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Jiang H, Ye J. The Warburg effect: the hacked mitochondrial-nuclear communication in cancer. Semin Cancer Biol 2025:S1044-579X(25)00053-7. [PMID: 40147702 DOI: 10.1016/j.semcancer.2025.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 02/23/2025] [Accepted: 03/17/2025] [Indexed: 03/29/2025]
Abstract
Mitochondrial-nuclear communication is vital for maintaining cellular homeostasis. This communication begins with mitochondria sensing environmental cues and transmitting signals to the nucleus through the retrograde cascade, involving metabolic signals such as substrates for epigenetic modifications, ATP and AMP levels, calcium flux, etc. These signals inform the nucleus about the cell's metabolic state, remodel epigenome and regulate gene expression, and modulate mitochondrial function and dynamics through the anterograde feedback cascade to control cell fate and physiology. Disruption of this communication can lead to cellular dysfunction and disease progression, particularly in cancer. The Warburg effect is the metabolic hallmark of cancer, characterized by disruption of mitochondrial respiration and increased lactate generation from glycolysis. This metabolic reprogramming rewires retrograde signaling, leading to epigenetic changes and dedifferentiation, further reprogramming mitochondrial function and promoting carcinogenesis. Understanding these processes and their link to tumorigenesis is crucial for uncovering tumorigenesis mechanisms. Therapeutic strategies targeting these disrupted pathways, including metabolic and epigenetic components, provide promising avenues for cancer treatment.
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Affiliation(s)
- Haowen Jiang
- Department of Radiation Oncology, Stanford University School of Medicine. Stanford, CA 94305, US
| | - Jiangbin Ye
- Department of Radiation Oncology, Stanford University School of Medicine. Stanford, CA 94305, US; Cancer Biology Program, Stanford University School of Medicine. Stanford, CA 94305, US; Stanford Cancer Institute, Stanford University School of Medicine. Stanford, CA 94305, US.
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Reyila A, Gao X, Yu J, Nie Y. Insight into the role of DNA methylation in prognosis and treatment response prediction of gastrointestinal cancers. Epigenomics 2025:1-14. [PMID: 40084815 DOI: 10.1080/17501911.2025.2476380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Accepted: 03/04/2025] [Indexed: 03/16/2025] Open
Abstract
Gastrointestinal (GI) cancers impose a significant disease burden, underscoring the critical importance of accurate prognosis prediction and treatment response evaluation. DNA methylation, one of the most extensively studied epigenetic modifications, has gained prominence due to its reliable measurement across various sample types. Numerous studies have reported that DNA methylation was linked to the diagnosis, prognosis and treatment response in malignancies, including GI cancers. While its diagnostic role in GI cancers has been comprehensively reviewed. Recent research has increasingly highlighted its potential in prognosis prediction and treatment response evaluation. However, no existing reviews have exclusively focused on these two aspects. In this review, we retrieved relevant studies and included 230 of them in our discussion, thereby providing an overview of the clinical applicability of aberrant DNA methylation in these two fields among patients with esophageal, gastric, colorectal, pancreatic cancers, and hepatocellular carcinomas. Additionally, we discuss the limitations of the current literature and propose directions for future research. Specifically, we emphasize the need for standardized DNA methylation methodologies and advocate for the integration of gene panels, rather than single genes, to address tumor heterogeneity more effectively.
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Affiliation(s)
- Abudurousuli Reyila
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, Shaanxi, China
- National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xianchun Gao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, Shaanxi, China
- National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Jun Yu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, Shaanxi, China
- National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Yongzhan Nie
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi'an, Shaanxi, China
- National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, Shaanxi, China
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Minoura H, Okamoto R, Hiki N, Yamashita K. Cancer-Associated Fibroblasts Genes and Transforming Growth Factor Beta Pathway in Gastric Cancer for Novel Therapeutic Strategy. Cancers (Basel) 2025; 17:795. [PMID: 40075643 PMCID: PMC11899367 DOI: 10.3390/cancers17050795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 01/28/2025] [Accepted: 02/06/2025] [Indexed: 03/14/2025] Open
Abstract
Background-Objective: Cancer-associated fibroblasts (CAFs) play a crucial role in the tumor microenvironment of gastric cancer (GC). Understanding the molecular characteristics of CAFs-associated genes (CAFGs) is essential for elucidating their role in tumor progression and prognosis. This review aims to summarize the current knowledge on CAFGs, highlighting their expression patterns, prognostic significance, and potential functional mechanisms. Methods: A comprehensive review of existing literature was conducted, focusing on molecular features of CAFGs in GC. Single-cell RNA sequencing (scRNA-seq) analyses were examined to assess the expression patterns of CAFGs in broad-sense CAFs, which include both CAFs and pericytes. Additionally, clinicopathological studies validating the prognostic significance of CAFGs were reviewed. Results: ScRNA-seq analyses revealed that CAFGs are not necessarily restricted to CAFs alone but may also reflect the activation status of surrounding cells. Several CAFGs, including SPARC, THBS2, COL1A1, COL3A1, INHBA, PDGFC, and SDC2, have been validated for their prognostic relevance in GC. However, compared with other cancers, the functional mechanisms of these genes in GC remain poorly understood. While CAFGs exhibit synchronized expression with TGFB1 in colorectal cancer (CRC), such patterns have yet to be confirmed in GC due to the limitations of available microdissected data. Conclusions: A comprehensive understanding of CAFGs and their interaction with the TGFB pathway, including LTBP family genes, may be critical for developing novel therapeutic strategies for GC. Further research is needed to elucidate their functional mechanisms and therapeutic potential.
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Affiliation(s)
- Hiroyuki Minoura
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan; (H.M.); (R.O.)
| | - Riku Okamoto
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan; (H.M.); (R.O.)
| | - Naoki Hiki
- Department of Upper Gastrointestinal Surgery, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan;
| | - Keishi Yamashita
- Division of Advanced Surgical Oncology, Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Kitasato 1-15-1, Minami-ku, Sagamihara, Kanagawa 252-0374, Japan; (H.M.); (R.O.)
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Zhang X, Li P, Gan Y, Xiang S, Gu L, Zhou J, Zhou X, Wu P, Zhang B, Deng D. Driving effect of P16 methylation on telomerase reverse transcriptase-mediated immortalization and transformation of normal human fibroblasts. Chin Med J (Engl) 2025; 138:332-342. [PMID: 38420748 PMCID: PMC11771662 DOI: 10.1097/cm9.0000000000003004] [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: 05/29/2023] [Indexed: 03/02/2024] Open
Abstract
BACKGROUND P16 inactivation is frequently accompanied by telomerase reverse transcriptase ( TERT ) amplification in human cancer genomes. P16 inactivation by DNA methylation often occurs automatically during immortalization of normal cells by TERT . However, direct evidence remains to be obtained to support the causal effect of epigenetic changes, such as P16 methylation, on cancer development. This study aimed to provide experimental evidence that P16 methylation directly drives cancer development. METHODS A zinc finger protein-based P16 -specific DNA methyltransferase (P16-Dnmt) vector containing a "Tet-On" switch was used to induce extensive methylation of P16 CpG islands in normal human fibroblast CCD-18Co cells. Battery assays were used to evaluate cell immortalization and transformation throughout their lifespan. Cell subcloning and DNA barcoding were used to track the diversity of cell evolution. RESULTS Leaking P16-Dnmt expression (without doxycycline-induction) could specifically inactivate P16 expression by DNA methylation. P16 methylation only promoted proliferation and prolonged lifespan but did not induce immortalization of CCD-18Co cells. Notably, cell immortalization, loss of contact inhibition, and anchorage-independent growth were always prevalent in P16-Dnmt&TERT cells, indicating cell transformation. In contrast, almost all TERT cells died in the replicative crisis. Only a few TERT cells recovered from the crisis, in which spontaneous P16 inactivation by DNA methylation occurred. Furthermore, the subclone formation capacity of P16-Dnmt&TERT cells was two-fold that of TERT cells. DNA barcoding analysis showed that the diversity of the P16-Dnmt&TERT cell population was much greater than that of the TERT cell population. CONCLUSION P16 methylation drives TERT -mediated immortalization and transformation of normal human cells that may contribute to cancer development.
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Affiliation(s)
- Xuehong Zhang
- Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Paiyun Li
- Division of Etiology, Beijing Cancer Hospital, Beijing 100142, China
- Radiation Oncology Department, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Ying Gan
- Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Shengyan Xiang
- Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Liankun Gu
- Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Jing Zhou
- Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Xiaorui Zhou
- Department of Biomedical Engineering, Peking University Cancer Hospital and Institute, Beijing 100871, China
| | - Peihuang Wu
- Department of Biomedical Engineering, Peking University Cancer Hospital and Institute, Beijing 100871, China
| | - Baozhen Zhang
- Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
- Division of Etiology, Beijing Cancer Hospital, Beijing 100142, China
| | - Dajun Deng
- Key Laboratory of Carcinogenesis and Translational Research (MOE/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Beijing 100142, China
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5
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Wang Q, Ma C, Yang B, Zheng W, Liu X, Jian G. Dysregulation of DNA methylation in colorectal cancer: biomarker, immune regulation, and therapeutic potential. Int Immunopharmacol 2025; 145:113766. [PMID: 39644791 DOI: 10.1016/j.intimp.2024.113766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 11/16/2024] [Accepted: 11/30/2024] [Indexed: 12/09/2024]
Abstract
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, with morbidity and mortality ranking third and second among all cancers, respectively. As a result of a sequence of genetic and DNA methylation alterations that gradually accumulate in the healthy colonic epithelium, colorectal adenomas and invasive adenocarcinomas eventually give rise to CRC. Global hypomethylation and promoter-specific DNA methylation are characteristics of CRC. The pathophysiological role of aberrant DNA methylation in malignant tumors has garnered significant interest in the last few decades. In addition, DNA methylation has been shown to play a critical role in influencing immune cell function and tumor immune evasion. This review summarizes the most recent research on DNA methylation changes in CRC, including the role of DNA methylation-related enzymes in CRC tumorigenesis and biomarkers for diagnosis, predictive and prognostic. Besides, we focus on the emerging potential of epigenetic interventions to enhance antitumor immune responses and improve the CRC clinical practice.
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Affiliation(s)
- Qin Wang
- School of Pharmacy, Southwest Minzu University, Chengdu, China; Department of Pathology, Yong Yoo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Chen Ma
- School of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Bin Yang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Wenxin Zheng
- School of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Xinya Liu
- School of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Gu Jian
- School of Pharmacy, Southwest Minzu University, Chengdu, China
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Sreeram A, Stroobant EE, Laszkowska M, Guilford P, Shimada S, Nishimura M, Shah S, Vardhana S, Tang LH, Strong VE. Disappearing Signet Ring Cell Adenocarcinoma in Gastric Cancer Patients. Ann Surg Oncol 2024; 31:9030-9038. [PMID: 39343820 DOI: 10.1245/s10434-024-16117-8] [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: 05/07/2024] [Accepted: 08/16/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND The incidence of diffuse-type gastric cancer is increasing steadily in the United States, Europe, and Asia. This subtype is known for aggressive clinical characteristics and transmural invasion. However, T1a diffuse-type cancers have been observed to have a better 5-year, disease-specific mortality than stage-matched intestinal tumors, supporting a clinical difference in these early-stage cancers. METHODS Data on all living patients with T1a gastric adenocarcinoma with a finding of signet ring cell morphology on pathology and ≥1 year of follow-up from 2013 to 2023 at Memorial Sloan Kettering Cancer Center (MSK) was collected from a prospectively maintained database. Patients with known CDH1 or CTNNA1 mutations were excluded. RESULTS In 7 of 30 patients, sporadic pathologically confirmed T1a signet ring cell (diffuse) cancer identified on initial biopsy was no longer detectable upon subsequent biopsy or resection with mean follow-up of 50 months. CONCLUSIONS These cases allude to the distinct pathways of carcinogenesis in T1a signet ring cell cancers. Potential factors that may underlie the spontaneous regression of these T1a cancers include complete removal at initial biopsy, immune clearance, and lack of survival advantage conferred by signet ring cell genetic alterations in these cases. Given their more indolent behavior at an earlier stage, we suggest that these lesions can be closely followed by endoscopy in select circumstances with thorough disease assessment and an experienced care team.
