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Jayagopal A, Walsh RJ, Hariprasannan KK, Mariappan R, Mahapatra D, Jaynes PW, Lim D, Peng Tan DS, Tan TZ, Pitt JJ, Jeyasekharan AD, Rajan V. A multi-task domain-adapted model to predict chemotherapy response from mutations in recurrently altered cancer genes. iScience 2025; 28:111992. [PMID: 40160429 PMCID: PMC11952854 DOI: 10.1016/j.isci.2025.111992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 08/23/2024] [Accepted: 02/06/2025] [Indexed: 04/02/2025] Open
Abstract
Next-generation sequencing (NGS) is increasingly utilized in oncological practice; however, only a minority of patients benefit from targeted therapy. Developing drug response prediction (DRP) models is important for the "untargetable" majority. Prior DRP models typically use whole-transcriptome and whole-exome sequencing data, which are clinically unavailable. We aim to develop a DRP model toward the repurposing of chemotherapy, requiring only information from clinical-grade NGS (cNGS) panels of restricted gene sets. Data sparsity and limited patient drug response information make this challenging. We firstly show that existing DRPs perform equally with whole-exome versus cNGS (∼300 genes) data. Drug IDentifier (DruID) is then described, a DRP model for restricted gene sets using transfer learning, variant annotations, domain-invariant representation learning, and multi-task learning. DruID outperformed state-of-the-art DRP methods on pan-cancer data and showed robust response classification on two real-world clinical datasets, representing a step toward a clinically applicable DRP tool.
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Affiliation(s)
- Aishwarya Jayagopal
- Department of Information Systems and Analytics, School of Computing, National University of Singapore, Singapore 117417, Singapore
| | - Robert J. Walsh
- Department of Haematology-Oncology, National University Cancer Institute, NUHS Tower Block, Level 7, 1E Kent Ridge Road, Singapore 119228, Singapore
| | - Krishna Kumar Hariprasannan
- Department of Information Systems and Analytics, School of Computing, National University of Singapore, Singapore 117417, Singapore
| | - Ragunathan Mariappan
- Department of Information Systems and Analytics, School of Computing, National University of Singapore, Singapore 117417, Singapore
| | - Debabrata Mahapatra
- Department of Computer Science, School of Computing, National University of Singapore, Singapore 117417, Singapore
| | - Patrick William Jaynes
- Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599, Singapore
| | - Diana Lim
- Department of Pathology, National University Health System, 1E Kent Ridge Road Singapore 119228, Singapore
| | - David Shao Peng Tan
- Department of Haematology-Oncology, National University Cancer Institute, NUHS Tower Block, Level 7, 1E Kent Ridge Road, Singapore 119228, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599, Singapore
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore. 1E Kent Ridge Road, NUHS Tower Block, Level 10, Singapore 119228, Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599, Singapore
| | - Jason J. Pitt
- Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599, Singapore
| | - Anand D. Jeyasekharan
- Department of Haematology-Oncology, National University Cancer Institute, NUHS Tower Block, Level 7, 1E Kent Ridge Road, Singapore 119228, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Center for Translational Medicine, 14 Medical Drive, #12-01, Singapore 117599, Singapore
| | - Vaibhav Rajan
- Department of Information Systems and Analytics, School of Computing, National University of Singapore, Singapore 117417, Singapore
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Zhang C, Ran F, Du L, Cao Y, Chen H, Chen Q, Bi L, Hang H. Re-evaluation of the relationship between PrPc expression and patient prognosis in primary esophageal squamous cell carcinoma and primary hepatocellular carcinoma. Sci Rep 2024; 14:31122. [PMID: 39732816 DOI: 10.1038/s41598-024-82398-4] [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: 08/13/2024] [Accepted: 12/05/2024] [Indexed: 12/30/2024] Open
Abstract
PrPc is expressed in various tumors and is associated with cancer progression, but previous studies have shown conflicting results regarding its relationship with patient prognosis-potentially due to differences in the antibodies used. This study aimed to clarify the relationship between PrPc expression and primary esophageal squamous cell carcinoma (ESCC) and primary hepatocellular carcinoma (HCC) using a novel anti-PrPc antibody, 4AA-m, noted for its high specificity and sensitivity. We used flow cytometry to detect PrPc expression in ESCC and HCC cell lines. Immunohistochemistry with 4AA-m was then performed on tissue microarrays from 179 patients with primary ESCC and 92 patients with primary HCC. PrPc expression was semi-quantitatively assessed using the Tumor-DAB-H-Score, and its association with tumor prognosis was analyzed. In ESCC, PrPc expression was negatively correlated with lymph node metastasis, and patients with high PrPc expression had better overall survival compared to those with low expression. PrPc expression was identified as an independent prognostic factor for overall survival in ESCC. In HCC, patients with positive PrPc expression had shorter recurrence-free survival (RFS) than those without PrPc expression. PrPc expression was also found to be an independent prognostic factor for RFS in HCC.
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MESH Headings
- Humans
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/metabolism
- Liver Neoplasms/mortality
- Liver Neoplasms/genetics
- Female
- Male
- Esophageal Squamous Cell Carcinoma/pathology
- Esophageal Squamous Cell Carcinoma/metabolism
- Esophageal Squamous Cell Carcinoma/mortality
- Esophageal Squamous Cell Carcinoma/genetics
- Prognosis
- Middle Aged
- Esophageal Neoplasms/pathology
- Esophageal Neoplasms/metabolism
- Esophageal Neoplasms/mortality
- Esophageal Neoplasms/genetics
- Aged
- Cell Line, Tumor
- Biomarkers, Tumor/metabolism
- Carcinoma, Squamous Cell/pathology
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/mortality
- Carcinoma, Squamous Cell/genetics
- Adult
- Immunohistochemistry
- Gene Expression Regulation, Neoplastic
- Lymphatic Metastasis
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Affiliation(s)
- Cheng Zhang
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Fanlei Ran
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
- Guangzhou National Laboratory, Guangzhou, 510005, China
| | - Lei Du
- The State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Yang Cao
- Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resources and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, 610064, China
| | - Hong Chen
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China
| | - Quan Chen
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Lijun Bi
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- Guangzhou National Laboratory, Guangzhou, 510005, China.
