leukemia 2 (MLL2) gene is mutated in gastric cancer, with most resulting in inactivated proteins. In this study, we examined the expression of MLL2 protein in gastric cancers. PATIENTS AND METHODS The expression of MLL2 protein in cancer cell nuclei was studied by immunohistochemistry in tissue microarrays of 529 human gastric cancers. MLL2 expression was classified into low and high expression from the point of zygosity, and its relationships with mismatch repair protein expression and clinicopathological features were examined. RESULTS Low expression of MLL2 was associated with younger age, MSH6, and early cancers. MLL2-low pT1a cancers were associated with fibrosis, especially ulcer scars, and in 62.5% of them there was no direct contact between carcinoma and fibrosis. CONCLUSION There is potentially an association between low expression of MLL2 protein and gastric malignancy from chronic fibrosis.
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Affiliation(s)
- Satoe Numakura
- Department of Pathology, Teikyo University School of Medicine, Tokyo, Japan
| | - Hiroshi Uozaki
- Department of Pathology, Teikyo University School of Medicine, Tokyo, Japan
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19
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Imamura Y, Watanabe M, Oki E, Morita M, Baba H. Esophagogastric junction adenocarcinoma shares characteristics with gastric adenocarcinoma: Literature review and retrospective multicenter cohort study. Ann Gastroenterol Surg 2021; 5:46-59. [PMID: 33532680 PMCID: PMC7832959 DOI: 10.1002/ags3.12406] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 08/23/2020] [Accepted: 09/21/2020] [Indexed: 12/12/2022] Open
Abstract
The incidence of esophagogastric junction (EGJ) adenocarcinoma has been gradually increasing in Asia, just like in Western countries a few decades ago. Despite recent advances in next-generation sequencing and multimodal treatments, EGJ adenocarcinoma is still an aggressive malignancy with poor outcomes. Clinically, EGJ adenocarcinoma can be separated into Barrett's adenocarcinoma and cardiac adenocarcinoma, with frequent similarities observed. Barrett's adenocarcinoma is likely to be of gastric origin in terms of its premalignant background, risk factors, and stem cell regulators. Recent comprehensive genomic analyses suggest that immunotherapy may be essential for high-level microsatellite instability (MSI-H)- and Epstein-Barr virus (EBV)-associated subtypes, and against the immunosuppressive phenotype in genomically stable (GS) subtypes, in the treatment of EGJ and gastric adenocarcinoma. Although the chromosomal instability (CIN) subtype dominates EGJ adenocarcinoma, there is still a need to investigate the other molecular subtypes and their targets. Because of the distinctive characteristics of tumor location of EGJ adenocarcinoma, we also described the results of a multicenter cohort study of EGJ adenocarcinoma, comparing Siewert type I (distal esophagus), II (cardia of the stomach), and III (subcardia) tumors. We show that type I tumors were frequently accompanied by Barrett's esophagus (78%, P < .0001), with a significantly unfavorable outcome (multivariate EGJ-cancer-specific mortality hazard ratio = 1.81, 95% CI, 1.06-2.97; P = .031). In addition, over half (56%) of these cases experienced disease recurrence in the lymph nodes. Our findings suggest that Barrett's adenocarcinoma may be an aggressive phenotype of EGJ adenocarcinoma due to the potential risk of tumor spread through the complex lympho-vascular network of the esophagus.
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Affiliation(s)
- Yu Imamura
- Department of Gastroenterological SurgeryCancer Institute Hospital of Japanese Foundation of Cancer ResearchTokyoJapan
| | - Masayuki Watanabe
- Department of Gastroenterological SurgeryCancer Institute Hospital of Japanese Foundation of Cancer ResearchTokyoJapan
| | - Eiji Oki
- Department of Surgery and ScienceGraduate School of Medical SciencesKyushu UniversityFukuokaJapan
| | - Masaru Morita
- Department of Gastroenterological SurgeryKyushu Cancer CenterNational Hospital OrganizationFukuokaJapan
| | - Hideo Baba
- Department of Gastroenterological SurgeryGraduate School of Medical SciencesKumamoto UniversityKumamotoJapan
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20
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Wang R, Chen M, Ye X, Poon K. Role and potential clinical utility of ARID1A in gastrointestinal malignancy. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2020; 787:108360. [PMID: 34083049 DOI: 10.1016/j.mrrev.2020.108360] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 11/26/2020] [Accepted: 11/29/2020] [Indexed: 12/12/2022]
Abstract
ARID1A (AT-rich interactive domain 1A) is a newly discovered tumor suppressor gene, and its encoded product is an important component of the SWI/SNF chromatin remodeling complex. ARID1A plays an important role in cell proliferation, invasion and metastasis, apoptosis, cell cycle regulation, epithelial mesenchymal transition, and the regulation of other of biological behaviors. Recently, ARID1A mutations have been increasingly reported in esophageal adenocarcinoma, gastric cancer, colorectal cancer, hepatocellular carcinoma, cholangiocarcinoma, pancreatic cancer, and other malignant tumors of the digestive system. This article reviews the relationship between ARID1A mutation and the molecular mechanisms of carcinogenesis, including microsatellite instability and the PI3K/ATK signaling pathway, and relates these mechanisms to the prognostic assessment of digestive malignancy. Further, this review describes the potential for molecular pathologic epidemiology (MPE) to provide new insights into environment-tumor-host interactions.