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Affiliation(s)
- Aravind Sreeram
- Department of Surgery, Gastric and Mixed Tumor Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Emily E Stroobant
- Department of Surgery, Gastric and Mixed Tumor Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Monika Laszkowska
- Department of Medicine, Gastroenterology, Hepatology, and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Parry Guilford
- Department of Biochemistry, Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatu), University of Otago, Dunedin, New Zealand
| | - Shoji Shimada
- Department of Surgery, Gastric and Mixed Tumor Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Makoto Nishimura
- Department of Medicine, Gastroenterology, Hepatology, and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sohrab Shah
- Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Santosha Vardhana
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Laura H Tang
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Vivian E Strong
- Department of Surgery, Gastric and Mixed Tumor Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Gossner L, Rieder D, Müller T, Janecke AR. The Recurrent E-Cadherin (CDH1) Mutation c.760G>A Causes Orofacial Clefts but Does Not Predispose to Hereditary Cancer. Genes (Basel) 2024; 15:1475. [PMID: 39596675 PMCID: PMC11594193 DOI: 10.3390/genes15111475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2024] [Revised: 11/08/2024] [Accepted: 11/13/2024] [Indexed: 11/29/2024] Open
Abstract
Objective: Congenital, non-syndromic orofacial clefts (CL/P) are infrequently monogenic in etiology. However, heterozygous pathogenic CDH1 germline variants were reported in a few non-syndromic CL/P families, as well as in one syndromic form of CL/P: the blepharocheilodontic syndrome. CDH1 encodes epithelial cadherin (E-cadherin), and close to 300 different pathogenic CDH1 variants are listed in the ClinVar mutation database. The majority of CDH1 germline variants are implicated in hereditary diffuse gastric cancer (HDGC) susceptibility. The purpose of this study was to classify the CDH1 c.760G>A (p.Asp254Asn) mutation with respect to its resulting phenotype. Methods: Exome sequencing and targeted Sanger sequencing were performed in a family segregating CL/P. A review of pathogenic CDH1 variants in ClinVar and those identified in a PubMed/MEDLINE search was performed. Results: We identified a family with six individuals, who were 35-77 years old (mean 56 years) at their last examination, uniformly affected with bilateral CL/P. The CDH1 c.760G>A variant segregated with CL/P. This variant had been reported in 21 individuals, most often children and young adults, from six families. We determined a significant sex preponderance for this variant regarding CL/P: all 16 male and 5 of 11 female heterozygotes presented with CL/P. Furthermore, none of the heterozygous individuals in seven families reported any gastrointestinal tumors. Conclusions: The recurrent CDH1 c.760G>A mutation confers a high risk for CL/P, with strong male preponderance. This review of 27 mutation carriers, including 3 who were 68, 70, and 77 years of age, indicates that c.760G>A does not confer an increased risk for HDGC. The relevance of differentiating craniofacial from cancer phenotypes in mutation carriers is substantial for precision medicine and for counseling families.
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Affiliation(s)
- Lea Gossner
- Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria; (L.G.); (T.M.)
| | - Dietmar Rieder
- Division of Bioinformatics, Medical University of Innsbruck, 6020 Innsbruck, Austria;
| | - Thomas Müller
- Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria; (L.G.); (T.M.)
| | - Andreas R. Janecke
- Department of Pediatrics I, Medical University of Innsbruck, 6020 Innsbruck, Austria; (L.G.); (T.M.)
- Institute of Human Genetics, Medical University of Innsbruck, 6020 Innsbruck, Austria
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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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9
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Wang Y, Liu H, Zhang M, Xu J, Zheng L, Liu P, Chen J, Liu H, Chen C. Epigenetic reprogramming in gastrointestinal cancer: biology and translational perspectives. MedComm (Beijing) 2024; 5:e670. [PMID: 39184862 PMCID: PMC11344282 DOI: 10.1002/mco2.670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 07/03/2024] [Accepted: 07/08/2024] [Indexed: 08/27/2024] Open
Abstract
Gastrointestinal tumors, the second leading cause of human mortality, are characterized by their association with inflammation. Currently, progress in the early diagnosis and effective treatment of gastrointestinal tumors is limited. Recent whole-genome analyses have underscored their profound heterogeneity and extensive genetic and epigenetic reprogramming. Epigenetic reprogramming pertains to dynamic and hereditable alterations in epigenetic patterns, devoid of concurrent modifications in the underlying DNA sequence. Common epigenetic modifications encompass DNA methylation, histone modifications, noncoding RNA, RNA modifications, and chromatin remodeling. These modifications possess the potential to invoke or suppress a multitude of genes associated with cancer, thereby governing the establishment of chromatin configurations characterized by diverse levels of accessibility. This intricate interplay assumes a pivotal and indispensable role in governing the commencement and advancement of gastrointestinal cancer. This article focuses on the impact of epigenetic reprogramming in the initiation and progression of gastric cancer, esophageal cancer, and colorectal cancer, as well as other uncommon gastrointestinal tumors. We elucidate the epigenetic landscape of gastrointestinal tumors, encompassing DNA methylation, histone modifications, chromatin remodeling, and their interrelationships. Besides, this review summarizes the potential diagnostic, therapeutic, and prognostic targets in epigenetic reprogramming, with the aim of assisting clinical treatment strategies.
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Affiliation(s)
- Yingjie Wang
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Hongyu Liu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Mengsha Zhang
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Jing Xu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Liuxian Zheng
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Pengpeng Liu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Jingyao Chen
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Hongyu Liu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Chong Chen
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
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Shadi Vaziri S, Tajbakhsh E, Khamesipour F, Momtaz H, Mazaheri Z. Impact of Helicobacter Pylori-Derived Outer Membrane Vesicles on Inflammation, Immune Responses, and Tumor Cell Migration in Breast Cancer Through the Snail/Β-Catenin Pathway. Rep Biochem Mol Biol 2024; 13:263-272. [PMID: 39995644 PMCID: PMC11847590 DOI: 10.61186/rbmb.13.2.263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 10/14/2024] [Indexed: 02/26/2025]
Abstract
Background Breast cancer remains a significant global health concern, with challenges in treating advanced stages necessitating the exploration of novel therapeutic approaches. Bacterial outer membrane vesicles (OMVs) have shown promise in cancer immunotherapy by targeting cancer cells and modulating immune responses. This study investigated the effects of Helicobacter pylori-derived OMVs on the activation of the Snail/β-Catenin gene cascade in regulating inflammation and cell migration in a mouse model of breast cancer. Methods The OMVs were extracted from the culture of H. pylori strain 26695 (ATCC 700392) using ultracentrifugation. In the mouse model, the vesicles were injected intraperitoneally into Balb/c mice with breast tumors. Tumor growth was assessed through histological examination of tumor samples. IgA and IgG antibodies were measured using ELISA. The expression of E-cadherin and vimentin proteins was evaluated by immunohistochemistry, and real-time PCR was used for vimentin, Snail, α-SMA, and β-catenin in serum samples from the different groups. Results The OMV treatment led to a significant increase in the expression of α-SMA, β-catenin, Snail, and vimentin genes, indicating a potential induction of epithelial-mesenchymal transition and enhanced cancer cell growth. Additionally, a decrease in vimentin expression and an increase in E-cadherin expression were observed, suggesting inhibition of cell migration. The study also revealed alterations in systemic IgA and IgG antibody levels, indicating potential immunomodulatory effects of OMVs. Conclusions These findings highlight the therapeutic potential of OMVs derived from H. pylori in breast cancer treatment by targeting gene cascades involved in cancer progression and modulating immune responses.
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Affiliation(s)
- Seyedeh Shadi Vaziri
- Department of Microbiology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Elahe Tajbakhsh
- Department of Microbiology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Faham Khamesipour
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman, Iran.
| | - Hassan Momtaz
- Department of Microbiology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Zohre Mazaheri
- Assistant professor of anatomical sciences, Basic medical science research center, Histogenotechcompany, Tehran, Iran.
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Sasaki A, Takeshima H, Yamashita S, Ichita C, Kawachi J, Naito W, Ohashi Y, Takeuchi C, Fukuda M, Furuichi Y, Yamamichi N, Ando T, Kobara H, Kotera T, Itoi T, Sumida C, Hamada A, Koizumi K, Ushijima T. Severe induction of aberrant DNA methylation by nodular gastritis in adults. J Gastroenterol 2024; 59:442-456. [PMID: 38499886 DOI: 10.1007/s00535-024-02094-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 02/29/2024] [Indexed: 03/20/2024]
Abstract
BACKGROUND Nodular gastritis (NG) is characterized by marked antral lymphoid follicle formation, and is a strong risk factor for diffuse-type gastric cancer in adults. However, it is unknown whether aberrant DNA methylation, which is induced by atrophic gastritis (AG) and is a risk for gastric cancer, is induced by NG. Here, we analyzed methylation induction by NG. METHODS Gastric mucosal samples were obtained from non-cancerous antral tissues of 16 NG and 20 AG patients with gastric cancer and 5 NG and 6 AG patients without, all age- and gender-matched. Genome-wide methylation analysis and expression analysis were conducted by a BeadChip array and RNA-sequencing, respectively. RESULTS Clustering analysis of non-cancerous antral tissues of NG and AG patients with gastric cancer was conducted using methylation levels of 585 promoter CpG islands (CGIs) of methylation-resistant genes, and a large fraction of NG samples formed a cluster with strong methylation induction. Promoter CGIs of CDH1 and DAPK1 tumor-suppressor genes were more methylated in NG than in AG. Notably, methylation levels of these genes were also higher in the antrum of NG patients without cancer. Genes related to lymphoid follicle formation, such as CXCL13/CXCR5 and CXCL12/CXCR4, had higher expression in NG, and genes involved in DNA demethylation TET2 and IDH1, had only half the expression in NG. CONCLUSIONS Severe aberrant methylation, involving multiple tumor-suppressor genes, was induced in the gastric antrum and body of patients with NG, in accordance with their high gastric cancer risk.
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Affiliation(s)
- Akiko Sasaki
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
- Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Kanagawa, Japan
| | - Hideyuki Takeshima
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan
| | - Satoshi Yamashita
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Chikamasa Ichita
- Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Kanagawa, Japan
| | - Jun Kawachi
- Department of General Surgery, Shonan Kamakura General Hospital, Kanagawa, Japan
| | - Wataru Naito
- Department of Diagnostic Pathology, Shonan Kamakura General Hospital, Kanagawa, Japan
| | - Yui Ohashi
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan
| | - Chihiro Takeuchi
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan
| | - Masahide Fukuda
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
- Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan
| | - Yumi Furuichi
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Nobutake Yamamichi
- Center for Epidemiology and Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Takayuki Ando
- Third Department of Internal Medicine, University of Toyama, Toyama, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Kagawa University, Kagawa, Japan
| | - Tohru Kotera
- Department of Medical Examination, Uji-Tokushukai Medical Center, Kyoto, Japan
| | - Takao Itoi
- Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan
| | - Chihiro Sumida
- Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Kanagawa, Japan
| | - Akinobu Hamada
- Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo, Japan
| | - Kazuya Koizumi
- Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Kanagawa, Japan
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Tokyo, Japan.