| | - Haiying Hang
- Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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3
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He S, Liu Q, Luo S, Cai B, Chen J, Peng T, Wang W, Liu T, Lu X, Zheng S. Immune cell infiltration and drug sensitivity in PIK3CA-mutated esophageal squamous cell carcinoma: A TCGA database analysis. Hum Immunol 2024; 85:111167. [PMID: 39490157 DOI: 10.1016/j.humimm.2024.111167] [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: 07/25/2024] [Revised: 10/14/2024] [Accepted: 10/17/2024] [Indexed: 11/05/2024]
Abstract
Recent studies have increasingly focused on PIK3CA mutations in esophageal squamous cell carcinoma (ESCC); however, the clinicopathological significance of these mutations within the tumor microenvironment remains underexplored. This study aimed to evaluate and compare the clinicopathological significance of mutated PIK3CA in ESCC using in silico analyses of the ESCC dataset from the TCGA database. We assessed prognosis, differential expression, correlation with immune cell infiltration and immune checkpoint expression, heterogeneity, and drug sensitivity in comparison with wild-type PIK3CA. Our findings revealed that PIK3CA mutation is associated with increased tumor mutation burden and significantly correlated with the infiltration of CD4 naive and effector memory CD4 T cells. Additionally, ESCC cells harboring PIK3CA mutations exhibited reduced sensitivity to p38/JNK MAPK inhibitors compared to those with wild-type PIK3CA. Collectively, our in silico analysis suggests that mutational PIK3CA plays a role in resistance to p38 and JNK MAPK inhibitors in ESCC.
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Affiliation(s)
- Shuo He
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi 830011, China; Department of Pathology, Basic Medicine College, Xinjiang Medical University, Urumqi 830017, China
| | - Qing Liu
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi 830011, China
| | - Shujuan Luo
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi 830011, China; Department of Pathology, Basic Medicine College, Xinjiang Medical University, Urumqi 830017, China
| | - Bangwu Cai
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi 830011, China; Department of Pathology, Basic Medicine College, Xinjiang Medical University, Urumqi 830017, China
| | - Jiao Chen
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi 830011, China
| | - Tianyuan Peng
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi 830011, China
| | - Wei Wang
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi 830011, China
| | - Tao Liu
- Department of Clinical Laboratory, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi, 830011, China
| | - Xiaomei Lu
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi 830011, China.
| | - Shutao Zheng
- State Key Laboratory of Pathogenesis, Prevention, Treatment of Central Asian High Incidence Diseases, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, Urumqi 830011, China; Department of Pathology, Basic Medicine College, Xinjiang Medical University, Urumqi 830017, China.
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Zheng S, He S, Liang Y, Tan Y, Liu Q, Liu T, Lu X. Understanding PI3K/Akt/mTOR signaling in squamous cell carcinoma: mutated PIK3CA as an example. MOLECULAR BIOMEDICINE 2024; 5:13. [PMID: 38616230 PMCID: PMC11016524 DOI: 10.1186/s43556-024-00176-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Accepted: 02/29/2024] [Indexed: 04/16/2024] Open
Abstract
Compared with those in adenocarcinoma, PIK3CA mutations are more common in squamous cell carcinoma (SCC), which arises from stratified squamous epithelia that are usually exposed to adverse environmental factors. Although hotspot mutations in exons 9 and 20 of PIK3CA, including E542K, E545K, H1047L and H1047R, are frequently encountered in the clinic, their clinicopathological meaning remains to be determined in the context of SCC. Considering that few reviews on PIK3CA mutations in SCC are available in the literature, we undertook this review to shed light on the clinical significance of PIK3CA mutations, mainly regarding the implications and ramifications of PIK3CA mutations in malignant cell behavior, prognosis, relapse or recurrence and chemo- or radioresistance of SCC. It should be noted that only those studies regarding SCC in which PIK3CA was mutated were cherry-picked, which fell within the scope of this review. However, the role of mutated PIK3CA in adenocarcinoma has not been discussed. In addition, mutations occurring in other main members of the PI3K-AKT-mTOR signaling pathway other than PIK3CA were also excluded.
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Affiliation(s)
- Shutao Zheng
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, Xinjiang, People's Republic of China
| | - Shuo He
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, Xinjiang, People's Republic of China
| | - Yan Liang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, Xinjiang, People's Republic of China
| | - Yiyi Tan
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, Xinjiang, People's Republic of China
| | - Qing Liu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, Xinjiang, People's Republic of China
| | - Tao Liu
- Department of Clinical Laboratory, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, Xinjiang, People's Republic of China
| | - Xiaomei Lu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, Xinjiang, People's Republic of China.