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Affiliation(s)
- Ruihua Wang
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, 518000, Guangdong Province, China.
| | - Mei Chen
- Department of Gastroenterology, Shenzhen Hospital, Southern Medical University, Shenzhen, 518000, Guangdong Province, China.
| | - Xiaojun Ye
- Program of Food Science and Technology, Division of Science and Technology, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, 519085, Guangdong Province, China.
| | - Karen Poon
- Program of Food Science and Technology, Division of Science and Technology, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai, 519085, Guangdong Province, China.
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21
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Remodeling of the ARID1A tumor suppressor. Cancer Lett 2020; 491:1-10. [PMID: 32738271 DOI: 10.1016/j.canlet.2020.07.026] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 07/06/2020] [Accepted: 07/22/2020] [Indexed: 12/26/2022]
Abstract
In recent years, AT-rich interactive domain-containing protein 1A (ARID1A) has been widely accepted as a bona fide tumor suppressor due to its essential role in preventing tumorigenesis and tumor progression in both mouse and human contexts. ARID1A shows high mutation frequencies in both cancers and preneoplastic lesions. The loss of ARID1A expression in cancer cells leads to increases in cell proliferation, invasion and migration and reductions in cell apoptosis and chemosensitivity. The tumor-suppressive role of ARID1A is mainly attributed to its regulation of gene transcription, which can be induced either directly by chromatin remodeling or indirectly by affecting histone modifications. ARID1A also acts independently of its cardinal transcription-regulating mechanisms, which include interfering with protein-protein interactions. Interestingly, nonmutational mechanisms, such as regulation by DNA hypermethylation, microRNAs, and ubiquitinases/deubiquitinases, have provided another perspective on ARID1A inactivation in cancer. Since the critical tumor-suppressive role of ARID1A has been revealed, several studies have attempted to identify synthetic lethal targets with ARID1A mutation/inactivation as an alternative strategy for cancer treatment.
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Abstract
Many of the immunoglobulin superfamily (IgSF) molecules play pivotal roles in cell communication. The Sidekick (Sdk) gene, first described in Drosophila, encodes the single-pass transmembrane protein, Sdk, which is one of the largest among IgSF membrane proteins. Sdk first appeared in multicellular animals during the Precambrian age and later evolved to Sdk1 and Sdk2 in vertebrates by gene duplication. In flies, a single Sdk is involved in positioning photoreceptor neurons and their axons in the visual system and is responsible for dynamically rearranging cell shapes by strictly populating tricellular adherens junctions in epithelia. In vertebrates, Sdk1 and Sdk2 are expressed by unique sets of cell types and distinctively participate in the formation and/or maintenance of neural circuits in the retina, indicating that they are determinants of synaptic specificity. These functions are mediated by specific homophilic binding of their ectodomains and by intracellular association with PDZ scaffold proteins. Recent human genetic studies as well as animal experiments implicate that Sdk genes may influence various neurodevelopmental and psychiatric disorders, such as autism spectrum disorders, attention-deficit hyperactivity disorder, addiction, and depression. The gigantic Sdk1 gene is susceptible to erratic gene rearrangements or mutations in both somatic and germ-line cells, potentially contributing to neurological disorders and some types of cancers. This review summarizes what is known about the structure and roles of Sdks.
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Affiliation(s)
- Masahito Yamagata
- Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, Cambridge, MA, United States
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23
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Ye G, Yang Q, Lei X, Zhu X, Li F, He J, Chen H, Ling R, Zhang H, Lin T, Liang Z, Liang Y, Huang H, Guo W, Deng H, Liu H, Hu Y, Yu J, Li G. Nuclear MYH9-induced CTNNB1 transcription, targeted by staurosporin, promotes gastric cancer cell anoikis resistance and metastasis. Theranostics 2020; 10:7545-7560. [PMID: 32685004 PMCID: PMC7359096 DOI: 10.7150/thno.46001] [Citation(s) in RCA: 121] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 05/30/2020] [Indexed: 12/23/2022] Open
Abstract
Rationale: Peritoneal metastasis predicts poor prognosis of gastric cancer (GC) patients, and the underlying mechanisms are poorly understood. Methods: The 2-DIGE, MALDI-TOF/TOF MS and single-cell transcriptome were used to detect differentially expressed proteins among normal gastric mucosa, primary GC and peritoneal metastatic tissues. Lentiviruses carrying shRNA and transcription activator-like effector nuclease technology were used to knock down myosin heavy chain 9 (MYH9) expression in GC cell lines. Immunofluorescence, immune transmission electron microscopy, chromatin fractionation, co-immunoprecipitation, and assays for chromatin immunoprecipitation, dual luciferase reporter, agarose-oligonucleotide pull-down, flow cytometry and cell anoikis were performed to uncover nuclear MYH9-induced β-catenin (CTNNB1) transcription in vitro. Nude mice and conditional transgenic mice were used to investigate the findings in vivo. Results: We observed that MYH9 was upregulated in metastatic GC tissues and was associated with a poor prognosis of GC patients. Mechanistically, we confirmed that MYH9 was mainly localized in the GC cell nuclei by four potential nuclear localization signals. Nuclear MYH9 bound to the CTNNB1 promoter through its DNA-binding domain, and interacted with myosin light chain 9, β-actin and RNA polymerase II to promote CTNNB1 transcription, which conferred resistance to anoikis in GC cells in vitro and in vivo. Staurosporine reduced nuclear MYH9 S1943 phosphorylation to inhibit CTNNB1 transcription, Wnt/β-catenin signaling activation and GC progression in both orthotropic xenograft GC nude mouse and transgenic GC mouse models. Conclusion: This study identified that nuclear MYH9-induced CTNNB1 expression promotes GC metastasis, which could be inhibited by staurosporine, indicating a novel therapy for GC peritoneal metastasis.