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12
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Oh CK, Cho YS. Pathogenesis and biomarkers of colorectal cancer by epigenetic alteration. Intest Res 2024; 22:131-151. [PMID: 38295766 PMCID: PMC11079515 DOI: 10.5217/ir.2023.00115] [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: 09/05/2023] [Revised: 11/16/2023] [Accepted: 12/29/2023] [Indexed: 05/12/2024] Open
Abstract
Colorectal cancer (CRC) ranks third in cancer incidence and stands as the second leading cause of cancer-related deaths globally. CRC tumorigenesis results from a cumulative set of genetic and epigenetic alterations, disrupting cancer-regulatory processes like cell proliferation, metabolism, angiogenesis, cell death, invasion, and metastasis. Key epigenetic modifications observed in cancers encompass abnormal DNA methylation, atypical histone modifications, and irregularities in noncoding RNAs, such as microRNAs and long noncoding RNAs. The advancement in genomic technologies has positioned these genetic and epigenetic shifts as potential clinical biomarkers for CRC patients. This review concisely covers the fundamental principles of CRC-associated epigenetic changes, and examines in detail their emerging role as biomarkers for early detection, prognosis, and treatment response prediction.
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Affiliation(s)
- Chang Kyo Oh
- Division of Gastroenterology, Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Young-Seok Cho
- Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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13
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Qin Y, Li T, An P, Ren Z, Xi J, Tang B. Important role of DNA methylation hints at significant potential in tuberculosis. Arch Microbiol 2024; 206:177. [PMID: 38494532 DOI: 10.1007/s00203-024-03888-7] [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: 12/02/2023] [Revised: 02/05/2024] [Accepted: 02/06/2024] [Indexed: 03/19/2024]
Abstract
Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis (Mtb) infection, has persisted as a major global public health threat for millennia. Until now, TB continues to challenge efforts aimed at controlling it, with drug resistance and latent infections being the two main factors hindering treatment efficacy. The scientific community is still striving to understand the underlying mechanisms behind Mtb's drug resistance and latent infection. DNA methylation, a critical epigenetic modification occurring throughout an individual's growth and development, has gained attention following advances in high-throughput sequencing technologies. Researchers have observed abnormal DNA methylation patterns in the host genome during Mtb infection. Given the escalating issue of drug-resistant Mtb, delving into the role of DNA methylation in TB's development is crucial. This review article explores DNA methylation's significance in human growth, development and disease, and its role in regulating Mtb's evolution and infection processes. Additionally, it discusses potential applications of DNA methylation research in tuberculosis.
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Affiliation(s)
- Yuexuan Qin
- School of Life Science, Anhui Province Key Laboratory of Immunology in Chronic Diseases, Anhui Key Laboratory of Infection and Immunity, Bengbu Medical University, Bengbu, 233030, Anhui Province, China
| | - Tianyue Li
- School of Life Science, Anhui Province Key Laboratory of Immunology in Chronic Diseases, Anhui Key Laboratory of Infection and Immunity, Bengbu Medical University, Bengbu, 233030, Anhui Province, China
| | - Peiyan An
- School of Life Science, Anhui Province Key Laboratory of Immunology in Chronic Diseases, Anhui Key Laboratory of Infection and Immunity, Bengbu Medical University, Bengbu, 233030, Anhui Province, China
| | - Zhi Ren
- First Affiliated Hospital of Bengbu Medical University, Bengbu, 233030, Anhui Province, China
| | - Jun Xi
- School of Life Science, Anhui Province Key Laboratory of Immunology in Chronic Diseases, Anhui Key Laboratory of Infection and Immunity, Bengbu Medical University, Bengbu, 233030, Anhui Province, China.
| | - Bikui Tang
- School of Life Science, Anhui Province Key Laboratory of Immunology in Chronic Diseases, Anhui Key Laboratory of Infection and Immunity, Bengbu Medical University, Bengbu, 233030, Anhui Province, China.
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14
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Cai HQ, Zhang LY, Fu LM, Xu B, Jiao Y. Mutational landscape of TP53 and CDH1 in gastric cancer. World J Gastrointest Surg 2024; 16:276-283. [PMID: 38463349 PMCID: PMC10921187 DOI: 10.4240/wjgs.v16.i2.276] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 12/26/2023] [Accepted: 01/30/2024] [Indexed: 02/25/2024] Open
Abstract
In this editorial we comment on an article published in a recent issue of the World J Gastrointest Surg. A common gene mutation in gastric cancer (GC) is the TP53 mutation. As a tumor suppressor gene, TP53 is implicated in more than half of all tumor occurrences. TP53 gene mutations in GC tissue may be related with clinical pathological aspects. The TP53 mutation arose late in the progression of GC and aided in the final switch to malignancy. CDH1 encodes E-cadherin, which is involved in cell-to-cell adhesion, epithelial structure maintenance, cell polarity, differentiation, and intracellular signaling pathway modulation. CDH1 mutations and functional loss can result in diffuse GC, and CDH1 mutations can serve as independent prognostic indicators for poor prognosis. GC patients can benefit from genetic counseling and testing for CDH1 mutations. Demethylation therapy may assist to postpone the onset and progression of GC. The investigation of TP53 and CDH1 gene mutations in GC allows for the investigation of the relationship between these two gene mutations, as well as providing some basis for evaluating the prognosis of GC patients.
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Affiliation(s)
- Hong-Qiao Cai
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Yue Zhang
- Department of Critical Care Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Li-Ming Fu
- Department of Traditional Chinese Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Bin Xu
- Department of Traditional Chinese Medicine, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
| | - Yan Jiao
- Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
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15
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Fujii M, Sekine S, Sato T. Decoding the basis of histological variation in human cancer. Nat Rev Cancer 2024; 24:141-158. [PMID: 38135758 DOI: 10.1038/s41568-023-00648-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/21/2023] [Indexed: 12/24/2023]
Abstract
Molecular abnormalities that shape human neoplasms dissociate their phenotypic landscape from that of the healthy counterpart. Through the lens of a microscope, tumour pathology optically captures such aberrations projected onto a tissue slide and has categorized human epithelial neoplasms into distinct histological subtypes based on the diverse morphogenetic and molecular programmes that they manifest. Tumour histology often reflects tumour aggressiveness, patient prognosis and therapeutic vulnerability, and thus has been used as a de facto diagnostic tool and for making clinical decisions. However, it remains elusive how the diverse histological subtypes arise and translate into pleiotropic biological phenotypes. Molecular analysis of clinical tumour tissues and their culture, including patient-derived organoids, and add-back genetic reconstruction of tumorigenic pathways using gene engineering in culture models and rodents further elucidated molecular mechanisms that underlie morphological variations. Such mechanisms include genetic mutations and epigenetic alterations in cellular identity codes that erode hard-wired morphological programmes and histologically digress tumours from the native tissues. Interestingly, tumours acquire the ability to grow independently of the niche-driven stem cell ecosystem along with these morphological alterations, providing a biological rationale for histological diversification during tumorigenesis. This Review comprehensively summarizes our current understanding of such plasticity in the histological and lineage commitment fostered cooperatively by molecular alterations and the tumour environment, and describes basic and clinical implications for future cancer therapy.
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Affiliation(s)
- Masayuki Fujii
- Department of Integrated Medicine and Biochemistry, Keio University School of Medicine, Tokyo, Japan.
| | - Shigeki Sekine
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Toshiro Sato
- Department of Integrated Medicine and Biochemistry, Keio University School of Medicine, Tokyo, Japan.
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16
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Takane K, Cai T, Noguchi R, Gohda Y, Ikenoue T, Yamaguchi K, Ota Y, Kiyomatsu T, Yano H, Fukuyo M, Seki M, Bahityar R, Kaneda A, Furukawa Y. Genome-Wide Analysis of DNA Methylation in Pseudomyxoma Peritonei Originated from Appendiceal Neoplasms. Oncology 2024; 102:720-731. [PMID: 38262376 DOI: 10.1159/000536219] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 01/09/2024] [Indexed: 01/25/2024]
Abstract
INTRODUCTION Pseudomyxoma peritonei (PMP) is a disease characterized by progressive accumulation of intraperitoneal mucinous ascites produced by neoplasms in the abdominal cavity. Since the prognosis of patients with PMP remains unsatisfactory, the development of effective therapeutic drug(s) is a matter of pressing concern. Genetic analyses of PMP have clarified the frequent activation of GNAS and/or KRAS. However, the involvement of global epigenetic alterations in PMPs has not been reported. METHODS To clarify the genetic background of the 15 PMP tumors, we performed genetic analysis using AmpliSeq Cancer HotSpot Panel v2. We further investigated global DNA methylation in the 15 tumors and eight noncancerous colonic epithelial tissues using MethylationEPIC array BeadChip (Infinium 850k) containing a total of 865,918 probes. RESULTS This is the first report of comprehensive DNA methylation profiles of PMPs in the world. We clarified that the 15 PMPs could be classified into at least two epigenotypes, unique methylation epigenotype (UME) and normal-like methylation epigenotype (NLME), and that genes associated with neuronal development and synaptic signaling may be involved in the development of PMPs. In addition, we identified a set of hypermethylation marker genes such as HOXD1 and TSPYL5 in the 15 PMPs. CONCLUSIONS These findings may help the understanding of the molecular mechanism(s) of PMP and contribute to the development of therapeutic strategies for this life-threatening disease.
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Affiliation(s)
- Kiyoko Takane
- Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan,
| | - Tingwei Cai
- Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Rei Noguchi
- Division of Rare Cancer Research, National Cancer Center Research Institute, Tokyo, Japan
| | - Yoshimasa Gohda
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
| | - Tsuneo Ikenoue
- Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Kiyoshi Yamaguchi
- Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yasunori Ota
- Department of Pathology, Research Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Tomomichi Kiyomatsu
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
| | - Hideaki Yano
- Department of Surgery, National Center for Global Health and Medicine, Tokyo, Japan
| | - Masaki Fukuyo
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Motoaki Seki
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Rahmutulla Bahityar
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Atsushi Kaneda
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yoichi Furukawa
- Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
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17
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Cheung KS, Chan AOO, Yu Wong BC. Intestinal‐type Gastric Cancer. GASTROINTESTINAL ONCOLOGY ‐ A CRITICAL MULTIDISCIPLINARY TEAM APPROACH 2E 2024:120-138. [DOI: 10.1002/9781119756422.ch7] [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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18
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Krimpenfort RA, van der Meulen SA, Verhagen H, Driessen M, Filonova G, Hoogenboezem M, van den Akker E, von Lindern M, Nethe M. E-cadherin/β-catenin expression is conserved in human and rat erythropoiesis and marks stress erythropoiesis. Blood Adv 2023; 7:7169-7183. [PMID: 37792794 PMCID: PMC10698263 DOI: 10.1182/bloodadvances.2023010875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 09/07/2023] [Accepted: 09/27/2023] [Indexed: 10/06/2023] Open
Abstract
E-cadherin is a crucial regulator of epithelial cell-to-cell adhesion and an established tumor suppressor. Aside epithelia, E-cadherin expression marks the erythroid cell lineage during human but not mouse hematopoiesis. However, the role of E-cadherin in human erythropoiesis remains unknown. Because rat erythropoiesis was postulated to reflect human erythropoiesis more closely than mouse erythropoiesis, we investigated E-cadherin expression in rat erythroid progenitors. E-cadherin expression is conserved within the erythroid lineage between rat and human. In response to anemia, erythroblasts in rat bone marrow (BM) upregulate E-cadherin as well as its binding partner β-catenin. CRISPR/Cas9-mediated knock out of E-cadherin revealed that E-cadherin expression is required to stabilize β-catenin in human and rat erythroblasts. Suppression of β-catenin degradation by glycogen synthase kinase 3β (GSK3β) inhibitor CHIR99021 also enhances β-catenin stability in human erythroblasts but hampers erythroblast differentiation and survival. In contrast, direct activation of β-catenin signaling, using an inducible, stable β-catenin variant, does not perturb maturation or survival of human erythroblasts but rather enhances their differentiation. Although human erythroblasts do not respond to Wnt ligands and direct GSK3β inhibition even reduces their survival, we postulate that β-catenin stability and signaling is mostly controlled by E-cadherin in human and rat erythroblasts. In response to anemia, E-cadherin-driven upregulation and subsequent activation of β-catenin signaling may stimulate erythroblast differentiation to support stress erythropoiesis in the BM. Overall, we uncover E-cadherin/β-catenin expression to mark stress erythropoiesis in rat BM. This may provide further understanding of the underlying molecular regulation of stress erythropoiesis in the BM, which is currently poorly understood.