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Li K, Hao W, Wu J, Liu X, Xing W, Zheng Y. Biofunctional study on chemoresistance in esophageal squamous carcinoma cells induced by missense mutation of NOTCH1 p.E450K. J Thorac Dis 2024; 16:1947-1959. [PMID: 38617785 PMCID: PMC11009606 DOI: 10.21037/jtd-23-1880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Accepted: 02/16/2024] [Indexed: 04/16/2024]
Abstract
Background Neoadjuvant chemotherapy (nCT) combined with surgery is one of the main strategies for the treatment of resectable locally advanced esophageal squamous cell carcinoma (ESCC). However, nearly 40% of patients did not benefit from nCT, and the detection rate of NOTCH1 missense mutation was significantly increased in patients who did not respond to chemotherapy, suggesting that the missense mutation may be related to tumor chemoresistance. We aim to explore the effect of a NOTCH1 missense mutation on cell phenotype, to interpret the biofunctional changes in cell lines with a NOTCH1 missense mutation and to analyze the effect of a NOTCH1 missense mutation on drug resistance in ESCC cell lines. Methods Sanger sequencing was used to evaluate the exon mutations in the NOTCH1 ligand binding region of candidate ESCC cell lines. After screening, KYSE450 and KYSE140 cells were selected as the research objects, and point mutation cell lines [KYSE140-mutant-type (MT) and KYSE450-MT] were constructed by CRISPR/Cas9 technology. Then, functional experiments were performed with the four cell lines [KYSE450-MT/wild-type (WT) and KYSE140-MT/WT]. The drug resistance of ESCC cell lines was assessed with a drug sensitivity test, and the proliferation, invasion and migration of ESCC lines were evaluated by proliferation test, scratch test and Transwell test. The cell cycle status of ESCC cells was assessed using flow cytometry. Results Drug sensitivity tests showed that the NOTCH1 p.E450K point mutation caused chemotherapy resistance in KYSE140 and KYSE450 ESCC cell lines. Cell proliferation, Wound scratch and Transwell assays showed that the NOTCH1 p.E450K point mutation enhanced the proliferation, invasion and migration abilities of KYSE140 and KYSE450 cells. Flow cytometry analysis showed that the NOTCH1 p.E450K point mutation caused an increase in KYSE140 and KYSE450 cells in S phase. Conclusions The NOTCH1 p.E450K point mutation causes chemotherapy resistance in KYSE140 and KYSE450 ESCC cells. Cell functional experiments showed that the NOTCH1 p.E450K point mutation enhanced the proliferation, migration and invasion abilities of KYSE140 and KYSE450 cells and increased the number of cells in S phase.
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Affiliation(s)
- Keting Li
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou, China
| | - Wentao Hao
- Department of Thoracic Surgery, Shanghai Public Health Clinical Center, Shanghai, China
| | - Jiwei Wu
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou, China
| | - Xianben Liu
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou, China
| | - Wenqun Xing
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou, China
| | - Yan Zheng
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Zhengzhou University/Henan Cancer Hospital, Zhengzhou, China
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Zhang X, Wang Y, Meng L. Comparative genomic analysis of esophageal squamous cell carcinoma and adenocarcinoma: New opportunities towards molecularly targeted therapy. Acta Pharm Sin B 2022; 12:1054-1067. [PMID: 35530133 PMCID: PMC9069403 DOI: 10.1016/j.apsb.2021.09.028] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 08/23/2021] [Accepted: 08/27/2021] [Indexed: 12/12/2022] Open
Abstract
Esophageal cancer is one of the most lethal cancers worldwide because of its rapid progression and poor prognosis. Esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) are two major subtypes of esophageal cancer. ESCC predominantly affects African and Asian populations, which is closely related to chronic smoking and alcohol consumption. EAC typically arises in Barrett's esophagus with a predilection for Western countries. While surgical operation and chemoradiotherapy have been applied to combat this deadly cancer, molecularly targeted therapy is still at the early stages. With the development of large-scale next-generation sequencing, various genomic alterations in ESCC and EAC have been revealed and their potential roles in the initiation and progression of esophageal cancer have been studied. Potential therapeutic targets have been identified and novel approaches have been developed to combat esophageal cancer. In this review, we comprehensively analyze the genomic alterations in EAC and ESCC and summarize the potential role of the genetic alterations in the development of esophageal cancer. Progresses in the therapeutics based on the different tissue types and molecular signatures have also been reviewed and discussed.
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Yin F, Wang K, Hu M, Starostik P, Newsom KJ, Liu X. Deleterious mutations in esophageal carcinoma cuniculatum detected by next generation sequencing. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2022; 15:38-45. [PMID: 35145582 PMCID: PMC8822209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 12/08/2021] [Indexed: 06/14/2023]
Abstract
Esophageal carcinoma cuniculatum (ECC) is a rare form of extremely well-differentiated squamous cell carcinoma of esophagus that is often misdiagnosed preoperatively. The molecular changes underlying ECC remain unknown. This study aimed to explore the molecular signature of ECC using next-generation sequencing (NGS). Five cases of ECC were collected from our pathology database from 2014 to 2019. One patient received chemoradiation and the remaining four patients were treatment-naïve. Areas of normal squamous mucosa, non-invasive component, and invasive component of ECC were circled and macrodissected. Genomic DNA extracted from the macrodissected tissue was sequenced using GatorSeq NGS Panel. Deleterious mutations, predicted by Sorting Intolerant from Tolerant (SIFT), were identified using tumor/normal pairs and annotated by amino acid change. The normal-appearing squamous mucosa in the ECC harbored recurrent deleterious somatic mutations in ROS1 and POLE genes. ECC tumor-specific deleterious mutations were identified on TP53, NOTCH1, and PIK3CA genes. Our results support a mutually exclusive pattern in NOTCH1 and PIK3CA mutation. Non-invasive and invasive components in ECC had identical mutation profiles. Chemoradiation therapy led to disappearance of NOTCH1 mutation in one ECC case. Our results suggest molecular testing may help pre-operative diagnosis, and provide therapeutic targets in patients with advanced or unresectable ECC.