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Affiliation(s)
- Gengtai Ye
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
| | - Qingbin Yang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
| | - Xuetao Lei
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
| | - Xianjun Zhu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Present address: Department of General Surgery, Panyu Central Hospital, Guangzhou, Guangdong 511400, China
| | - Fengping Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
| | - Jiayong He
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
| | - Hao Chen
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
| | - Ruoyu Ling
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
| | - Haisheng Zhang
- Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Tian Lin
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
| | - Zhiping Liang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
| | - Yanrui Liang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
| | - Haipeng Huang
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
| | - Weihong Guo
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
| | - Haijun Deng
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
| | - Hao Liu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
| | - Yanfeng Hu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
| | - Jiang Yu
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
| | - Guoxin Li
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guangdong 510515, China
- Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Guangzhou, Guangdong 510515, China
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24
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Dragani TA, Matarese V, Colombo F. Biomarkers for Early Cancer Diagnosis: Prospects for Success through the Lens of Tumor Genetics. Bioessays 2020; 42:e1900122. [PMID: 32128843 DOI: 10.1002/bies.201900122] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 01/15/2020] [Indexed: 12/14/2022]
Abstract
Thousands of candidate cancer biomarkers have been proposed, but so far, few are used in cancer screening. Failure to implement these biomarkers is attributed to technical and design flaws in the discovery and validation phases, but a major obstacle stems from cancer biology itself. Oncogenomics has revealed broad genetic heterogeneity among tumors of the same histology and same tissue (or organ) from different patients, while tumors of different tissue origins also share common genetic mutations. Moreover, there is wide intratumor genetic heterogeneity among cells within any single neoplasm. These findings seriously limit the prospects of finding a single biomarker with high specificity for early cancer detection. Current research focuses on developing biomarker panels, with data assessment by machine-learning algorithms. Whether such approaches will overcome the inherent limitations posed by tumor biology and lead to tests with true clinical value remains to be seen.
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Affiliation(s)
- Tommaso A Dragani
- Department of Research , Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. A. Amadeo, 42, I-20133, Milan, Italy
| | | | - Francesca Colombo
- Department of Research , Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. A. Amadeo, 42, I-20133, Milan, Italy
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25
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Hung YH, Hsu MC, Chen LT, Hung WC, Pan MR. Alteration of Epigenetic Modifiers in Pancreatic Cancer and Its Clinical Implication. J Clin Med 2019; 8:jcm8060903. [PMID: 31238554 PMCID: PMC6617267 DOI: 10.3390/jcm8060903] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 06/15/2019] [Accepted: 06/20/2019] [Indexed: 12/12/2022] Open
Abstract
The incidence of pancreatic cancer has considerably increased in the past decade. Pancreatic cancer has the worst prognosis among the cancers of the digestive tract because the pancreas is located in the posterior abdominal cavity, and most patients do not show clinical symptoms for early detection. Approximately 55% of all patients are diagnosed with pancreatic cancer only after the tumors metastasize. Therefore, identifying useful biomarkers for early diagnosis and screening high-risk groups are important to improve pancreatic cancer therapy. Recent emerging evidence has suggested that genetic and epigenetic alterations play a crucial role in the molecular aspects of pancreatic tumorigenesis. Here, we summarize recent progress in our understanding of the epigenetic alterations in pancreatic cancer and propose potential synthetic lethal strategies to target these genetic defects to treat this deadly disease.
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Affiliation(s)
- Yu-Hsuan Hung
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
| | - Ming-Chuan Hsu
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
- Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan.
| | - Wen-Chun Hung
- National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan.
- Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
| | - Mei-Ren Pan
- Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
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26
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Zhang G, Zhou S, Zhong W, Hong L, Wang Y, Lu S, Pan J, Huang Y, Su M, Crawford R, Zhou Y, Mai R. Whole-Exome Sequencing Reveals Frequent Mutations in Chromatin Remodeling Genes in Mammary and Extramammary Paget's Diseases. J Invest Dermatol 2019; 139:789-795. [PMID: 30905357 DOI: 10.1016/j.jid.2018.08.030] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 08/06/2018] [Accepted: 08/06/2018] [Indexed: 02/05/2023]
Abstract
Paget's disease (PD) is an intraepidermal adenocarcinoma of the skin at the breast (mammary PD) or urogenital locations (extramammary PD [EMPD]). At present, there is lack of clarity on PD's pathogenesis, the relationship between its subtypes, and its lineage link with the underlying invasive carcinomas. Here we describe that mammary PD and EMPD have similar mutational profiles, with the most frequent recurrent mutations occurring in the chromatin remodeling genes, such as KMT2C (MLL3, 39%) and ARID2 (22%), with additional recurrent somatic mutations detected in genes previously not known to be mutated in cancers, such as CDCC168 (34%), FSIP2 (29%), CASP8AP2 (29%), and BIRC6 (24%). In paired mammary PD and underlying breast carcinoma samples, distinct gene mutations were detected, indicating that they represent independent oncogenic events. Finally, multistage EMPD tissue sequencing revealed KMT2C gene occurring early in EMPD oncogenesis, and that multifocal EMPD samples share the same early gene mutations, suggesting clonal origin of multifocal EMPD. Our results reveal similar genomic landscapes between mammary PD and EMPD, including early aberrations in chromatin remodeling genes. In addition, mammary PD and underlying breast ductal carcinomas represent independent oncogenic events. These findings provide approaches for developing diagnostic tools and therapeutic interventions for PD.