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Affiliation(s)
- Rosa A. Krimpenfort
- Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, Amsterdam, The Netherlands
| | - Santhe A. van der Meulen
- Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, Amsterdam, The Netherlands
| | - Han Verhagen
- Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, Amsterdam, The Netherlands
| | - Michel Driessen
- Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, Amsterdam, The Netherlands
| | - Galina Filonova
- Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, Amsterdam, The Netherlands
| | - Mark Hoogenboezem
- Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, Amsterdam, The Netherlands
| | - Emile van den Akker
- Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, Amsterdam, The Netherlands
| | - Marieke von Lindern
- Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, Amsterdam, The Netherlands
| | - Micha Nethe
- Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Amsterdam UMC, Amsterdam, The Netherlands
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19
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Lim NR, Chung WC. Helicobacter pylori-associated Chronic Atrophic Gastritis and Progression of Gastric Carcinogenesis. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2023; 82:171-179. [PMID: 37876256 DOI: 10.4166/kjg.2023.097] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 08/23/2023] [Accepted: 08/25/2023] [Indexed: 10/26/2023]
Abstract
Chronic inflammation due to a Helicobacter pylori (H. pylori) infection is a representative cause of gastric cancer that can promote gastric carcinogenesis by abnormally activating immune cells and increasing the inflammatory cytokines levels. H. pylori infections directly cause DNA double-strand breaks in gastric epithelial cells and genetic damage by increasing the enzymatic activity of cytidine deaminase. Eventually, gastric cancer is induced through dysplasia. Hypermethylation of tumor suppressor genes is an important cause of gastric cancer because of a H. pylori infection. In addition, the changes in gastric microbiota and the mucosal inflammatory changes associated with a co-infection with the Epstein-Barr virus are associated with gastric cancer development. DNA damage induced by H. pylori and the subsequent responses of gastric stem cells have implications for gastric carcinogenesis. Although the pathogenesis of H. pylori has been established, many uncertainties remain, requiring more study.
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Affiliation(s)
- Na Rae Lim
- Department of Internal Medicine, St. Vincent Hospital, The Catholic University of Korea, Suwon, Korea
| | - Woo Chul Chung
- Department of Internal Medicine, St. Vincent Hospital, The Catholic University of Korea, Suwon, Korea
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20
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Wu HW, Wu JD, Yeh YP, Wu TH, Chao CH, Wang W, Chen TW. DoSurvive: A webtool for investigating the prognostic power of a single or combined cancer biomarker. iScience 2023; 26:107269. [PMID: 37609633 PMCID: PMC10440714 DOI: 10.1016/j.isci.2023.107269] [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: 11/22/2022] [Revised: 05/26/2023] [Accepted: 06/28/2023] [Indexed: 08/24/2023] Open
Abstract
We present DoSurvive, a user-friendly survival analysis web tool and a cancer prognostic biomarker centered database. DoSurvive is the first database that allows users to perform multivariant survival analysis for cancers with customized gene/patient list. DoSurvive offers three survival analysis methods, Log rank test, Cox regression and accelerated failure time model (AFT), for users to analyze five types of quantitative features (mRNA, miRNA, lncRNA, protein and methylation of CpG islands) with four survival types, i.e. overall survival, disease-specific survival, disease-free interval, and progression-free interval, in 33 cancer types. Notably, the implemented AFT model provides an alternative method for genes/features which failed the proportional hazard assumption in Cox regression. With the unprecedented number of survival models implemented and high flexibility in analysis, DoSurvive is a unique platform for the identification of clinically relevant targets for cancer researcher and practitioners. DoSurvive is freely available at http://dosurvive.lab.nycu.edu.tw/.
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Affiliation(s)
- Hao-Wei Wu
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan
| | - Jian-De Wu
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan
| | - Yen-Ping Yeh
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan
| | - Timothy H. Wu
- Institute of Ecology and Evolutionary Biology, National Taiwan University, Taipei 10617, Taiwan
| | - Chi-Hong Chao
- Institute of Molecular Medicine and Bioengineering, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan
- Center For Intelligent Drug Systems and Smart Bio-devices (IDSB), National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan
| | - Weijing Wang
- Institute of Statistics, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan
| | - Ting-Wen Chen
- Institute of Bioinformatics and Systems Biology, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan
- Department of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan
- Center For Intelligent Drug Systems and Smart Bio-devices (IDSB), National Yang Ming Chiao Tung University, Hsinchu 30068, Taiwan
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21
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Alvizi L, Nani D, Brito LA, Kobayashi GS, Passos-Bueno MR, Mayor R. Neural crest E-cadherin loss drives cleft lip/palate by epigenetic modulation via pro-inflammatory gene-environment interaction. Nat Commun 2023; 14:2868. [PMID: 37225711 PMCID: PMC10209087 DOI: 10.1038/s41467-023-38526-1] [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: 08/03/2022] [Accepted: 05/05/2023] [Indexed: 05/26/2023] Open
Abstract
Gene-environment interactions are believed to play a role in multifactorial phenotypes, although poorly described mechanistically. Cleft lip/palate (CLP), the most common craniofacial malformation, has been associated with both genetic and environmental factors, with little gene-environment interaction experimentally demonstrated. Here, we study CLP families harbouring CDH1/E-Cadherin variants with incomplete penetrance and we explore the association of pro-inflammatory conditions to CLP. By studying neural crest (NC) from mouse, Xenopus and humans, we show that CLP can be explained by a 2-hit model, where NC migration is impaired by a combination of genetic (CDH1 loss-of-function) and environmental (pro-inflammatory activation) factors, leading to CLP. Finally, using in vivo targeted methylation assays, we demonstrate that CDH1 hypermethylation is the major target of the pro-inflammatory response, and a direct regulator of E-cadherin levels and NC migration. These results unveil a gene-environment interaction during craniofacial development and provide a 2-hit mechanism to explain cleft lip/palate aetiology.
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Affiliation(s)
- Lucas Alvizi
- Department of Cell and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK.
| | - Diogo Nani
- Centro de Estudos do Genoma Humano e Celulas-Tronco, Departamento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Luciano Abreu Brito
- Centro de Estudos do Genoma Humano e Celulas-Tronco, Departamento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Gerson Shigeru Kobayashi
- Centro de Estudos do Genoma Humano e Celulas-Tronco, Departamento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Maria Rita Passos-Bueno
- Centro de Estudos do Genoma Humano e Celulas-Tronco, Departamento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de Sao Paulo, Sao Paulo, Brazil.
| | - Roberto Mayor
- Department of Cell and Developmental Biology, University College London, Gower Street, London, WC1E 6BT, UK.
- Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile.
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22
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Danishevich AM, Lisitsa TS, Nikolaev SE, Abramov IS, Filippova MG, Pospekhova NI, Stroganova AM, Nikulin MP, Kalinin AE, Stilidi IS, Lyubchenko LN. Hereditary diffuse gastric cancer associated with a novel germline variant c.1596G>A in the <i>CDH1</i> gene. ADVANCES IN MOLECULAR ONCOLOGY 2023. [DOI: 10.17650/2313-805x-2023-10-1-87-93] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Gastric cancer is one of the most common malignancies worldwide. Approximately 10 % of patients with gastric cancer are characterized by accumulation of gastric cancer cases in their family. The hereditary forms of gastric cancer account for 1–3 % of all gastric cancer cases. Hereditary diffuse GC syndrome is caused by germline mutations in CDH1 gene and determines a high risk of developing diffuse GC and lobular breast cancer. In this article, we present a clinical case of a 41-year-old patient with diffuse gastric cancer, who was found to be a carrier of novel germline mutation in the CDH1 gene. Next-generation sequencing (NGS) has facilitated an identification of CDH1 c.1596G>A genetic variant, thus enabling an accurate clinical diagnosis hereditary diffuse gastric cancer.
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Affiliation(s)
- A. M. Danishevich
- A.S. Loginov Moscow Clinical Scientific Center, Moscow Healthcare Department
| | - T. S. Lisitsa
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - S. E. Nikolaev
- A.S. Loginov Moscow Clinical Scientific Center, Moscow Healthcare Department
| | - I. S. Abramov
- Centre for Strategic Planning and Management of Biomedical Health Risks, Federal Medical Biological Agency
| | - M. G. Filippova
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - N. I. Pospekhova
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - A. M. Stroganova
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - M. P. Nikulin
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - A. E. Kalinin
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - I. S. Stilidi
- N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia
| | - L. N. Lyubchenko
- National Medical Research Center for Radiology, Ministry of Health of Russia; 5
N.A. Lopatkin Research Center for Urology and Interventional Radiology – branch of the National Medical Research Center for Radiology, Ministry of Health of Russia
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23
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Lim HJ, Zhuang L, Fitzgerald RC. Current advances in understanding the molecular profile of hereditary diffuse gastric cancer and its clinical implications. J Exp Clin Cancer Res 2023; 42:57. [PMID: 36869400 PMCID: PMC9985294 DOI: 10.1186/s13046-023-02622-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 02/13/2023] [Indexed: 03/05/2023] Open
Abstract
Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome attributed to germline CDH1 mutations that carries a high risk for early onset DGC. HDGC raises a significant health issue due to its high penetrance and mortality unless diagnosed early. The definitive treatment is to undergo prophylactic total gastrectomy which is associated with significant morbidity., highlighting the urgent need for alternative treatment methods. However, there is limited literature examining potential therapeutic strategies building on emerging insights into the molecular basis of progressive lesions in the context of HDGC. The aim of this review is to summarise the current understanding of HDGC in the context of CDH1 pathogenic variants followed by a review of the proposed mechanisms for progression. In addition, we discuss the development of novel therapeutic approaches and highlight pertinent areas for further research. A literature search was therefore performed for relevant studies examining CDH1 germline variants, second-hit mechanisms of CDH1, pathogenesis of HDGC and potential therapeutic strategies in databases, including PubMed, ScienceDirect and Scopus. Germline mutations are mostly truncating CDH1 variants affecting extracellular domains of E-cadherin, generally due to frameshift, single nucleotide variants or splice site mutations. A second somatic hit of CDH1 most commonly occurs via promoter methylation as shown in 3 studies, but studies are limited with a small sample size. The multi-focal development of indolent lesions in HDGC provide a unique opportunity to understand genetic events that drive the transition to the invasive phenotype. To date, a few signalling pathways have been shown to facilitate the progression of HDGC, including Notch and Wnt. In in-vitro studies, the ability to inhibit Notch signalling was lost in cells transfected with mutant forms of E-cadherin, and increased Notch-1 activity correlated with apoptosis resistance. Furthermore, in patient samples, overexpression of Wnt-2 was associated with cytoplasmic and nuclear β-catenin accumulation and increased metastatic potential. As loss-of-function mutations are challenging to target therapeutically, these findings pave the way towards a synthetic lethal approach in CDH1-deficient cells with some promising results in-vitro. In future, if we could better understand the molecular vulnerabilities in HDGC, there may be opportunities to offer alternative treatment pathways to avoid gastrectomy.