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Affiliation(s)
- Feng Yin
- Department of Pathology and Anatomical Sciences, University of MissouriColumbia, MO, USA
| | - Kai Wang
- Department of Pathology, Immunology and Lab Medicine, University of FloridaGainesville, FL, USA
| | - Ming Hu
- Department of Pathology, Immunology and Lab Medicine, University of FloridaGainesville, FL, USA
| | - Petr Starostik
- Department of Pathology, Immunology and Lab Medicine, University of FloridaGainesville, FL, USA
| | - Kimberly J Newsom
- Department of Pathology, Immunology and Lab Medicine, University of FloridaGainesville, FL, USA
| | - Xiuli Liu
- Department of Pathology, Immunology and Lab Medicine, University of FloridaGainesville, FL, USA
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Li Y, Li Y, Chen X. NOTCH and Esophageal Squamous Cell Carcinoma. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1287:59-68. [PMID: 33034026 PMCID: PMC7895477 DOI: 10.1007/978-3-030-55031-8_5] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a deadly disease that requires extensive research on its mechanisms, prevention, and therapy. Recent studies have shown that NOTCH mutations are commonly seen in human ESCC. This chapter summarizes our current understanding of the NOTCH pathway in normal esophagus and in ESCC. In normal esophagus, NOTCH pathway regulates the development of esophageal squamous epithelium, in particular, squamous differentiation. Exposure to extrinsic and intrinsic factors, such as gastroesophageal reflux, alcohol drinking, and inflammation, downregulates the NOTCH pathway and thus inhibits squamous differentiation of esophageal squamous epithelial cells. In ESCC, NOTCH plays a dual role as both a tumor suppressor pathway and an oncogenic pathway. In summary, further studies are warranted to develop NOTCH activators for the prevention of ESCC and NOTCH inhibitors for targeted therapy of a subset of ESCC with activated NOTCH pathway.
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Affiliation(s)
- Yong Li
- Department of Thoracic Surgery, National Cancer Center, Cancer Hospital of Chinese Academy of Medical Sciences, Beijing, China
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA
| | - Yahui Li
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA
| | - Xiaoxin Chen
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, NC, USA.
- Center for Gastrointestinal Biology and Disease, Division of Gastroenterology and Hepatology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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Mangalaparthi KK, Patel K, Khan AA, Manoharan M, Karunakaran C, Murugan S, Gupta R, Gupta R, Khanna-Gupta A, Chaudhuri A, Kumar P, Nair B, Kumar RV, Prasad TSK, Chatterjee A, Pandey A, Gowda H. Mutational Landscape of Esophageal Squamous Cell Carcinoma in an Indian Cohort. Front Oncol 2020; 10:1457. [PMID: 32974170 PMCID: PMC7469928 DOI: 10.3389/fonc.2020.01457] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 07/09/2020] [Indexed: 12/18/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is the most common histological subtype of esophageal cancer in India. Cigarette smoking and chewing tobacco are known risk factors associated with ESCC. However, genomic alterations associated with ESCC in India are not well-characterized. In this study, we carried out exome sequencing to characterize the mutational landscape of ESCC tumors from subjects with a varied history of tobacco usage. Whole exome sequence analysis of ESCC from an Indian cohort revealed several genes that were mutated or had copy number changes. ESCC from tobacco chewers had a higher frequency of C:G > A:T transversions and 2-fold enrichment for mutation signature 4 compared to smokers and non-users of tobacco. Genes, such as TP53, CSMD3, SYNE1, PIK3CA, and NOTCH1 were found to be frequently mutated in Indian cohort. Mutually exclusive mutation patterns were observed in PIK3CA-NOTCH1, DNAH5-ZFHX4, MUC16-FAT1, and ZFHX4-NOTCH1 gene pairs. Recurrent amplifications were observed in 3q22-3q29, 11q13.3-q13.4, 7q22.1-q31.1, and 8q24 regions. Approximately 53% of tumors had genomic alterations in PIK3CA making this pathway a promising candidate for targeted therapy. In conclusion, we observe enrichment of mutation signature 4 in ESCC tumors from patients with a history of tobacco chewing. This is likely due to direct exposure of esophagus to tobacco carcinogens when it is chewed and swallowed. Genomic alterations were frequently observed in PIK3CA-AKT pathway members independent of the history of tobacco usage. PIK3CA pathway can be potentially targeted in ESCC which currently has no effective targeted therapeutic options.
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Affiliation(s)
- Kiran K. Mangalaparthi
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, India
| | - Krishna Patel
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, India
| | - Aafaque A. Khan
- Institute of Bioinformatics, International Technology Park, Bangalore, India
| | | | | | | | - Ravi Gupta
- Medgenome Labs Pvt. Ltd., Bangalore, India
| | | | | | | | - Prashant Kumar
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education, Manipal, India
| | - Bipin Nair
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, India
| | - Rekha V. Kumar
- Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore, India
| | - T. S. Keshava Prasad
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Center for Systems Biology and Molecular Medicine, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, India
| | - Aditi Chatterjee
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education, Manipal, India
| | - Akhilesh Pandey
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Manipal Academy of Higher Education, Manipal, India
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States
- Center for Molecular Medicine, National Institute of Mental Health and Neurosciences, Bangalore, India
| | - Harsha Gowda
- Institute of Bioinformatics, International Technology Park, Bangalore, India
- Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham, Kollam, India
- Manipal Academy of Higher Education, Manipal, India
- Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
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10
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de Carvalho AC, Perdomo S, Dos Santos W, Fernandes GC, de Jesus LM, Carvalho RS, Scapulatempo-Neto C, de Almeida GC, Sorroche BP, Arantes LMRB, Melendez ME, De Marchi P, Hayes N, Reis RM, Carvalho AL. Impact of genetic variants in clinical outcome of a cohort of patients with oropharyngeal squamous cell carcinoma. Sci Rep 2020; 10:9970. [PMID: 32561788 PMCID: PMC7305218 DOI: 10.1038/s41598-020-66741-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/21/2020] [Indexed: 02/07/2023] Open
Abstract
Tobacco- or human papillomavirus- driven oropharyngeal squamous cell carcinomas (OpSCC) represent distinct clinical, biological and epidemiological entities. The aim of this study was to identify genetic variants based on somatic alterations in OpSCC samples from an admixed population, and to test for association with clinical features. The entire coding region of 15 OpSCC driver genes was sequenced by next-generation sequencing in 51 OpSCC FFPE samples. Thirty-five percent of the patients (18/51) were HPV-positive and current or past tobacco consumption was reported in 86.3% (44/51). The mutation profile identified an average of 2.67 variants per sample. Sixty-three percent of patients (32/51; 62.7%) were mutated for at least one of the genes tested and TP53 was the most frequently mutated gene. The presence of mutation in NOTCH1 and PTEN, significantly decreased patient's recurrence-free survival, but only NOTCH1 mutation remained significant after stepwise selection, with a risk of recurrence of 4.5 (HR 95% CI = 1.11-14.57; Cox Regression p = 0.034). These results show that Brazilian OpSCC patients exhibit a similar clinical and genetic profile in comparison to other populations. Molecular characterization is a promising tool for the definition of clinical subgroups, aiding in a more precise tailoring of treatment and prognostication.