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Affiliation(s)
- Guohong Zhang
- Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China
| | - Songxia Zhou
- Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China
| | - Weixiang Zhong
- Department of Pathology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Liangli Hong
- Department of Pathology, First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Yuanyuan Wang
- Department of Pathology, Shantou Central Hospital of and the Affiliated Shantou Hospital of Sun Yat-Sen University, Shantou, Guangdong, China
| | - Shanming Lu
- Department of Pathology, Meizhou Central Hospital, Meizhou, Guangdong, China
| | - Jiankai Pan
- Department of Pathology, Shantou Hospital of Dermatology, Shantou, Guangdong, China
| | - Yuansheng Huang
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada
| | - Mingwan Su
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada
| | - Richard Crawford
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada
| | - Youwen Zhou
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, British Columbia, Canada.
| | - Ruiqin Mai
- Department of Laboratory Medicine, First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
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27
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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] [MESH Headings] [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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28
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Ghanavat M, Ebrahimi M, Rafieemehr H, Maniati M, Behzad MM, Shahrabi S. Thrombocytopenia in solid tumors: Prognostic significance. Oncol Rev 2019; 13:413. [PMID: 31205603 PMCID: PMC6542370 DOI: 10.4081/oncol.2019.413] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 03/18/2019] [Indexed: 01/01/2023] Open
Abstract
Solid tumors are a heterogeneous group of malignancies that result from out-of-control proliferation of cells. Thrombocytopenia is a common complication among patients with solid tumors that predispose them to bleeding disorders. The aim of this review article is to investigate the underlying mechanisms of the risk and incidence of thrombocytopenia in solid tumors. It can be argued that thrombocytopenia is a poor prognostic factor in solid tumors that can result from several factors such as polymorphism and mutation in some transcription factors and cytokines involved in megakaryocytic maturation or from the adverse effects of treatment. Therefore, an understanding of the exact mechanism of thrombocytopenia pathogenesis in each stage of solid tumors can help in developing therapeutic strategies to decrease bleeding complications in these malignancies.
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Affiliation(s)
- Majid Ghanavat
- Child Growth and Development Research Center, Isfahan University of Medical Sciences, Isfahan
| | - Mina Ebrahimi
- Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz
| | - Hassan Rafieemehr
- Department of Medical Laboratory Sciences, School of Paramedicine, Hamadan University of Medical Sciences, Hamadan
| | - Mahmood Maniati
- Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz
| | - Masumeh Maleki Behzad
- Thalassemia and Hemoglobinopathy Research Center, Research Institute of Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz
| | - Saeid Shahrabi
- Department of Biochemistry and Hematology, Faculty of Medicine, Semnan University Of Medical Sciences, Semnan, Iran
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29
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Cabel L, Aparicio T, Bieche I, Svrcek M, Zaanan A, Afchain P, Di Fiore F, Gornet JM, Le Corre D, Vacher S, Callens C, Bernard V, Laurent-Puig P, Bidard FC. ERBB3-Activating Mutations in Small Bowel Adenocarcinomas. JCO Precis Oncol 2018; 2:1-9. [DOI: 10.1200/po.17.00243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Purpose Functional studies have demonstrated that some mutations of ERBB3, which encodes for human epidermal growth factor receptor (HER) 3, are oncogenic via activation of the ErbB family signaling pathway. Significant clinical activity of anti-HER2 therapies (trastuzumab plus lapatinib combination or afatinib) has been reported in patients with ERBB3-mutated cancers. This study was designed to report the rate of activating ERBB3 mutations in small bowel adenocarcinoma (SBA), a rare tumor type in which we previously reported a high rate (12%) of ERBB2-activating mutations. Materials and Methods DNA from 74 SBAs, previously characterized for ERBB2 mutations and mismatch repair status, was submitted for sequencing of ERBB3 exons 3, 6, 7, 8, and 23. Orthogonal validation by targeted next-generation sequencing was performed. Results Four of 74 SBAs (5.4%) displayed ERBB3-activating mutations, including three p.V104M mutations (c.310 G>A) in exon 3 and one p.E928G mutation (c.2783 A>G) in exon 23. No mutations were detected in exons 6, 7, and 8. ERBB3-activating mutations were associated with microsatellite instability ( P = .002) and the presence of ERBB2-activating mutations ( P = .002). Two SBAs with co-occurrence of ERBB2 and ERBB3 mutations were further analyzed by targeted next-generation sequencing. Mutant allelic frequencies suggested that both mutations were shared by the same clone rather than being harbored by mutually exclusive tumor subclones. Conclusion SBAs display a high rate of ERBB3-activating mutations, which have been shown to be targetable by anti-HER2 therapies. Strikingly, ERBB3 was frequently comutated with ERBB2, suggesting a strong oncogenic addiction of these SBAs to the HER2 pathway.