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Affiliation(s)
- Hui Jun Lim
- Department of Oncology, Early Cancer Institute, University of Cambridge, Box 197, Cambridge Biomedical Campus, CB2 0XZ, Cambridge, UK.
- Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
| | - Lizhe Zhuang
- Department of Oncology, Early Cancer Institute, University of Cambridge, Box 197, Cambridge Biomedical Campus, CB2 0XZ, Cambridge, UK
| | - Rebecca C Fitzgerald
- Department of Oncology, Early Cancer Institute, University of Cambridge, Box 197, Cambridge Biomedical Campus, CB2 0XZ, Cambridge, UK
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Hereditary Diffuse Gastric Cancer: A 2022 Update. J Pers Med 2022; 12:jpm12122032. [PMID: 36556253 PMCID: PMC9783673 DOI: 10.3390/jpm12122032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 11/21/2022] [Accepted: 12/06/2022] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer is ranked fifth among the most commonly diagnosed cancers, and is the fourth leading cause of cancer-related deaths worldwide. The majority of gastric cancers are sporadic, while only a small percentage, less than 1%, are hereditary. Hereditary diffuse gastric cancer (HDGC) is a rare malignancy, characterized by early-onset, highly-penetrant autosomal dominant inheritance mainly of the germline alterations in the E-cadherin gene (CDH1) and β-catenin (CTNNA1). In the present study, we provide an overview on the molecular basis of HDGC and outline the essential elements of genetic counseling and surveillance. We further provide a practical summary of current guidelines on clinical management and treatment of individuals at risk and patients with early disease.
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Malpeli G, Barbi S, Innamorati G, Alloggio M, Filippini F, Decimo I, Castelli C, Perris R, Bencivenga M. Landscape of Druggable Molecular Pathways Downstream of Genomic CDH1/Cadherin-1 Alterations in Gastric Cancer. J Pers Med 2022; 12:jpm12122006. [PMID: 36556227 PMCID: PMC9784514 DOI: 10.3390/jpm12122006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/03/2022] [Accepted: 11/24/2022] [Indexed: 12/09/2022] Open
Abstract
Loss of CDH1/Cadherin-1 is a common step towards the acquisition of an abnormal epithelial phenotype. In gastric cancer (GC), mutation and/or downregulation of CDH1/Cadherin-1 is recurrent in sporadic and hereditary diffuse GC type. To approach the molecular events downstream of CDH1/Cadherin-1 alterations and their relevance in gastric carcinogenesis, we queried public databases for genetic and DNA methylation data in search of molecular signatures with a still-uncertain role in the pathological mechanism of GC. In all GC subtypes, modulated genes correlating with CDH1/Cadherin-1 aberrations are associated with stem cell and epithelial-to-mesenchymal transition pathways. A higher level of genes upregulated in CDH1-mutated GC cases is associated with reduced overall survival. In the diffuse GC (DGC) subtype, genes downregulated in CDH1-mutated compared to cases with wild type CDH1/Cadherin-1 resulted in being strongly intertwined with the DREAM complex. The inverse correlation between hypermethylated CpGs and CDH1/Cadherin-1 transcription in diverse subtypes implies a common epigenetic program. We identified nonredundant protein-encoding isoforms of 22 genes among those differentially expressed in GC compared to normal stomach. These unique proteins represent potential agents involved in cell transformation and candidate therapeutic targets. Meanwhile, drug-induced and CDH1/Cadherin-1 mutation-related gene expression comparison predicts FIT, GR-127935 hydrochloride, amiodarone hydrochloride in GC and BRD-K55722623, BRD-K13169950, and AY 9944 in DGC as the most effective treatments, providing cues for the design of combined pharmacological treatments. By integrating genetic and epigenetic aspects with their expected functional outcome, we unveiled promising targets for combinatorial pharmacological treatments of GC.
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Affiliation(s)
- Giorgio Malpeli
- Department of Surgical, Odontostomatologic, Maternal and Child Sciences, University of Verona, 37134 Verona, Italy
- Correspondence:
| | - Stefano Barbi
- Department of Diagnostics and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Giulio Innamorati
- Department of Surgical, Odontostomatologic, Maternal and Child Sciences, University of Verona, 37134 Verona, Italy
| | - Mariella Alloggio
- General and Upper GI Surgery Division, Department and of Surgical, Odontostomatologic, Maternal and Child Sciences, University of Verona, 37134 Verona, Italy
| | - Federica Filippini
- General and Upper GI Surgery Division, Department and of Surgical, Odontostomatologic, Maternal and Child Sciences, University of Verona, 37134 Verona, Italy
| | - Ilaria Decimo
- Section of Pharmacology, Department of Diagnostic and Public Health, University of Verona, 37134 Verona, Italy
| | - Claudia Castelli
- Pathology Unit, Department of Diagnostics and Public Health, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Roberto Perris
- Department of Biosciences, COMT-Centre for Molecular and Translational Oncology, University of Parma, 43124 Parma, Italy
| | - Maria Bencivenga
- General and Upper GI Surgery Division, Department and of Surgical, Odontostomatologic, Maternal and Child Sciences, University of Verona, 37134 Verona, Italy
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Krimpenfort RA, Behr FM, Nieuwland M, de Rink I, Kerkhoven R, von Lindern M, Nethe M. E-Cadherin Expression Distinguishes Mouse from Human Hematopoiesis in the Basophil and Erythroid Lineages. Biomolecules 2022; 12:1706. [PMID: 36421719 PMCID: PMC9688100 DOI: 10.3390/biom12111706] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/10/2022] [Accepted: 11/12/2022] [Indexed: 09/11/2024] Open
Abstract
E-cadherin is a key regulator of epithelial cell-cell adhesion, the loss of which accelerates tumor growth and invasion. E-cadherin is also expressed in hematopoietic cells as well as epithelia. The function of hematopoietic E-cadherin is, however, mostly elusive. In this study, we explored the validity of mouse models to functionally investigate the role of hematopoietic E-cadherin in human hematopoiesis. We generated a hematopoietic-specific E-cadherin knockout mouse model. In mice, hematopoietic E-cadherin is predominantly expressed within the basophil lineage, the expression of which is dispensable for the generation of basophils. However, neither E-cadherin mRNA nor protein were detected in human basophils. In contrast, human hematopoietic E-cadherin marks the erythroid lineage. E-cadherin expression in hematopoiesis thereby revealed striking evolutionary differences between the basophil and erythroid cell lineage in humans and mice. This is remarkable as E-cadherin expression in epithelia is highly conserved among vertebrates including humans and mice. Our study therefore revealed that the mouse does not represent a suitable model to study the function of E-cadherin in human hematopoiesis and an alternative means to study the role of E-cadherin in human erythropoiesis needs to be developed.
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Affiliation(s)
- Rosa A. Krimpenfort
- Sanquin Research, Landsteiner Laboratory, Academic Medical Centre, Department of Hematopoiesis, University of Amsterdam, 1066 CX Amsterdam, The Netherlands
| | - Felix M. Behr
- Sanquin Research, Landsteiner Laboratory, Academic Medical Centre, Department of Hematopoiesis, University of Amsterdam, 1066 CX Amsterdam, The Netherlands
| | - Marja Nieuwland
- Genomics Core Facility, Netherlands Cancer Institute, 1006 BE Amsterdam, The Netherlands
| | - Iris de Rink
- Genomics Core Facility, Netherlands Cancer Institute, 1006 BE Amsterdam, The Netherlands
| | - Ron Kerkhoven
- Genomics Core Facility, Netherlands Cancer Institute, 1006 BE Amsterdam, The Netherlands
| | - Marieke von Lindern
- Sanquin Research, Landsteiner Laboratory, Academic Medical Centre, Department of Hematopoiesis, University of Amsterdam, 1066 CX Amsterdam, The Netherlands
| | - Micha Nethe
- Sanquin Research, Landsteiner Laboratory, Academic Medical Centre, Department of Hematopoiesis, University of Amsterdam, 1066 CX Amsterdam, The Netherlands
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Hereditary Diffuse Gastric Cancer: Molecular Genetics, Biological Mechanisms and Current Therapeutic Approaches. Int J Mol Sci 2022; 23:ijms23147821. [PMID: 35887173 PMCID: PMC9319245 DOI: 10.3390/ijms23147821] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 07/01/2022] [Accepted: 07/06/2022] [Indexed: 12/14/2022] Open
Abstract
Hereditary diffuse gastric cancer is an autosomal dominant syndrome characterized by a high prevalence of diffuse gastric cancer and lobular breast cancer. It is caused by inactivating mutations in the tumor suppressor gene CDH1. Genetic testing technologies have become more efficient over the years, also enabling the discovery of other susceptibility genes for gastric cancer, such as CTNNA1 among the most important genes. The diagnosis of pathogenic variant carriers with an increased risk of developing gastric cancer is a selection process involving a multidisciplinary team. To achieve optimal long-term results, it requires shared decision-making in risk management. In this review, we present a synopsis of the molecular changes and current therapeutic approaches in HDGC based on the current literature.
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Carneiro F. Familial and hereditary gastric cancer, an overview. Best Pract Res Clin Gastroenterol 2022; 58-59:101800. [PMID: 35988963 DOI: 10.1016/j.bpg.2022.101800] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 04/11/2022] [Accepted: 04/24/2022] [Indexed: 02/08/2023]
Abstract
There are three major hereditable syndromes that affect primarily the stomach: hereditary diffuse gastric cancer (HDGC), gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) and familial intestinal gastric cancer (FIGC). HDGC is caused by germline mutations in CDH1 gene that occur in 10-40% of HDGC families and, in a minority of cases, by mutations in CTNNA1 gene. GAPPS is caused by germline mutations in the promoter 1B of APC gene, and the genetic cause of FIGC is not fully elucidated. Gastric cancer can also be observed as part of other inherited cancer disorders, namely in familial adenomatous polyposis, MUTYH-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis syndrome, Lynch syndrome, Li-Fraumeni syndrome, Cowden syndrome, and hereditary breast and ovarian cancer syndrome. In this article, the state of the art of familial gastric cancer regarding the clinical, molecular and pathology features is reviewed, as well as the practical aspects for a correct diagnosis and clinical management.
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Affiliation(s)
- Fátima Carneiro
- Ipatimup - Institute of Molecular Pathology and Immunology of the University of Porto, Rua Júlio Amaral de Carvalho,45, 4200-135, Porto, Portugal; Department of Pathology, Faculty of Medicine of the University of Porto, Alameda Prof. Hernâni Monteiro, 4100-319, Porto, Portugal; Centro Hospitalar Universitário São João, Alameda Prof. Hernani Monteiro, 4100-319, Porto, Portugal.
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Diffuse gastric cancer: Emerging mechanisms of tumor initiation and progression. Biochim Biophys Acta Rev Cancer 2022; 1877:188719. [PMID: 35307354 DOI: 10.1016/j.bbcan.2022.188719] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 03/10/2022] [Accepted: 03/11/2022] [Indexed: 02/07/2023]
Abstract
Gastric cancer is globally the fourth leading cause of cancer-related deaths. Patients with diffuse-type gastric cancer (DGC) particularly have a poor prognosis that only marginally improved over the last decades, as conventional chemotherapies are frequently ineffective and specific therapies are unavailable. Early-stage DGC is characterized by intramucosal lesions of discohesive cells, which can be present for many years before the emergence of advanced DGC consisting of highly proliferative and invasive cells. The mechanisms underlying the key steps of DGC development and transition to aggressive tumors are starting to emerge. Novel mouse- and organoid models for DGC, together with multi-omic analyses of DGC tumors, revealed contributions of both tumor cell-intrinsic alterations and gradual changes in the tumor microenvironment to DGC progression. In this review, we will discuss how these recent findings are leading towards an understanding of the cellular and molecular mechanisms responsible for DGC initiation and malignancy, which may provide opportunities for targeted therapies.