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Affiliation(s)
| | - Sandra Perdomo
- Institute of Nutrition, Genetics and Metabolism Research, Faculty of Medicine, Universidad El Bosque, Bogotá, Colombia
- International Agency of Research on Cancer, Lyon, France
| | | | | | | | | | - Cristovam Scapulatempo-Neto
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
- Pathology and Molecular Diagnostics Service, Diagnósticos da América-DASA, São Paulo, SP, Brazil
| | | | | | | | - Matias Eliseo Melendez
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
- Pelé Little Prince Research Institute, Curitiba, PR, Brazil
- Little Prince College, Curitiba, PR, Brazil
| | - Pedro De Marchi
- Department of Medical Oncology, Barretos Cancer Hospital, Barretos, SP, Brazil
- Oncoclinicas, Rio de Janeiro, RJ, Brazil
| | - Neil Hayes
- Department of Medicine, Division of Oncology, UTHSC Center for Cancer Research, University of Tennessee Health Science Center, Memphis, USA
| | - Rui Manuel Reis
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil
- Life and Health Sciences Research Institute (ICVS), Medical School, University of Minho, Braga, Portugal
- ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal
| | - André Lopes Carvalho
- Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil.
- International Agency of Research on Cancer, Lyon, France.
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11
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Matsuoka T, Yashiro M. Precision medicine for gastrointestinal cancer: Recent progress and future perspective. World J Gastrointest Oncol 2020; 12:1-20. [PMID: 31966910 PMCID: PMC6960076 DOI: 10.4251/wjgo.v12.i1.1] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 10/12/2019] [Accepted: 11/04/2019] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal (GI) cancer has a high tumor incidence and mortality rate worldwide. Despite significant improvements in radiotherapy, chemotherapy, and targeted therapy for GI cancer over the last decade, GI cancer is characterized by high recurrence rates and a dismal prognosis. There is an urgent need for new diagnostic and therapeutic approaches. Recent technological advances and the accumulation of clinical data are moving toward the use of precision medicine in GI cancer. Here we review the application and status of precision medicine in GI cancer. Analyses of liquid biopsy specimens provide comprehensive real-time data of the tumor-associated changes in an individual GI cancer patient with malignancy. With the introduction of gene panels including next-generation sequencing, it has become possible to identify a variety of mutations and genetic biomarkers in GI cancer. Although the genomic aberration of GI cancer is apparently less actionable compared to other solid tumors, novel informative analyses derived from comprehensive gene profiling may lead to the discovery of precise molecular targeted drugs. These progressions will make it feasible to incorporate clinical, genome-based, and phenotype-based diagnostic and therapeutic approaches and apply them to individual GI cancer patients for precision medicine.
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Affiliation(s)
- Tasuku Matsuoka
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
| | - Masakazu Yashiro
- Department of Gastroenterological Surgery, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
- Oncology Institute of Geriatrics and Medical Science, Osaka City University Graduate School of Medicine, Osaka 5458585, Japan
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12
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Huang J, Song Q, Wang H, Wang H, Xu C, Wang X, Jiang Z, Wang Y, Xu Y, Su J, Zeng H, Tan L, Zhu H, Jiang D, Hou Y. Poor prognostic impact of FGF4 amplification in patients with esophageal squamous cell carcinoma. Hum Pathol 2018; 80:210-218. [PMID: 29936056 DOI: 10.1016/j.humpath.2018.06.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 06/04/2018] [Accepted: 06/09/2018] [Indexed: 12/09/2022]
Abstract
In the present study, we aimed to determine the prognostic impact and clinicopathological feature of FGF4 amplification in patients with esophageal squamous cell carcinoma (ESCC). Fluorescence in situ hybridization with FGF4 probe was analyzed using tissue microarray consisting of representative cores of 267 ESCC cases. FGF4 amplification was observed in 52.8% (141/267) of patients. Patients with FGF4 amplification showed a significantly shorter disease-free survival (DFS) or disease-specific overall survival (OS) compared with those without FGF4 amplification (both P < .05). Moreover, FGF4 amplification was an independent prognostic factor (DFS, P = .036; OS, P = .021) along with clinical stage and lymph node metastasis in multivariate analysis. Among stage I-II or III patients whose DFS was greater than or equal to 24 months (n = 125 or 32), patients with FGF4 amplification showed a significantly worse prognosis (OS, P = .027 or P = .010). Moreover, the survival curve of stage I-II patients with FGF4 amplification was identical to stage III patients without FGF4 amplification (DFS, P = .643; OS, P = .707). Taken together, FGF4 amplification was an independent prognostic factor in ESCC patients, and ESCC might have potentially been upstaged by FGF4 amplification. Therefore, FGF4 amplification in combination with clinical stage could be used as a relatively accurate predictor for the 5-year probability of death and recurrence for ESCC patients.
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Affiliation(s)
- Jie Huang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Qi Song
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Hao Wang
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Haixing Wang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Chen Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Xin Wang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Zhengzeng Jiang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Yanqiu Wang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Yifan Xu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Jieakesu Su
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Haiying Zeng
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Lijie Tan
- Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Hongguang Zhu
- Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai 200032, PR China
| | - Dongxian Jiang
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China.
| | - Yingyong Hou
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; Department of Pathology, School of Basic Medical Sciences & Zhongshan Hospital, Fudan University, Shanghai 200032, PR China; Department of Pathology, Qingpu Branch of Zhongshan Hospital, Fudan University, Shanghai 201700, PR China.
