|
1
|
Al Bakir I, Curtius K, Cresswell GD, Grant HE, Nasreddin N, Smith K, Nowinski S, Guo Q, Belnoue-Davis HL, Fisher J, Clarke T, Kimberley C, Mossner M, Dunne PD, Loughrey MB, Speight A, East JE, Wright NA, Rodriguez-Justo M, Jansen M, Moorghen M, Baker AM, Leedham SJ, Hart AL, Graham TA. Low-coverage whole genome sequencing of low-grade dysplasia strongly predicts advanced neoplasia risk in ulcerative colitis. Gut 2025:gutjnl-2024-333353. [PMID: 39880602 DOI: 10.1136/gutjnl-2024-333353] [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: 07/12/2024] [Accepted: 12/19/2024] [Indexed: 01/31/2025]
Abstract
BACKGROUND The risk of developing advanced neoplasia (AN; colorectal cancer and/or high-grade dysplasia) in ulcerative colitis (UC) patients with a low-grade dysplasia (LGD) lesion is variable and difficult to predict. This is a major challenge for effective clinical management. OBJECTIVE We aimed to provide accurate AN risk stratification in UC patients with LGD. We hypothesised that the pattern and burden of somatic genomic copy number alterations (CNAs) in LGD lesions could predict future AN risk. DESIGN We performed a retrospective multicentre validated case-control study using n=270 LGD samples from n=122 patients with UC. Patients were designated progressors (n=40) if they had a diagnosis of AN in the ~5 years following LGD diagnosis or non-progressors (n=82) if they remained AN-free during follow-up. DNA was extracted from the baseline LGD lesion, low-coverage whole genome sequencing performed and data processed to detect CNAs. Survival analysis was used to evaluate CNAs as predictors of future AN risk. RESULTS CNA burden was significantly higher in progressors than non-progressors (p=2×10-6 in discovery cohort) and was a very significant predictor of AN risk in univariate analysis (OR=36; p=9×10-7), outperforming existing clinical risk factors such as lesion size, shape and focality. Optimal risk prediction was achieved with a multivariate model combining CNA burden with the known clinical risk factor of incomplete LGD resection. Within-LGD lesion genetic heterogeneity did not confound risk prediction. CONCLUSION Measurement of CNAs in LGD is an accurate predictor of AN risk in inflammatory bowel disease and is likely to support clinical management.
Collapse
Affiliation(s)
- Ibrahim Al Bakir
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Inflammatory Bowel Disease Unit, St Mark's Hospital, Harrow, UK
- Chelsea & Westminster Hospital, London, UK
| | - Kit Curtius
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, California, USA
- VA San Diego Healthcare System, San Diego, California, USA
- Moores Cancer Center, Univeristy of California San Diego, La Jolla, California, USA
| | - George D Cresswell
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
- St. Anna Children's Cancer Research Institute, Vienna, Austria
| | - Heather E Grant
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Nadia Nasreddin
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Kane Smith
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Salpie Nowinski
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Qingli Guo
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | | | - Jennifer Fisher
- Inflammatory Bowel Disease Unit, St Mark's Hospital, Harrow, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Theo Clarke
- Barts Cancer Institute, Queen Mary University of London, London, UK
| | | | - Maximilian Mossner
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Philip D Dunne
- Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK
| | - Maurice B Loughrey
- Cellular Pathology, Belfast Health and Social Care Trust, Belfast, UK
- Centre for Public Health and Patrick G. Johnston for Cancer Research, Queen's University Belfast, Belfast, UK
| | - Ally Speight
- Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, UK
| | - James E East
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Univerity of Oxford, Oxford, UK
| | | | - Manuel Rodriguez-Justo
- Department of Pathology, University College London Hospital, London, UK
- UCL Cancer Institute, University College London, London, UK
| | - Marnix Jansen
- Department of Pathology, University College London Hospital, London, UK