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Decourtye-Espiard L, Bougen-Zhukov N, Godwin T, Brew T, Schulpen E, Black MA, Guilford P. E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors. Cancers (Basel) 2021; 14:cancers14010175. [PMID: 35008338 PMCID: PMC8749989 DOI: 10.3390/cancers14010175] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2021] [Revised: 12/21/2021] [Accepted: 12/28/2021] [Indexed: 12/18/2022] Open
Abstract
Inactivating germline mutations in the CDH1 gene (encoding the E-cadherin protein) are the genetic hallmark of hereditary diffuse gastric cancer (HDGC), and somatic CDH1 mutations are an early event in the development of sporadic diffuse gastric cancer (DGC) and lobular breast cancer (LBC). In this study, histone deacetylase (HDAC) inhibitors were tested for their ability to preferentially inhibit the growth of human cell lines (MCF10A and NCI-N87) and murine organoids lacking CDH1 expression. CDH1-/- breast and gastric cells were more sensitive to the pan-HDAC inhibitors entinostat, pracinostat, mocetinostat and vorinostat than wild-type cells, with an elevated growth inhibition that was, in part, attributable to increased apoptosis. CDH1-null cells were also sensitive to more class-specific HDAC inhibitors, but compared to the pan-inhibitors, these effects were less robust to genetic background. Increased sensitivity to entinostat was also observed in gastric organoids with both Cdh1 and Tp53 deletions. However, the deletion of Tp53 largely abrogated the sensitivity of the Cdh1-null organoids to pracinostat and mocetinostat. Finally, entinostat enhanced Cdh1 expression in heterozygous Cdh1+/- murine organoids. In conclusion, entinostat is a promising drug for the chemoprevention and/or treatment of HDGC and may also be beneficial for the treatment of sporadic CDH1-deficient cancers.
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31
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Choi JM, Kim SG. Effect of Helicobacter pylori Eradication on Epigenetic Changes in Gastric Cancer-related Genes. THE KOREAN JOURNAL OF HELICOBACTER AND UPPER GASTROINTESTINAL RESEARCH 2021. [DOI: 10.7704/kjhugr.2021.0042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
It is known that gastric carcinogenesis results from the progressive changes from chronic gastritis to gastric atrophy, intestinal metaplasia, dysplasia, and invasive carcinoma. Several genetic and epigenetic alterations are involved in this process, and Helicobacter pylori (H. pylori) infection is believed to induce the initiation and progression of these steps. From an epigenetic point of view, H. pylori induces hypermethylation of genes involved in the development of gastric cancer and regulates the expression of various microRNAs (miRNAs). These H. pylori-related epigenetic changes are accumulated not only at the site of neoplasm but also in the adjacent non-cancerous gastric mucosa. Thereby, a state vulnerable to gastric cancer known as an epigenetic field defect is formed. H. pylori eradication can have an effective chemopreventive effect in gastric carcinogenesis. However, the molecular biological changes that occur in the stomach environment during H. pylori eradication have not yet been established. Several studies have reported that H. pylori eradication can restore infection-related changes, especially epigenetic alterations in gastric cancer-related genes, but some studies have shown otherwise. Simply put, it appears that the recovery of methylated gastric cancer-related genes and miRNAs during H. pylori eradication may vary among genes and may also differ depending on the histological subtype of the gastric mucosa. In this review, we will discuss the potential mechanism of gastric cancer prevention by H. pylori eradication, mainly from an epigenetic perspective.
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Garcia-Pelaez J, Barbosa-Matos R, São José C, Sousa S, Gullo I, Hoogerbrugge N, Carneiro F, Oliveira C. Gastric cancer genetic predisposition and clinical presentations: Established heritable causes and potential candidate genes. Eur J Med Genet 2021; 65:104401. [PMID: 34871783 DOI: 10.1016/j.ejmg.2021.104401] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 11/10/2021] [Accepted: 11/28/2021] [Indexed: 12/12/2022]
Abstract
Tumour risk syndromes (TRS) are characterized by an increased risk of early-onset cancers in a familial context. High cancer risk is mostly driven by loss-of-function variants in a single cancer-associated gene. Presently, predisposition to diffuse gastric cancer (DGC) is explained by CDH1 and CTNNA1 pathogenic and likely pathogenic variants (P/LP), causing Hereditary Diffuse Gastric Cancer (HDGC); while APC promoter 1B single nucleotide variants predispose to Gastric Adenocarcinoma and Proximal Polyposis of the Stomach (GAPPS). Familial Intestinal Gastric Cancer (FIGC), recognized as a GC-predisposing disease, remains understudied and genetically unsolved. GC can also occur in the spectrum of other TRS. Identification of heritable causes allows defining diagnostic testing criteria, helps to clinically classify GC families into the appropriate TRS, and allows performing pre-symptomatic testing identifying at-risk individuals for downstream surveillance, risk reduction and/or treatment. However, most of HDGC, some GAPPS, and most FIGC patients/families remain unsolved, expecting a heritable factor to be discovered. The missing heritability in GC-associated tumour risk syndromes (GC-TRS) is likely explained not by a single major gene, but by a diversity of genes, some, predisposing to other TRS. This would gain support if GC-enriched small families or apparently isolated early-onset GC cases were hiding a family history compatible with another TRS. Herein, we revisited current knowledge on GC-TRS, and searched in the literature for individuals/families bearing P/LP variants predisposing for other TRS, but whose probands display a clinical presentation and/or family history also fitting GC-TRS criteria. We found 27 families with family history compatible with HDGC or FIGC, harbouring 28 P/LP variants in 16 TRS-associated genes, mainly associated with DNA repair. PALB2 or BRCA2 were the most frequently mutated candidate genes in individuals with family history compatible with HDGC and FIGC, respectively. Consolidation of PALB2 and BRCA2 as HDGC- or FIGC-associated genes, respectively, holds promise and worth additional research. This analysis further highlighted the influence, that proband's choice and small or unreported family history have, for a correct TRS diagnosis, genetic screening, and disease management. In this review, we provide a rational for identification of particularly relevant candidate genes in GC-TRS.
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Affiliation(s)
- José Garcia-Pelaez
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; Doctoral Programme in Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Rita Barbosa-Matos
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; International Doctoral Programme in Molecular and Cellular Biotechnology Applied to Health Sciences from Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Celina São José
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; Doctoral Programme in Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Sónia Sousa
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
| | - Irene Gullo
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal; Centro Hospitalar e Universitário S. João, Porto, Portugal
| | - Nicoline Hoogerbrugge
- Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands
| | - Fátima Carneiro
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal; Centro Hospitalar e Universitário S. João, Porto, Portugal
| | - Carla Oliveira
- i3S - Instituto de Investigação e Inovação em Saúde, Porto, Portugal; IPATIMUP - Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal; FMUP - Faculty of Medicine of the University of Porto, Porto, Portugal.
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Abstract
E-cadherin is the main component of epithelial adherens junctions (AJs), which play a crucial role in the maintenance of stable cell-cell adhesion and overall tissue integrity. Down-regulation of E-cadherin expression has been found in many carcinomas, and loss of E-cadherin is generally associated with poor prognosis in patients. During the last decade, however, numerous studies have shown that E-cadherin is essential for several aspects of cancer cell biology that contribute to cancer progression, most importantly, active cell migration. In this review, we summarize the available data about the input of E-cadherin in cancer progression, focusing on the latest advances in the research of the various roles E-cadherin-based AJs play in cancer cell dissemination. The review also touches upon the "cadherin switching" in cancer cells where N- or P-cadherin replace or are co-expressed with E-cadherin and its influence on the migratory properties of cancer cells.
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Affiliation(s)
- Svetlana N Rubtsova
- N.N. Blokhin National Medical Research Center of Oncology, Institute of Carcinogenesis, Moscow, Russia
| | - Irina Y Zhitnyak
- N.N. Blokhin National Medical Research Center of Oncology, Institute of Carcinogenesis, Moscow, Russia
| | - Natalya A Gloushankova
- N.N. Blokhin National Medical Research Center of Oncology, Institute of Carcinogenesis, Moscow, Russia
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Molecular Landscapes of Gastric Pre-Neoplastic and Pre-Invasive Lesions. Int J Mol Sci 2021; 22:ijms22189950. [PMID: 34576114 PMCID: PMC8468646 DOI: 10.3390/ijms22189950] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/03/2021] [Accepted: 09/11/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric carcinoma (GC) represents one of the most common and most lethal malignancies worldwide. The histopathological characterization of GC precursor lesions has provided great knowledge about gastric carcinogenesis, with the consequent introduction of effective strategies of primary and secondary prevention. In recent years, a large amount of data about the molecular events in GC development is emerging, flanking the histomorphological descriptions. In this review, we describe the landscape of molecular alterations in gastric pre-invasive lesions with a glance at their potential use in the diagnostic and therapeutic decision-making process.
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Zhao H, Hu H, Chen B, Xu W, Zhao J, Huang C, Xing Y, Lv H, Nie C, Wang J, He Y, Wang SQ, Chen XB. Overview on the Role of E-Cadherin in Gastric Cancer: Dysregulation and Clinical Implications. Front Mol Biosci 2021; 8:689139. [PMID: 34422902 PMCID: PMC8371966 DOI: 10.3389/fmolb.2021.689139] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 07/19/2021] [Indexed: 01/04/2023] Open
Abstract
Gastric cancer is the fifth most common cancer and the third most common cause of cancer death all over the world. E-cadherin encoded by human CDH1 gene plays important roles in tumorigenesis as well as in tumor progression, invasion and metastasis. Full-length E-cadhrin tethered on the cell membrane mainly mediates adherens junctions between cells and is involved in maintaining the normal structure of epithelial tissues. After proteolysis, the extracellular fragment of the full-length E-cadhein is released into the extracellular environment and the blood, which is called soluble E-cadherin (sE-cadherin). sE-cadherin promots invasion and metastasis as a paracrine/autocrine signaling molecule in the progression of various types of cancer including gastric cancer. This review mainly summarizes the dysregulation of E-cadherin and the regulatory roles in the progression, invasion, metastasis, and drug-resistance, as well as its clinical applications in diagnosis, prognosis, and therapeutics of gastric cancer.
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Affiliation(s)
- Huichen Zhao
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Huihui Hu
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Beibei Chen
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
| | - Weifeng Xu
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jing Zhao
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Chen Huang
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yishu Xing
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Huifang Lv
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Caiyun Nie
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Jianzheng Wang
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Yunduan He
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Sai-Qi Wang
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
| | - Xiao-Bing Chen
- Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou, China
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36
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Nishiyama A, Nakanishi M. Navigating the DNA methylation landscape of cancer. Trends Genet 2021; 37:1012-1027. [PMID: 34120771 DOI: 10.1016/j.tig.2021.05.002] [Citation(s) in RCA: 425] [Impact Index Per Article: 106.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 05/06/2021] [Accepted: 05/11/2021] [Indexed: 12/11/2022]
Abstract
DNA methylation is a chemical modification that defines cell type and lineage through the control of gene expression and genome stability. Disruption of DNA methylation control mechanisms causes a variety of diseases, including cancer. Cancer cells are characterized by aberrant DNA methylation (i.e., genome-wide hypomethylation and site-specific hypermethylation), mainly targeting CpG islands in gene expression regulatory elements. In particular, the early findings that a variety of tumor suppressor genes (TSGs) are targets of DNA hypermethylation in cancer led to the proposal of a model in which aberrant DNA methylation promotes cellular oncogenesis through TSGs silencing. However, recent genome-wide analyses have revealed that this classical model needs to be reconsidered. In this review, we will discuss the molecular mechanisms of DNA methylation abnormalities in cancer as well as their therapeutic potential.