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13
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Li J, Chen S, Zhu G. Comparative study of computed tomography (CT) and pathological diagnosis toward mediastinal lymph node metastasis in esophageal carcinoma. ACTA ACUST UNITED AC 2018; 64:170-174. [PMID: 29641678 DOI: 10.1590/1806-9282.64.02.170] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 06/26/2017] [Indexed: 12/22/2022]
Abstract
OBJECTIVE To investigate the diagnostic criteria of mediastinal lymph node metastasis (MLNM) in esophageal carcinoma (EC) by comparing the lymph node sizes measured by computed tomography (CT) and obtained by postoperative pathological examination. METHOD A total of 305 EC patients were selected. MLNM location, shortest diameter and number were investigated one week before surgery, and then compared with their pathological findings. RESULTS The receiver operating characteristic (ROC) curve analysis revealed that the minimum diameters of MLNM in the thoracic cavity was 8 mm (area under curve [AUC] = 0.766, Youden index = 0.424), 5 mm in supraclavicular fossa (AUC = 0.785, Youden index = 0.494), 6 mm in tracheoesophageal groove (AUC = 0.755, Youden index = 0.405); the sensitivity was increased significantly, and the Youden index was increased significantly when compared with 10 mm. CONCLUSION The shortest diameter of diagnostic criteria of lymph nodes in EC could be less than 10 mm on CT.
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Affiliation(s)
- Jiancheng Li
- Department of Radiation Oncology, Fujian Provincial Cancer Hospital, Provincial Clinical College of Fujian Medical University, Fuzhou, China
| | - Shanshan Chen
- Department of Medical Oncology, 180th Hospital of PLA, Quanzhou, China
| | - Guangying Zhu
- Department of Radiation Oncology, China-Japan Friendship Hospital, Beijing, China
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14
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Dong Q, Fu L, Zhao Y, Liu Y, Li Q, Qiu X, Wang E. Derlin-1 is a target to improve radiotherapy effect of esophageal squamous cell carcinoma. Oncotarget 2017; 8:55135-55146. [PMID: 28903408 PMCID: PMC5589647 DOI: 10.18632/oncotarget.19069] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 06/18/2017] [Indexed: 01/12/2023] Open
Abstract
Radiotherapy is widely used for treatment of esophageal squamous cell carcinoma (ESCC). This study aimed to explore the role of Derlin-1 on the sensitivity of ESCC to radiotherapy and its underlying mechanism. We examined the clinical significance of Derlin-1 in 125 ESCC tissues. We found that Derlin-1 protein was higher in ESCC tissues than that in normal esophageal epithelial tissues. Derlin-1 overexpression was correlated with chemoradiotherapy resistance in ESCC patients and served an independent predictor for short overall survival. siRNA knockdown and plasmid transfection were carried out in ESCC cell lines. Derlin-1 depletion inhibited cell growth while its overexpression facilitated cell growth. Derlin-1 overexpression in Eca-109 cells dramatically enhanced its resistance to radiotherapy with decreased apoptosis rate. On the contrary, Derlin-1 depletion in TE-1 cell line showed the opposite effects. In addition, radioresistance conferred by Derlin-1 was attributed to its role of activating AKT/Bcl-2 signaling pathway and reducing caspase3 cleavage. Blockage of AKT signaling attenuated the role of Derlin-1 on radioresistance. Furthermore, Derlin-1 could interact with PI3K p110α in ESCC cell lines. Taken together, Our data demonstrate that Derlin-1 overexpression predicts poor prognosis and protects ESCC from irradiation induced apoptosis through PI3K/AKT/Bcl-2 signaling pathway. Derlin-1 may serve as a novel predictor for radiosentivity and a molecular target for ESCC.
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Affiliation(s)
- Qianze Dong
- Department of Pathology, College of Basic Medical Sciences and The First Affiliated Hospital, China Medical University, Shenyang, China
| | - Lin Fu
- Department of Pathology, College of Basic Medical Sciences and The First Affiliated Hospital, China Medical University, Shenyang, China
| | - Yue Zhao
- Department of Pathology, College of Basic Medical Sciences and The First Affiliated Hospital, China Medical University, Shenyang, China
| | - Yang Liu
- Department of Pathology, College of Basic Medical Sciences and The First Affiliated Hospital, China Medical University, Shenyang, China
| | - Qingchang Li
- Department of Pathology, College of Basic Medical Sciences and The First Affiliated Hospital, China Medical University, Shenyang, China
| | - Xueshan Qiu
- Department of Pathology, College of Basic Medical Sciences and The First Affiliated Hospital, China Medical University, Shenyang, China
| | - Enhua Wang
- Department of Pathology, College of Basic Medical Sciences and The First Affiliated Hospital, China Medical University, Shenyang, China
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15
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Ge XQ, Yang YZ, Li SS, Hou L, Ren JL, Yang KP, Fa XE. No significant association between PIK3CA mutation and survival of esophageal squamous cell carcinoma: A meta-analysis. ACTA ACUST UNITED AC 2017; 37:462-468. [PMID: 28585132 DOI: 10.1007/s11596-017-1758-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Revised: 05/10/2017] [Indexed: 12/29/2022]
Abstract
The prognostic value of phosphatidylinositol-4, 5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) in patients with esophageal squamous cell carcinoma (ESCC) is controversial. We aimed to investigate the prognostic significance of PIK3CA mutation in patients with ESCC. EMBASE, PubMed, and Web of Science databases were systematically searched from inception through Oct. 3, 2016. The hazard ratios (HRs) and 95% confidence intervals (CI) were calculated using a random effects model for overall survival (OS) and disease-free survival (DFS). Seven studies enrolling 1505 patients were eligible for inclusion of the current meta-analysis. Results revealed that PIK3CA mutation was not significantly associated with OS (HR: 0.90, 95% CI: 0.63-1.30, P=0.591), with a significant heterogeneity (I 2=65.7%, P=0.012). Additionally, subgroup analyses were further conducted according to various variables, such as types of specimen, the sample size, technique and statistical methodology. All results suggested that no significant relationship was found between PIK3CA mutation and OS in patients with ESCC. For DFS, there was no significant association between PIK3CA mutation and DFS in patients with ESCC (HR: 1.00, 95% CI=0.47-2.11, P=0.993, I 2=73.7%). Publication bias was not present and the results of sensitivity analysis were very stable in the current meta-analysis. Our findings suggest that PIK3CA mutation has no significant effects on OS and DFS in ESCC patients. More well-designed prospective studies with better methodology for PIK3CA assessment are required to clarify the prognostic significance of PIK3CA mutation in ESCC patients.