- UCL Cancer Institute, University College London, London, UK
| | - Morgan Moorghen
- Department of Histopathology, St Mark's Hospital, Harrow, UK
| | - Ann-Marie Baker
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| | - Simon J Leedham
- Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Univerity of Oxford, Oxford, UK
| | - Ailsa L Hart
- Inflammatory Bowel Disease Unit, St Mark's Hospital, Harrow, UK
- Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK
| | - Trevor A Graham
- Barts Cancer Institute, Queen Mary University of London, London, UK
- Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK
| |
Collapse
|
|
2
|
Hartl K, Bayram Ş, Wetzel A, Harnack C, Lin M, Fischer AS, Liu L, Beccaceci G, Mastrobuoni G, Geisberger S, Forbes M, Monteiro BJE, Macino M, Flores RE, Engelmann C, Mollenkopf HJ, Schupp M, Tacke F, Sanders AD, Kempa S, Berger H, Sigal M. p53 terminates the regenerative fetal-like state after colitis-associated injury. SCIENCE ADVANCES 2024; 10:eadp8783. [PMID: 39453996 PMCID: PMC11506124 DOI: 10.1126/sciadv.adp8783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 09/20/2024] [Indexed: 10/27/2024]
Abstract
Cells that lack p53 signaling frequently occur in ulcerative colitis (UC) and are considered early drivers in UC-associated colorectal cancer (CRC). Epithelial injury during colitis is associated with transient stem cell reprogramming from the adult, homeostatic to a "fetal-like" regenerative state. Here, we use murine and organoid-based models to study the role of Trp53 during epithelial reprogramming. We find that p53 signaling is silent and dispensable during homeostasis but strongly up-regulated in the epithelium upon DSS-induced colitis. While in WT cells this causes termination of the regenerative state, crypts that lack Trp53 remain locked in the highly proliferative, regenerative state long-term. The regenerative state in WT cells requires high Wnt signaling to maintain elevated levels of glycolysis. Instead, Trp53 deficiency enables Wnt-independent glycolysis due to overexpression of rate-limiting enzyme PKM2. Our study reveals the context-dependent relevance of p53 signaling specifically in the injury-induced regenerative state, explaining the high abundance of clones lacking p53 signaling in UC and UC-associated CRC.
Collapse
Affiliation(s)
- Kimberly Hartl
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Şafak Bayram
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Alexandra Wetzel
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Christine Harnack
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Manqiang Lin
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Anne-Sophie Fischer
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Lichao Liu
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Giulia Beccaceci
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Guido Mastrobuoni
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Sabrina Geisberger
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Martin Forbes
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Benedict J. E. Monteiro
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Berlin Institute of Health (BIH) at Charité–Universitätsmedizin Berlin, Berlin, Germany
- Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Martina Macino
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Berlin Institute of Health (BIH) at Charité–Universitätsmedizin Berlin, Berlin, Germany
- Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Roberto E. Flores
- Institute of Pharmacology, Max Rubner Center (MRC) for Cardiovascular Metabolic Renal Research, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Cornelius Engelmann
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | | | - Michael Schupp
- Institute of Pharmacology, Max Rubner Center (MRC) for Cardiovascular Metabolic Renal Research, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
| | - Frank Tacke
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Ashley D. Sanders
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
- Berlin Institute of Health (BIH) at Charité–Universitätsmedizin Berlin, Berlin, Germany
- Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Stefan Kempa