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Affiliation(s)
- Atsuya Nishiyama
- Division of Cancer Cell Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
| | - Makoto Nakanishi
- Division of Cancer Cell Biology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
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37
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Genetic and Epigenetic Alterations of CDH1 Regulatory Regions in Hereditary and Sporadic Gastric Cancer. Pharmaceuticals (Basel) 2021; 14:ph14050457. [PMID: 34066170 PMCID: PMC8151134 DOI: 10.3390/ph14050457] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/04/2021] [Accepted: 05/07/2021] [Indexed: 02/06/2023] Open
Abstract
E-cadherin is a key player in gastric cancer (GC) and germline alterations of CDH1, its encoding gene, are responsible for Hereditary Diffuse Gastric Cancer (HDGC) syndrome. This study aimed at elucidating the role of genetic variants and DNA methylation of CDH1 promoter and enhancers in the regulation of gene expression. For this purpose, we analyzed genetic variants of the CDH1 gene through Next-Generation Sequencing (NGS) in a series of GC cell lines (NCI-N87, KATO-III, SNU-1, SNU-5, GK2, AKG, KKP) and the corresponding CDH1 expression levels. By bisulfite genomic sequencing, we analyzed the methylation status of CDH1 regulatory regions in 8 GC cell lines, in a series of 13 sporadic GC tissues and in a group of 20 HDGC CDH1-negative patients and 6 healthy controls. The NGS analysis on CDH1 coding and regulatory regions detected genetic alterations in 3 out of 5 GC cell lines lacking functional E-cadherin. CDH1 regulatory regions showed different methylation patterns in patients and controls, GC cell lines and GC tissues, expressing different E-cadherin levels. Our results showed that alterations in terms of genetic variants and DNA methylation patterns of both promoter and enhancers are associated with CDH1 expression levels and have a role in its regulation.
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38
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Gamble LA, Heller T, Davis JL. Hereditary Diffuse Gastric Cancer Syndrome and the Role of CDH1: A Review. JAMA Surg 2021; 156:387-392. [PMID: 33404644 DOI: 10.1001/jamasurg.2020.6155] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Importance Inherited variants in the tumor suppressor gene CDH1 are associated with an increased risk of gastric and breast cancers. This review aims to address the most current topics in management of the hereditary diffuse gastric cancer syndrome attributed to CDH1. Observations Consensus management guidelines have broadened genetic testing criteria for CDH1. Prophylactic total gastrectomy is recommended for any pathogenic or likely pathogenic CDH1 variant carrier starting at the age of 20 years. Annual surveillance endoscopy is recommended to those who defer prophylactic total gastrectomy. Women with a CDH1 variant should initiate magnetic resonance imaging breast surveillance starting at age 30 years. Further research is needed to understand the pathogenesis of early-stage gastric cancers (T1a), which are pathognomonic of hereditary diffuse gastric cancer syndrome, that lead to advanced gastric cancer to develop both treatment and prevention strategies for this patient population. Conclusions and Relevance The heritable CDH1 gene mutation is of importance to today's surgeons because it is associated with a substantial increased risk of developing both gastric and breast cancers. Management of this cancer syndrome currently uses prophylactic surgery and enhanced cancer surveillance strategies.
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Affiliation(s)
- Lauren A Gamble
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Theo Heller
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Jeremy L Davis
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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39
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Grady WM. Epigenetic alterations in the gastrointestinal tract: Current and emerging use for biomarkers of cancer. Adv Cancer Res 2021; 151:425-468. [PMID: 34148620 DOI: 10.1016/bs.acr.2021.02.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Colorectal cancer is a leading cause of cancer related deaths worldwide. One of the hallmarks of cancer and a fundamental trait of virtually all gastrointestinal cancers is genomic and epigenomic DNA alterations. Cancer cells acquire genetic and epigenetic alterations that drive the initiation and progression of the cancers by altering the molecular and cell biological process of the cells. These alterations, as well as other host and microenvironment factors, ultimately mediate the initiation and progression of cancers, including colorectal cancer. Epigenetic alterations, which include changes affecting DNA methylation, histone modifications, chromatin structure, and noncoding RNA expression, have emerged as a major class of molecular alteration in colon polyps and colorectal cancer. The classes of epigenetic alterations, their status in colorectal polyps and cancer, their effects on neoplasm biology, and their application to clinical care will be discussed.
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Affiliation(s)
- William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA, United States.
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40
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Grady WM, Yu M, Markowitz SD. Epigenetic Alterations in the Gastrointestinal Tract: Current and Emerging Use for Biomarkers of Cancer. Gastroenterology 2021; 160:690-709. [PMID: 33279516 PMCID: PMC7878343 DOI: 10.1053/j.gastro.2020.09.058] [Citation(s) in RCA: 133] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 09/24/2020] [Accepted: 09/28/2020] [Indexed: 02/06/2023]
Abstract
Colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, and esophageal cancer are leading causes of cancer-related deaths worldwide. A fundamental trait of virtually all gastrointestinal cancers is genomic and epigenomic DNA alterations. Cancer cells acquire genetic and epigenetic alterations that drive the initiation and progression of the cancers by altering the molecular and cell biological processes of the cells. These alterations, as well as other host and microenvironment factors, ultimately mediate the clinical behavior of the precancers and cancers and can be used as biomarkers for cancer risk determination, early detection of cancer and precancer, determination of the prognosis of cancer and prediction of the response to therapy. Epigenetic alterations have emerged as one of most robust classes of biomarkers and are the basis for a growing number of clinical tests for cancer screening and surveillance.
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Affiliation(s)
- William M. Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA,Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Ming Yu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
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41
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Zhao L, Wu X, Zheng J, Dong D. DNA methylome profiling of circulating tumor cells in lung cancer at single base-pair resolution. Oncogene 2021; 40:1884-1895. [PMID: 33564067 PMCID: PMC7946637 DOI: 10.1038/s41388-021-01657-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 12/14/2020] [Accepted: 01/13/2021] [Indexed: 01/30/2023]
Abstract
DNA methylation plays a pivotal role in regulating cellular processes, and altered DNA methylation pattern is a general hallmark of cancer. However, DNA methylome in circulating tumor cells (CTCs) is still a mystery due to the lack of proper analytical techniques. We introduced an efficient workflow, LCM-µWGBS, which can efficiently profile the DNA methylation of microdissected CTC samples. LCM-µWGBS combines the laser capture microdissection (LCM)-based CTC capture method and whole-genome bisulfite sequencing in very small CTC population (µWGBS) to gain insight into the DNA methylation landscape of CTCs. We herein profiled the DNA methylome of CTCs from lung cancer patients. Deriving from a comprehensive analysis of CTC methylome, a unique "CTC DNA methylation signature" that is distinct from primary lung cancer tissues was identified. Further analysis showed that promoter hypermethylation of epithelial genes is a hallmark of stable epithelial-mesenchymal transition process. Moreover, it has been suggested that CTCs are endowed with a stemness-related feature during dissemination and metastasis. This work constitutes a unique DNA methylation analysis of CTCs at single base-pair resolution, which might facilitate to propose noninvasive CTC DNA methylation biomarkers contributing to clinical diagnosis.
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Affiliation(s)
- Lei Zhao
- grid.417303.20000 0000 9927 0537Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu China ,grid.413389.4Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China ,grid.22069.3f0000 0004 0369 6365Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China
| | - Xiaohong Wu
- Department of General Surgery, Affiliated Yixing Hospital of Jiangsu University, Yixing, 214200 Jiangsu China
| | - Junnian Zheng
- grid.417303.20000 0000 9927 0537Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu China ,grid.413389.4Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Dong Dong
- grid.417303.20000 0000 9927 0537Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu China ,grid.413389.4Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
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42
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Bresalier RS, Grady WM, Markowitz SD, Nielsen HJ, Batra SK, Lampe PD. Biomarkers for Early Detection of Colorectal Cancer: The Early Detection Research Network, a Framework for Clinical Translation. Cancer Epidemiol Biomarkers Prev 2020; 29:2431-2440. [PMID: 32299850 PMCID: PMC7572434 DOI: 10.1158/1055-9965.epi-20-0234] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 02/26/2020] [Accepted: 04/09/2020] [Indexed: 12/26/2022] Open
Abstract
Early detection by screening significantly reduces mortality from colorectal cancer, but 40% of guideline-eligible patients are not screened as recommended in the United States. Novel strategies to improve screening uptake overall and efforts to deploy best practices to underserved populations are a high priority for health care. This review focuses on existing biomarkers in practice and those in development with clinical relevance to early detection of colorectal neoplasia, with an emphasis on those developed by investigators of the NCI's Early Detection Research Network. Aberrantly methylated DNA markers (blood and stool), stool-based markers (including fecal immunochemical test-DNA), and a variety of blood-based marker assays in development (protein markers, glycoproteins including mucins, and cell-free DNA tests) are reviewed. Individual markers and biomarker panels, sample resources, and barriers to translating biomarkers to clinical practice are discussed.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."
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Affiliation(s)
- Robert S Bresalier
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center and the Department of Medicine, Division of Gastroenterology, University of Washington School of Medicine, Seattle, Washington
| | - Sanford D Markowitz
- Case Comprehensive Cancer Center and the Division of Hematology-Oncology, University Hospitals Cleveland Medical Center, Cleveland, Ohio
| | - Hans Jørgen Nielsen
- Department of Surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark
- The Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, Omaha, Nebraska
| | - Paul D Lampe
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
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43
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Iyer P, Moslim M, Farma JM, Denlinger CS. Diffuse gastric cancer: histologic, molecular, and genetic basis of disease. Transl Gastroenterol Hepatol 2020; 5:52. [PMID: 33073047 DOI: 10.21037/tgh.2020.01.02] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 01/15/2020] [Indexed: 12/24/2022] Open
Abstract
Diffuse gastric cancer (DGC) is a distinct histopathologic and molecular disease, characterized by mutations in CDH1, RHOA, and others. In addition, DGC is associated with familial syndromes, including hereditary DGC and germline mutation in CDH1. Clinically, this subtype of gastric adenocarcinoma is associated with a poor prognosis and possible resistance to available systemic therapies. An understanding of the genetic and molecular underpinnings of DGC may help inform of its clinical behavior and aid in screening, diagnosis, and response to treatment. In this review, we will review the current histologic, molecular, and genetic landscape of DGC and its relevance to clinical practice.