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Affiliation(s)
- Xiao-Qing Ge
- Department of Thoracic Surgery, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450014, China
| | - Yan-Zheng Yang
- Operating Room, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450014, China
| | - Sha-Sha Li
- Operating Room, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450014, China
| | - Lu Hou
- Department of Thoracic Surgery, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450014, China
| | - Jing-Li Ren
- Department of Pathology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450014, China
| | - Kun-Peng Yang
- Department of Thoracic Surgery, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450014, China
| | - Xian-En Fa
- Department of Cardiac Surgery, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, 450014, China.
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16
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Huang T, Zhou Y, Cheng ASL, Yu J, To KF, Kang W. NOTCH receptors in gastric and other gastrointestinal cancers: oncogenes or tumor suppressors? Mol Cancer 2016; 15:80. [PMID: 27938406 PMCID: PMC5148895 DOI: 10.1186/s12943-016-0566-7] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Accepted: 12/01/2016] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer (GC) ranks the most common cancer types and is one of the leading causes of cancer-related death. Due to delayed diagnosis and high metastatic frequency, 5-year survival rate of GC is rather low. It is a complex disease resulting from the interaction between environmental factors and host genetic alterations that deregulate multiple signaling pathways. The Notch signaling pathway, a highly conserved system in the regulation of the fate in several cell types, plays a pivotal role in cell differentiation, survival and proliferation. Notch is also one of the most commonly activated signaling pathways in tumors and its aberrant activation plays a key role in cancer advancement. Whether Notch cascade exerts oncogenic or tumor suppressive function in different cancer types depends on the cellular context. Mammals have four NOTCH receptors that modulate Notch pathway activity. In this review, we provide a comprehensive summary on the functional role of NOTCH receptors in gastric and other gastrointestinal cancers. Increasing knowledge of NOTCH receptors in gastrointestinal cancers will help us recognize the underlying mechanisms of Notch signaling and develop novel therapeutic strategies for GC.
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Affiliation(s)
- Tingting Huang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T, Hong Kong, SAR, People's Republic of China.,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China
| | - Yuhang Zhou
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T, Hong Kong, SAR, People's Republic of China.,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China
| | - Alfred S L Cheng
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China.,School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, People's Republic of China
| | - Jun Yu
- Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China.,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China.,Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, People's Republic of China
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T, Hong Kong, SAR, People's Republic of China. .,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China.
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Oncology in South China, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, N.T, Hong Kong, SAR, People's Republic of China. .,Institute of Digestive Disease, Partner State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China. .,Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, SAR, People's Republic of China. .,Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen, People's Republic of China.
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17
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Liu Y, Xiong Z, Beasley A, D'Amico T, Chen XL. Personalized and targeted therapy of esophageal squamous cell carcinoma: an update. Ann N Y Acad Sci 2016; 1381:66-73. [PMID: 27399176 PMCID: PMC5083215 DOI: 10.1111/nyas.13144] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 05/16/2016] [Accepted: 05/23/2016] [Indexed: 12/20/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a deadly disease that requires extensive research. In this review, we update recent progress in the research area of targeted therapy for ESCC. SOX2 and its associated proteins (e.g., ΔNP63α), which regulate lineage survival of ESCC cells, are proposed as therapeutic targets. It is believed that targeting the lineage-survival mechanism may be more effective than targeting other mechanisms. With the advent of a new era of personalized targeted therapy, there is a need to move from the tumor-centric model into an organismic model.
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Affiliation(s)
- Yongjing Liu
- Department of Cardiothoracic Surgery, 105th Hospital of PLA, Hefei, Anhui Province, China
- Division of Thoracic Surgery, Duke University Medical Center, Durham, North Carolina
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina
| | - Zhaohui Xiong
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina
| | - Andrea Beasley
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina
| | - Thomas D'Amico
- Division of Thoracic Surgery, Duke University Medical Center, Durham, North Carolina
| | - Xiaoxin Luke Chen
- Cancer Research Program, Julius L. Chambers Biomedical Biotechnology Research Institute, North Carolina Central University, Durham, North Carolina.