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Affiliation(s)
- Luc Cabel
- Luc Cabel, Ivan Bieche, Sophie Vacher, Celine Callens, Virginie Bernard, and François-Clément Bidard, Institut Curie; Thomas Aparicio and Jean-Marc Gornet, Hôpital Saint Louis; Magali Svrcek and Pauline Afchain, Hôpital Saint Antoine; Aziz Zaanan, Hôpital Européen Georges Pompidou; Delphine Le Corre and Pierre Laurent-Puig, Paris Descartes University, Paris; and Frédéric Di Fiore, CHU Charles Nicolle, Rouen, France
| | - Thomas Aparicio
- Luc Cabel, Ivan Bieche, Sophie Vacher, Celine Callens, Virginie Bernard, and François-Clément Bidard, Institut Curie; Thomas Aparicio and Jean-Marc Gornet, Hôpital Saint Louis; Magali Svrcek and Pauline Afchain, Hôpital Saint Antoine; Aziz Zaanan, Hôpital Européen Georges Pompidou; Delphine Le Corre and Pierre Laurent-Puig, Paris Descartes University, Paris; and Frédéric Di Fiore, CHU Charles Nicolle, Rouen, France
| | - Ivan Bieche
- Luc Cabel, Ivan Bieche, Sophie Vacher, Celine Callens, Virginie Bernard, and François-Clément Bidard, Institut Curie; Thomas Aparicio and Jean-Marc Gornet, Hôpital Saint Louis; Magali Svrcek and Pauline Afchain, Hôpital Saint Antoine; Aziz Zaanan, Hôpital Européen Georges Pompidou; Delphine Le Corre and Pierre Laurent-Puig, Paris Descartes University, Paris; and Frédéric Di Fiore, CHU Charles Nicolle, Rouen, France
| | - Magali Svrcek
- Luc Cabel, Ivan Bieche, Sophie Vacher, Celine Callens, Virginie Bernard, and François-Clément Bidard, Institut Curie; Thomas Aparicio and Jean-Marc Gornet, Hôpital Saint Louis; Magali Svrcek and Pauline Afchain, Hôpital Saint Antoine; Aziz Zaanan, Hôpital Européen Georges Pompidou; Delphine Le Corre and Pierre Laurent-Puig, Paris Descartes University, Paris; and Frédéric Di Fiore, CHU Charles Nicolle, Rouen, France
| | - Aziz Zaanan
- Luc Cabel, Ivan Bieche, Sophie Vacher, Celine Callens, Virginie Bernard, and François-Clément Bidard, Institut Curie; Thomas Aparicio and Jean-Marc Gornet, Hôpital Saint Louis; Magali Svrcek and Pauline Afchain, Hôpital Saint Antoine; Aziz Zaanan, Hôpital Européen Georges Pompidou; Delphine Le Corre and Pierre Laurent-Puig, Paris Descartes University, Paris; and Frédéric Di Fiore, CHU Charles Nicolle, Rouen, France
| | - Pauline Afchain
- Luc Cabel, Ivan Bieche, Sophie Vacher, Celine Callens, Virginie Bernard, and François-Clément Bidard, Institut Curie; Thomas Aparicio and Jean-Marc Gornet, Hôpital Saint Louis; Magali Svrcek and Pauline Afchain, Hôpital Saint Antoine; Aziz Zaanan, Hôpital Européen Georges Pompidou; Delphine Le Corre and Pierre Laurent-Puig, Paris Descartes University, Paris; and Frédéric Di Fiore, CHU Charles Nicolle, Rouen, France
| | - Frédéric Di Fiore
- Luc Cabel, Ivan Bieche, Sophie Vacher, Celine Callens, Virginie Bernard, and François-Clément Bidard, Institut Curie; Thomas Aparicio and Jean-Marc Gornet, Hôpital Saint Louis; Magali Svrcek and Pauline Afchain, Hôpital Saint Antoine; Aziz Zaanan, Hôpital Européen Georges Pompidou; Delphine Le Corre and Pierre Laurent-Puig, Paris Descartes University, Paris; and Frédéric Di Fiore, CHU Charles Nicolle, Rouen, France
| | - Jean-Marc Gornet
- Luc Cabel, Ivan Bieche, Sophie Vacher, Celine Callens, Virginie Bernard, and François-Clément Bidard, Institut Curie; Thomas Aparicio and Jean-Marc Gornet, Hôpital Saint Louis; Magali Svrcek and Pauline Afchain, Hôpital Saint Antoine; Aziz Zaanan, Hôpital Européen Georges Pompidou; Delphine Le Corre and Pierre Laurent-Puig, Paris Descartes University, Paris; and Frédéric Di Fiore, CHU Charles Nicolle, Rouen, France
| | - Delphine Le Corre
- Luc Cabel, Ivan Bieche, Sophie Vacher, Celine Callens, Virginie Bernard, and François-Clément Bidard, Institut Curie; Thomas Aparicio and Jean-Marc Gornet, Hôpital Saint Louis; Magali Svrcek and Pauline Afchain, Hôpital Saint Antoine; Aziz Zaanan, Hôpital Européen Georges Pompidou; Delphine Le Corre and Pierre Laurent-Puig, Paris Descartes University, Paris; and Frédéric Di Fiore, CHU Charles Nicolle, Rouen, France
| | - Sophie Vacher
- Luc Cabel, Ivan Bieche, Sophie Vacher, Celine Callens, Virginie Bernard, and François-Clément Bidard, Institut Curie; Thomas Aparicio and Jean-Marc Gornet, Hôpital Saint Louis; Magali Svrcek and Pauline Afchain, Hôpital Saint Antoine; Aziz Zaanan, Hôpital Européen Georges Pompidou; Delphine Le Corre and Pierre Laurent-Puig, Paris Descartes University, Paris; and Frédéric Di Fiore, CHU Charles Nicolle, Rouen, France
| | - Celine Callens