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Affiliation(s)
- Pritish Iyer
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Maitham Moslim
- Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Jeffrey M Farma
- Department of Surgical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Crystal S Denlinger
- Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
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44
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Goud HK, Mehkari Z, Mohammed L, Javed M, Althwanay A, Ahsan F, Oliveri F, Rutkofsky IH. Significance of E-cadherin Gene Mutations in Patients With Hereditary Diffuse Gastric Cancer Syndrome: A Systematic Review. Cureus 2020; 12:e10406. [PMID: 33062523 PMCID: PMC7550226 DOI: 10.7759/cureus.10406] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 09/12/2020] [Indexed: 11/05/2022] Open
Abstract
Gastric cancer is the third-most fatal cancer in the world. Though over the years, we saw patients mostly with intestinal type accounting for the highest mortality rate, the recent rise of the diffuse form with germline E-cadherin (CDH1) mutations has added a whole new level of interest to study in detail about the association between CDH1 and diffuse gastric cancer (DGC). This introduced a set guideline formulated by Internal Gastric Cancer Linkage Consortium (IGCLC) for patients with family history of diffuse gastric cancer and invasive lobular breast cancer (ILBC). The analysis of this link was also important to set proper management protocol for patients who were CDH1 mutation carriers which now involves genetic counselling, endoscopic surveillance and screening and prophylactic total gastrectomy (PTG). The study was conducted in accordance to the 'PRISMA guidelines for reporting systematic review and meta-analysis'. Peer-reviewed studies were included from the PubMed database and relevant articles were selected to be included in the study. Appropriate inclusion/exclusion criteria with free full text English articles were applied while selecting the articles. A total of 10 studies on review with different study populations showed that of the 42 patients who were diagnosed with diffuse gastric cancer, 88% of them showed a positive germline E-cadherin gene mutation and 100% of the CDH1 mutation carriers showed microscopic changes of signet ring cell adenocarcinoma of the stomach. The beneficial effects of PTG with better survival rates and low mortality rates has outweighed other treatment modalities. Laparoscopic approach has proved to be more useful and a safer approach for gastrectomy surgeries with better post-operative management. The need for prophylactic mastectomy is also increased in the recent times and thus this requires a new set of guidelines for ILBC patients with hereditary diffuse gastric cancer (HDGC) syndrome.
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Affiliation(s)
- Harshit K Goud
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Zainab Mehkari
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Lubna Mohammed
- Obstetrics & Gynaecology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Moiz Javed
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Aldanah Althwanay
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Farah Ahsan
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Federico Oliveri
- Cardiology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ian H Rutkofsky
- Psychiatry, Neuroscience, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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45
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Hu MN, Hu SH, Zhang XW, Xiong SM, Deng H. Overview on new progress of hereditary diffuse gastric cancer with CDH1 variants. TUMORI JOURNAL 2020; 106:346-355. [PMID: 32811340 DOI: 10.1177/0300891620949668] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Hereditary diffuse gastric cancer (HDGC), comprising 1%-3% of gastric malignances, has been associated with CDH1 variants. Accumulating evidence has demonstrated more than 100 germline CDH1 variant types. E-cadherin encoded by the CDH1 gene serves as a tumor suppressor protein. CDH1 promoter hypermethylation and other molecular mechanisms resulting in E-cadherin dysfunction are involved in the tumorigenesis of HDGC. Histopathology exhibits characteristic signet ring cells, and immunohistochemical staining may show negativity for E-cadherin and other signaling proteins. Early HDGC is difficult to detect by endoscopy due to the development of lesions beneath the mucosa. Prophylactic gastrectomy is the most recommended treatment for pathogenic CDH1 variant carriers. Recent studies have promoted the progression of promising molecular-targeted therapies and management strategies. This review summarizes recent advances in CDH1 variant types, tumorigenesis mechanisms, diagnosis, and therapy, as well as clinical implications for future gene therapies.
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Affiliation(s)
- Mu-Ni Hu
- Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Shu-Hui Hu
- Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Xing-Wei Zhang
- Medical College, Nanchang University, Nanchang, Jiangxi Province, China
| | - Shu-Min Xiong
- Department of Ophthalmology, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China
| | - Huan Deng
- Molecular Medicine and Genetics Center, the Fourth Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China.,Renmin Institute of Forensic Medicine in Jiangxi, Nanchang, Jiangxi Province, China
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46
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Casalino L, Verde P. Multifaceted Roles of DNA Methylation in Neoplastic Transformation, from Tumor Suppressors to EMT and Metastasis. Genes (Basel) 2020; 11:E922. [PMID: 32806509 PMCID: PMC7463745 DOI: 10.3390/genes11080922] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 07/30/2020] [Accepted: 08/10/2020] [Indexed: 12/12/2022] Open
Abstract
Among the major mechanisms involved in tumorigenesis, DNA methylation is an important epigenetic modification impacting both genomic stability and gene expression. Methylation of promoter-proximal CpG islands (CGIs) and transcriptional silencing of tumor suppressors represent the best characterized epigenetic changes in neoplastic cells. The global cancer-associated effects of DNA hypomethylation influence chromatin architecture and reactivation of repetitive elements. Moreover, recent analyses of cancer cell methylomes highlight the role of the DNA hypomethylation of super-enhancer regions critically controlling the expression of key oncogenic players. We will first summarize some basic aspects of DNA methylation in tumorigenesis, along with the role of dysregulated DNA methyltransferases and TET (Ten-Eleven Translocation)-family methylcytosine dioxygenases. We will then examine the potential contribution of epimutations to causality and heritability of cancer. By reviewing some representative genes subjected to hypermethylation-mediated silencing, we will survey their oncosuppressor functions and roles as biomarkers in various types of cancer. Epithelial-to-mesenchymal transition (EMT) and the gain of stem-like properties are critically involved in cancer cell dissemination, metastasis, and therapeutic resistance. However, the driver vs passenger roles of epigenetic changes, such as DNA methylation in EMT, are still poorly understood. Therefore, we will focus our attention on several aspects of DNA methylation in control of EMT and metastasis suppressors, including both protein-coding and noncoding genes.
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Affiliation(s)
- Laura Casalino
- Institute of Genetics and Biophysics “Adriano Buzzati Traverso”, CNR, 80100 Naples, Italy
| | - Pasquale Verde
- Institute of Genetics and Biophysics “Adriano Buzzati Traverso”, CNR, 80100 Naples, Italy
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47
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Midorikawa Y, Yamamoto S, Tatsuno K, Renard-Guillet C, Tsuji S, Hayashi A, Ueda H, Fukuda S, Fujita T, Katoh H, Ishikawa S, Covington KR, Creighton CJ, Sugitani M, Wheeler DA, Shibata T, Nagae G, Takayama T, Aburatani H. Accumulation of Molecular Aberrations Distinctive to Hepatocellular Carcinoma Progression. Cancer Res 2020; 80:3810-3819. [DOI: 10.1158/0008-5472.can-20-0225] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 05/01/2020] [Accepted: 07/02/2020] [Indexed: 11/16/2022]
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48
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Zhou Y, Cheng X, Zhang F, Chen Q, Chen X, Shen Y, Lai C, Kota VG, Sun W, Huang Q, Yuan Y, Wang J, Lai M, Zhang D. Integrated multi-omics data analyses for exploring the co-occurring and mutually exclusive gene alteration events in colorectal cancer. Hum Mutat 2020; 41:1588-1599. [PMID: 32485022 DOI: 10.1002/humu.24059] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 03/04/2020] [Accepted: 05/29/2020] [Indexed: 12/19/2022]
Abstract
Co-occurring and mutually exclusive gene alteration events are helpful for understanding carcinogenesis but systematic screening for such events is quite limited. We conducted pairwise screening tests to identify "hit pairs" in colorectal cancer (CRC) by utilizing the cross-omics data from The Cancer Genome Atlas (TCGA). Numerous hit pairs involving somatic mutations, copy number variations, and DNA methylation were found to occur nonrandomly in CRC, such as KRAS and HOXB6, SMAD4 and PMEPA1. Based on these hit pairs, we identified 32 synthetic lethal pairs and 7,527 co-occurring pairs relating to drug response. Our further biological experiments showed that the co-occurrence of mutant FCGBP and NUDT12 silencing (or mutant TMC3 and RPS6KA6 silencing) with small interfering RNA reduced cell viability. Moreover, novel hit pairs could influence prognosis. The patients who carried concurrent mutations of IRF5 and NEFH, SYNE1 and TTN, or MUC16 and NEFH had worse survival outcomes. Particularly, the presence of mutant SYNE1 and TTN pair not only affects prognosis, but also is related to CRC patients' response to drug treatment. Our "hit pair" genes may provide insights into colorectal carcinogenesis and help open new avenues for CRC therapy.
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Affiliation(s)
- Yuan Zhou
- Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiaoqing Cheng
- Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Fenglan Zhang
- Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Qingqing Chen
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Xinyu Chen
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yaojia Shen
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Chong Lai
- Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Vishnu G Kota
- Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Wenjie Sun
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Qiong Huang
- The Core Facilities, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ying Yuan
- Department of Medical Oncology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, Chinese National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Jin Wang
- Department of Pathology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Maode Lai
- Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
| | - Dandan Zhang
- Department of Pathology, and Department of Medical Oncology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.,Department of Pathology, Key Laboratory of Disease Proteomics of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China
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49
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Niemeyer E, Mofid H, Zornig C, Burandt EC, Stein A, Block A, Volk AE. Case report: acute abdominal pain in a 37-year-old patient and the consequences for his family. BMC Gastroenterol 2020; 20:129. [PMID: 32362280 PMCID: PMC7197118 DOI: 10.1186/s12876-020-01283-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 04/22/2020] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND Hereditary diffuse gastric cancer is a rare condition that accounts for approximately 1-3% of all gastric cancer cases. Due to its rapid and invasive growth pattern, it is associated with a very poor prognosis. As a result, comprehensive genetic testing is imperative in patients who meet the current testing criteria in order to identify relatives at risk. This case report illustrates the substantial benefit of genetic testing in the family of a patient diagnosed with hereditary diffuse gastric cancer. CASE PRESENTATION A 37-year-old patient was admitted to the emergency department with acute abdominal pain. Following explorative laparoscopy, locally advanced diffuse gastric cancer was diagnosed. The indication for genetic testing of CDH1 was given due to the patient's young age. A germline mutation in CDH1 was identified in the index patient. As a result, several family members underwent genetic testing. The patient's father, brother and one aunt were identified as carriers of the familial CDH1 mutation and subsequently received gastrectomy. In both the father and the aunt, histology of the surgical specimen revealed a diffuse growing adenocarcinoma after an unremarkable preoperative gastroscopy. CONCLUSION Awareness and recognition of a potential hereditary diffuse gastric cancer can provide a substantial health benefit not only for the patient but especially for affected family members.
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Affiliation(s)
- Elisabeth Niemeyer
- Department of Medical Oncology and Hematology, University Cancer Center Hamburg, University Hamburg-Eppendorf, Hamburg, Germany.
| | - Hamid Mofid
- Department of Surgery, Regio Klinikum Pinneberg, Pinneberg, Germany
| | | | | | - Alexander Stein
- Department of Medical Oncology and Hematology, University Cancer Center Hamburg, University Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas Block
- Department of Medical Oncology and Hematology, University Cancer Center Hamburg, University Hamburg-Eppendorf, Hamburg, Germany
| | - Alexander E Volk
- Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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CDH1 Mutation Distribution and Type Suggests Genetic Differences between the Etiology of Orofacial Clefting and Gastric Cancer. Genes (Basel) 2020; 11:genes11040391. [PMID: 32260281 PMCID: PMC7231129 DOI: 10.3390/genes11040391] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 03/26/2020] [Accepted: 03/31/2020] [Indexed: 01/16/2023] Open
Abstract
Pathogenic variants in CDH1, encoding epithelial cadherin (E-cadherin), have been implicated in hereditary diffuse gastric cancer (HDGC), lobular breast cancer, and both syndromic and non-syndromic cleft lip/palate (CL/P). Despite the large number of CDH1 mutations described, the nature of the phenotypic consequence of such mutations is currently not able to be predicted, creating significant challenges for genetic counselling. This study collates the phenotype and molecular data for available CDH1 variants that have been classified, using the American College of Medical Genetics and Genomics criteria, as at least ‘likely pathogenic’, and correlates their molecular and structural characteristics to phenotype. We demonstrate that CDH1 variant type and location differ between HDGC and CL/P, and that there is clustering of CL/P variants within linker regions between the extracellular domains of the cadherin protein. While these differences do not provide for exact prediction of the phenotype for a given mutation, they may contribute to more accurate assessments of risk for HDGC or CL/P for individuals with specific CDH1 variants.
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