- Division of Gastroenterology and Hepatology, Department of Medicine, Center for Esophageal Disease and Swallowing, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
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18
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MicroRNA-21 promotes cell proliferation, migration, and resistance to apoptosis through PTEN/PI3K/AKT signaling pathway in esophageal cancer. Tumour Biol 2016; 37:12061-12070. [PMID: 27188433 DOI: 10.1007/s13277-016-5074-2] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 05/05/2016] [Indexed: 01/06/2023] Open
Abstract
Our study aimed to explore associations between microRNA-21 (miR-21) and PTEN/PI3K/AKT signaling pathway and, further, to elucidate the regulation of miR-21 on biological behaviors in human esophageal cancer cells. The expressions of miR-21, PTEN, PI3K, and AKT were detected in 89 esophageal cancer samples and 58 adjacent normal tissues respectively. The human esophageal cancer cells (TE11) were grouped as following: blank (TE11 cells without transfection), negative (TE11 cells with miR-21 negative inhibitor), and Inhibition-miR21 (TE11 cells with miR-21 inhibitor). Western blot was used for detection of PTEN, P13K, and AKT protein expressions, MTT method for cell proliferation, Transwell assay for cell migration and invasion, and flow cytometry for cell cycle and apoptosis. MiR-21, PI3K, and AKT have higher expressions, but PTEN has lower expression in esophageal cancer tissues compared with adjacent normal tissues. The esophageal cancer tissues with lymph node metastasis and poor differentiation showed significantly low positive rate of PTEN protein, but high positive rates of PI3K and AKT proteins. Compared with blank and negative groups, PTEN expression of TE11 cells in Inhibition-miR21 group was significantly up-regulated, but PI3K and AKT were down-regulated. Further, PTEN was a target gene of miR-21. Besides, compared with blank and negative groups, the proliferation, migration, and invasion of TE11 cells were less active in Inhibition-miR21 group. TE11 cells were significantly increased in the G0/G1 phase of cell cycles, but decreased in the S and G2/M phase in Inhibition-miR21 group. The TE11 cells exhibited significantly increased apoptosis rates. MiR-21 targets key proteins in PTEN/PI3K/AKT signal pathway, promoting proliferation, migration, invasion, and cell cycle, and inhibiting apoptosis of human esophageal cancer cells. It may serve as a novel therapeutic target in esophageal cancer.
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19
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Wang C, Li Q, Liu F, Chen X, Liu B, Nesa EU, Guan S, Han L, Tan B, Wang N, Wang X, Song Q, Jia Y, Wang J, Lu M, Cheng Y. Notch2 as a promising prognostic biomarker for oesophageal squamous cell carcinoma. Sci Rep 2016; 6:25722. [PMID: 27158037 PMCID: PMC4860585 DOI: 10.1038/srep25722] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 04/21/2016] [Indexed: 12/28/2022] Open
Abstract
We aimed to examine Notch2 expression in oesophageal squamous cell carcinoma (ESCC) patients and to evaluate its prognostic potential. Immunohistochemical (IHC) staining, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis were utilized to investigate the Notch2 expression status and prognostic value. Furtherly, CCK8 and clonogenic assays were conducted to determine if Notch2 inhibition by shRNA could lead to a decrease in the proliferation and survival of ESCC cells. A notably higher Notch2 expression level was found in ESCC tissues at the mRNA (P < 0.0001) and protein levels (IHC: P = 0.004; western blot: P = 0.021). Log-rank analysis demonstrated that Notch2 overexpression was significantly associated with worse overall survival (OS) (29.1% vs. 49.1%; P = 0.013) and progression-free survival (PFS) (15.3% vs. 34.4%; P = 0.006) rates in ESCC patients. The multivariate analysis revealed Notch2 as an independent prognostic factor for OS and PFS (P = 0.002 and 0.006, resp.). Besides, in vitro assays showed that OD450 values and colony formations were significantly reduced in Notch2-shRNA group (all P < 0.0001). In conclusion, these results show that Notch2 is up-regulated in ESCC tissues and could serve as a promising biomarker for identifying individuals with poor prognostic potential.
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Affiliation(s)
- Cong Wang
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Qingbao Li
- Department of Cardiac Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, 250021, People's Republic of China
| | - Fang Liu
- Department of Imaging, Shandong Medical College, Jinan, Shandong, 250002, China
| | - Xuan Chen
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Bowen Liu
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Effat Un Nesa
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Shanghui Guan
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Lihui Han
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Bingxu Tan
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Nana Wang
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Xintong Wang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Jinan, Shandong, 250117, China
| | - Qingxu Song
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Yibin Jia
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Jianbo Wang
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Ming Lu
- Department of Thoracic Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Yufeng Cheng
- Department of Radiation Oncology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
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Ma G, Zhang F, Dong X, Wang X, Ren Y. Low expression of microRNA-202 is associated with the metastasis of esophageal squamous cell carcinoma. Exp Ther Med 2016; 11:951-956. [PMID: 26998018 DOI: 10.3892/etm.2016.3014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2014] [Accepted: 11/25/2015] [Indexed: 12/23/2022] Open
Abstract
The present study aimed to determine the expression levels and biological functions of microRNA-202 (miR-202) in patients with esophageal squamous cell carcinoma (ESCC). A total of 60 patients with ESCC and 30 healthy individuals were enrolled and reverse transcription-quantitative polymerase chain reaction was performed to measure the expression levels of miR-202. In order to investigate the effects of miR-202 expression levels on the proliferative, migratory and invasive abilities of ESCC cells, methylthiazolyl-tetrazolium bromide proliferation, in vitro scratch and Transwell® chamber assays were performed. Expression levels of miR-202 were significantly decreased in the peripheral blood of patients with ESCC, which is associated with the degree of cell differentiation and lymph node metastasis (P<0.05). Following miR-202 transfection, cell proliferation was significantly inhibited (P<0.05). Cell migration and invasion was also significantly inhibited by miR-202 transfection (P<0.05). The results of the present study demonstrated that the expression of miR-202 inhibited the proliferation, migration and invasion of ESCC cells. Furthermore, low expression levels of miR-202 were detected in the peripheral blood of patients with ESCC, which is associated with the development, invasion and metastasis of ESCC.
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Affiliation(s)
- Guoliang Ma
- Department of Clinical Laboratory, Laiwu People's Hospital, Laiwu, Shandong 271199, P.R. China
| | - Fengmei Zhang
- Department of Endocrinology, Laiwu People's Hospital, Laiwu, Shandong 271199, P.R. China
| | - Xueguang Dong
- Department of Clinical Laboratory, Laiwu People's Hospital, Laiwu, Shandong 271199, P.R. China
| | - Xiaoli Wang
- Department of Clinical Laboratory, Laiwu People's Hospital, Laiwu, Shandong 271199, P.R. China
| | - Yuguo Ren
- Department of Clinical Laboratory, Laiwu People's Hospital, Laiwu, Shandong 271199, P.R. China
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