- Luc Cabel, Ivan Bieche, Sophie Vacher, Celine Callens, Virginie Bernard, and François-Clément Bidard, Institut Curie; Thomas Aparicio and Jean-Marc Gornet, Hôpital Saint Louis; Magali Svrcek and Pauline Afchain, Hôpital Saint Antoine; Aziz Zaanan, Hôpital Européen Georges Pompidou; Delphine Le Corre and Pierre Laurent-Puig, Paris Descartes University, Paris; and Frédéric Di Fiore, CHU Charles Nicolle, Rouen, France
| | - Virginie Bernard
- Luc Cabel, Ivan Bieche, Sophie Vacher, Celine Callens, Virginie Bernard, and François-Clément Bidard, Institut Curie; Thomas Aparicio and Jean-Marc Gornet, Hôpital Saint Louis; Magali Svrcek and Pauline Afchain, Hôpital Saint Antoine; Aziz Zaanan, Hôpital Européen Georges Pompidou; Delphine Le Corre and Pierre Laurent-Puig, Paris Descartes University, Paris; and Frédéric Di Fiore, CHU Charles Nicolle, Rouen, France
| | - Pierre Laurent-Puig
- Luc Cabel, Ivan Bieche, Sophie Vacher, Celine Callens, Virginie Bernard, and François-Clément Bidard, Institut Curie; Thomas Aparicio and Jean-Marc Gornet, Hôpital Saint Louis; Magali Svrcek and Pauline Afchain, Hôpital Saint Antoine; Aziz Zaanan, Hôpital Européen Georges Pompidou; Delphine Le Corre and Pierre Laurent-Puig, Paris Descartes University, Paris; and Frédéric Di Fiore, CHU Charles Nicolle, Rouen, France
| | - François-Clément Bidard
- Luc Cabel, Ivan Bieche, Sophie Vacher, Celine Callens, Virginie Bernard, and François-Clément Bidard, Institut Curie; Thomas Aparicio and Jean-Marc Gornet, Hôpital Saint Louis; Magali Svrcek and Pauline Afchain, Hôpital Saint Antoine; Aziz Zaanan, Hôpital Européen Georges Pompidou; Delphine Le Corre and Pierre Laurent-Puig, Paris Descartes University, Paris; and Frédéric Di Fiore, CHU Charles Nicolle, Rouen, France
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30
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Abstract
The genetic concept of synthetic lethality has now been validated clinically through the demonstrated efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors for the treatment of cancers in individuals with germline loss-of-function mutations in either BRCA1 or BRCA2. Three different PARP inhibitors have now been approved for the treatment of patients with BRCA-mutant ovarian cancer and one for those with BRCA-mutant breast cancer; these agents have also shown promising results in patients with BRCA-mutant prostate cancer. Here, we describe a number of other synthetic lethal interactions that have been discovered in cancer. We discuss some of the underlying principles that might increase the likelihood of clinical efficacy and how new computational and experimental approaches are now facilitating the discovery and validation of synthetic lethal interactions. Finally, we make suggestions on possible future directions and challenges facing researchers in this field.
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Affiliation(s)
- Alan Ashworth
- UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA.
| | - Christopher J Lord
- The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.
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31
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Bustelo XR. RHO GTPases in cancer: known facts, open questions, and therapeutic challenges. Biochem Soc Trans 2018; 46:741-760. [PMID: 29871878 PMCID: PMC7615761 DOI: 10.1042/bst20170531] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 04/17/2018] [Accepted: 05/03/2018] [Indexed: 02/06/2023]
Abstract
RHO GTPases have been traditionally associated with protumorigenic functions. While this paradigm is still valid in many cases, recent data have unexpectedly revealed that RHO proteins can also play tumor suppressor roles. RHO signaling elements can also promote both pro- and antitumorigenic effects using GTPase-independent mechanisms, thus giving an extra layer of complexity to the role of these proteins in cancer. Consistent with these variegated roles, both gain- and loss-of-function mutations in RHO pathway genes have been found in cancer patients. Collectively, these observations challenge long-held functional archetypes for RHO proteins in both normal and cancer cells. In this review, I will summarize these data and discuss new questions arising from them such as the functional and clinical relevance of the mutations found in patients, the mechanistic orchestration of those antagonistic functions in tumors, and the pros and cons that these results represent for the development of RHO-based anticancer drugs.
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Affiliation(s)
- Xosé R Bustelo
- Centro de Investigación del Cáncer, Instituto de Biología Molecular y Celular del Cáncer, and Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, 37007 Salamanca, Spain
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32
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Wen KW, Grenert JP, Joseph NM, Shafizadeh N, Huang A, Hosseini M, Kakar S. Genomic profile of appendiceal goblet cell carcinoid is distinct compared to appendiceal neuroendocrine tumor and conventional adenocarcinoma. Hum Pathol 2018; 77:166-174. [PMID: 29634977 DOI: 10.1016/j.humpath.2018.03.026] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 03/08/2018] [Accepted: 03/29/2018] [Indexed: 02/07/2023]
Abstract
Goblet cell carcinoid (GCC) is a rare appendiceal tumor with unique morphologic features that shows glandular and neuroendocrine differentiation on immunohistochemistry. An additional component of adenocarcinoma (AC) can be present (GCC-AC). Both GCC and GCC-AC are staged and treated like AC. The histogenesis and genetic alterations underlying GCC and GCC-AC are unclear. Capture-based next-generation DNA sequencing targeting 479 cancer genes was performed on 19 appendiceal tumors: 4 GCC, 9 GCC-AC, 3 neuroendocrine tumors (NET), and 3 AC (2 conventional, 1 mucinous). Somatic coding mutations were not seen in any NET. Pathogenic (P)/likely pathogenic (LP) mutations were present in 1 GCC, 8 GCC-AC and all 3 AC cases. P/LP mutations in chromatin remodeling genes were seen in 4 (44.4%) GCC-AC cases, but not in NET, GCC or AC. In GCC-AC, P/LP mutations in ARID1A and RHOA were each present in 3 cases, and KDM6A and SOX9 mutations were each seen in 2 cases. APC and KRAS mutations were present in 1 conventional AC case, but were not observed in any GCC or GCC-AC. This limited series reveals mutations in SOX9, RHOA, and chromatin-modifier genes in goblet cell tumors, and shows that the mutational profile of GCC/GCC-AC is distinct from NET and conventional appendiceal AC.
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Affiliation(s)
- Kwun Wah Wen
- Department of Pathology, University of California, San Francisco, San Francisco, CA 91343, United States
| | - James P Grenert
- Department of Pathology, University of California, San Francisco, San Francisco, CA 91343, United States
| | - Nancy M Joseph
- Department of Pathology, University of California, San Francisco, San Francisco, CA 91343, United States
| | | | - Anne Huang
- Vista Pathology, Medford, OR 97504, United States
| | - Mojgan Hosseini
- University of California, San Diego, San Diego, CA 92093, United States
| | - Sanjay Kakar
- Department of Pathology, University of California, San Francisco, San Francisco, CA 91343, United States.
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33
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Andricovich J, Perkail S, Kai Y, Casasanta N, Peng W, Tzatsos A. Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors. Cancer Cell 2018; 33. [PMID: 29533787 PMCID: PMC5854186 DOI: 10.1016/j.ccell.2018.02.003] [Citation(s) in RCA: 225] [Impact Index Per Article: 32.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
KDM6A, an X chromosome-encoded histone demethylase and member of the COMPASS-like complex, is frequently mutated in a broad spectrum of malignancies and contributes to oncogenesis with poorly characterized mechanisms. We found that KDM6A loss induced squamous-like, metastatic pancreatic cancer selectively in females through deregulation of the COMPASS-like complex and aberrant activation of super-enhancers regulating ΔNp63, MYC, and RUNX3 oncogenes. This subtype of tumor developed in males had concomitant loss of UTY and KDM6A, suggesting overlapping roles, and points to largely demethylase independent tumor suppressor functions. We also demonstrate that KDM6A-deficient pancreatic cancer is selectively sensitive to BET inhibitors, which reversed squamous differentiation and restrained tumor growth in vivo, highlighting a therapeutic niche for patient tailored therapies.
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Affiliation(s)
- Jaclyn Andricovich
- Cancer Epigenetics Laboratory, Department of Anatomy and Regenerative Biology, George Washington University (GWU) School of Medicine and Health Sciences, Washington, DC 20052, USA; GWU Cancer Center, GWU School of Medicine and Health Sciences, Washington, DC 20052, USA
| | - Stephanie Perkail
- Cancer Epigenetics Laboratory, Department of Anatomy and Regenerative Biology, George Washington University (GWU) School of Medicine and Health Sciences, Washington, DC 20052, USA; GWU Cancer Center, GWU School of Medicine and Health Sciences, Washington, DC 20052, USA
| | - Yan Kai
- Cancer Epigenetics Laboratory, Department of Anatomy and Regenerative Biology, George Washington University (GWU) School of Medicine and Health Sciences, Washington, DC 20052, USA; GWU Cancer Center, GWU School of Medicine and Health Sciences, Washington, DC 20052, USA; Department of Physics, GWU, Washington, DC 20052, USA
| | - Nicole Casasanta
- Cancer Epigenetics Laboratory, Department of Anatomy and Regenerative Biology, George Washington University (GWU) School of Medicine and Health Sciences, Washington, DC 20052, USA
| | - Weiqun Peng
- GWU Cancer Center, GWU School of Medicine and Health Sciences, Washington, DC 20052, USA; Department of Physics, GWU, Washington, DC 20052, USA
| | - Alexandros Tzatsos
- Cancer Epigenetics Laboratory, Department of Anatomy and Regenerative Biology, George Washington University (GWU) School of Medicine and Health Sciences, Washington, DC 20052, USA; GWU Cancer Center, GWU School of Medicine and Health Sciences, Washington, DC 20052, USA.
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34
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Cai L, Li Y, Yang XW, Lian X, Guo M, Xiao SA, Wang WB, Zhang HW. Prognostic significance of mucinous component in gastric adenocarcinoma after radical D2 gastrectomy. Onco Targets Ther 2018; 11:967-973. [PMID: 29503571 PMCID: PMC5827682 DOI: 10.2147/ott.s152614] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND The mucinous component is a special histologic factor in gastric adenocarcinoma. The aim of this study was to assess the prognostic significance of mucinous component in gastric adenocarcinoma according to proportion. PATIENTS AND METHODS Candidate patients with gastric adenocarcinoma were given radical D2 gastrectomies from September 2008 to May 2015 in our division. Clinicopathologic data and prognosis were monitored and analyzed among gastric adenocarcinoma patients with various proportions of mucinous component. RESULTS A total of 690 gastric adenocarcinomas with various proportions of mucinous component from 6,025 gastric adenocarcinoma patients were included. Higher numbers of patients with mucinous component came from: young patients, females, those with drinking history, at lower locations, Borrmann type III and IV, T4 stage, and positive for dissected lymph nodes. Tumors and pathological molecular markers showed more positivity in CEA, CA19-9, S100, and CD34. As the various proportions increased, more mucinous component seemed to be accompanied by more Borrmann type III and IV, T4 stage, and more positive expression of CEA and CA19-9. However, no significant difference in 5-year overall survival rate was observed among various proportions or existence of mucinous component. Also, proportion or existence of mucinous component was not an independent prognostic factor in multivariate analysis. CONCLUSION Mucinous component was not a prognostic factor for gastric adenocarcinoma after radical D2 gastrectomy, no matter what proportion the component comprised. However, gastric adenocarcinoma with mucinous component showed specific clinicopathological characteristics, such as more advanced tumor stage, different age and sex, and more positive rate of molecular markers, which might provide a new strategy for optimal individual diagnosis and therapies.
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Affiliation(s)
- Lei Cai
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University
| | - Yan Li
- Department of Anesthesiology, Northwest Women’s and Children’s Hospital, Xi’an, China
| | - Xue-wen Yang
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University
| | - Xiao Lian
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University
| | - Man Guo
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University
| | - Shu-ao Xiao
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University
| | - Wen-bin Wang
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University
| | - Hong-wei Zhang
- Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University
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35
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Kohmoto T, Masuda K, Naruto T, Tange S, Shoda K, Hamada J, Saito M, Ichikawa D, Tajima A, Otsuji E, Imoto I. Construction of a combinatorial pipeline using two somatic variant calling methods for whole exome sequence data of gastric cancer. THE JOURNAL OF MEDICAL INVESTIGATION 2017; 64:233-240. [PMID: 28954988 DOI: 10.2152/jmi.64.233] [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: 11/14/2022]
Abstract
High-throughput next-generation sequencing is a powerful tool to identify the genotypic landscapes of somatic variants and therapeutic targets in various cancers including gastric cancer, forming the basis for personalized medicine in the clinical setting. Although the advent of many computational algorithms leads to higher accuracy in somatic variant calling, no standard method exists due to the limitations of each method. Here, we constructed a new pipeline. We combined two different somatic variant callers with different algorithms, Strelka and VarScan 2, and evaluated performance using whole exome sequencing data obtained from 19 Japanese cases with gastric cancer (GC); then, we characterized these tumors based on identified driver molecular alterations. More single nucleotide variants (SNVs) and small insertions/deletions were detected by Strelka and VarScan 2, respectively. SNVs detected by both tools showed higher accuracy for estimating somatic variants compared with those detected by only one of the two tools and accurately showed the mutation signature and mutations of driver genes reported for GC. Our combinatorial pipeline may have an advantage in detection of somatic mutations in GC and may be useful for further genomic characterization of Japanese patients with GC to improve the efficacy of GC treatments. J. Med. Invest. 64: 233-240, August, 2017.
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Affiliation(s)
- Tomohiro Kohmoto
- Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University
| | - Kiyoshi Masuda
- Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University
| | - Takuya Naruto
- Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University
| | - Shoichiro Tange
- Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University
| | - Katsutoshi Shoda
- Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University.,Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine
| | - Junichi Hamada
- Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University.,Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine
| | - Masako Saito
- Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University
| | - Daisuke Ichikawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine
| | - Atsushi Tajima
- Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University.,Department of Bioinformatics and Genomics, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine
| | - Issei Imoto
- Department of Human Genetics, Graduate School of Biomedical Sciences, Tokushima University
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36
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Katoh H, Ishikawa S. Genomic pathobiology of gastric carcinoma. Pathol Int 2016; 67:63-71. [DOI: 10.1111/pin.12493] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2016] [Accepted: 11/24/2016] [Indexed: 12/26/2022]
Affiliation(s)
- Hiroto Katoh
- Department of Genomic Pathology; Medical Research Institute; Tokyo Medical and Dental University; Tokyo Japan
| | - Shumpei Ishikawa
- Department of Genomic Pathology; Medical Research Institute; Tokyo Medical and Dental University; Tokyo Japan
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