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Hilmar Berger
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Michael Sigal
- Medical Department, Division of Gastroenterology and Hepatology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| |
Collapse
|
|
3
|
Cunha AF, Delou JM, Barbosa PS, Conceição JSM, Souza KCS, Chagas V, Soletti RC, de Souza HSP, Borges HL. Trp53 Deletion Promotes Exacerbated Colitis, Facilitates Lgr5+ Cancer Stem Cell Expansion, and Fuels Tumorigenesis in AOM/DSS-Induced Colorectal Cancer. Int J Mol Sci 2024; 25:10953. [PMID: 39456736 PMCID: PMC11507199 DOI: 10.3390/ijms252010953] [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: 09/20/2024] [Accepted: 10/07/2024] [Indexed: 10/28/2024] Open
Abstract
Colorectal cancer CRC remains one of the leading causes of cancer-related deaths worldwide, with chronic intestinal inflammation identified as a major risk factor. Notably, the tumor suppressor TP53 undergoes mutation at higher rates and earlier stages during human inflammation-driven colon tumorigenesis than in sporadic cases. We investigated whether deleting Trp53 affects inflammation-induced tumor growth and the expression of Lgr5+ cancer stem cells in mice. We examined azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon tumorigenesis in wild-type Trp53 (+/+), heterozygous (+/-), and knockout (-/-) mice. Trp53-/- mice showed increased sensitivity to DSS colitis and earlier accelerated tumorigenesis with 100% incidence. All groups could develop invasive tumors, but knockouts displayed the most aggressive features. Unlike wild-type CRC, knockouts selectively showed increased populations of Lgr5+ colon cancer stem-like cells. Trp53 loss also boosted laminin, possibly facilitating the disruption of the tumor border. This study highlights how Trp53 deletion promotes the perfect storm of inflammation and stemness, driving colon cancer progression. Trp53 deletion dramatically shortened AOM/DSS latency and improved tumor induction efficiency, offering an excellent inflammation-driven CRC model.
Collapse
Affiliation(s)
- Anderson F. Cunha
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-90, RJ, Brazil; (A.F.C.); (J.M.D.); (P.S.B.); (J.S.M.C.)
- Instituto D’Or de Ensino e Pesquisa, Rio de Janeiro 22281-100, RJ, Brazil
| | - João M. Delou
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-90, RJ, Brazil; (A.F.C.); (J.M.D.); (P.S.B.); (J.S.M.C.)
- Instituto D’Or de Ensino e Pesquisa, Rio de Janeiro 22281-100, RJ, Brazil
| | - Pedro S. Barbosa
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-90, RJ, Brazil; (A.F.C.); (J.M.D.); (P.S.B.); (J.S.M.C.)
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-913, RJ, Brazil; (K.C.S.S.); (H.S.P.d.S.)
| | - Julia S. M. Conceição
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-90, RJ, Brazil; (A.F.C.); (J.M.D.); (P.S.B.); (J.S.M.C.)
| | - Karen C. S. Souza
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-913, RJ, Brazil; (K.C.S.S.); (H.S.P.d.S.)
| | - Vera Chagas
- Departamento de Patologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-913, RJ, Brazil;
| | - Rossana C. Soletti
- Departamento Interdisciplinar, Universidade Federal do Rio Grande do Sul, Tramandaí 95590-000, RS, Brazil;
| | - Heitor S. P. de Souza
- Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-913, RJ, Brazil; (K.C.S.S.); (H.S.P.d.S.)
| | - Helena L. Borges
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-90, RJ, Brazil; (A.F.C.); (J.M.D.); (P.S.B.); (J.S.M.C.)
| |
Collapse
|
|
4
|
Zhang H, Xin H, Zhao M, Bi C, Xiao Y, Li Y, Qin C. Global research trends on the relationship between IBD and CRC: a bibliometric analysis from 2000 to 2023. JOURNAL OF HEALTH, POPULATION, AND NUTRITION 2024; 43:83. [PMID: 38867343 PMCID: PMC11170923 DOI: 10.1186/s41043-024-00577-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Accepted: 06/04/2024] [Indexed: 06/14/2024]
Abstract
OBJECTIVE This study aimed to conduct a bibliometric analysis of research articles on the relationship between inflammatory bowel disease (IBD) and colorectal cancer (CRC) using CiteSpace to summarize the current research status, hotspots, and trends in this field and present the results visually. METHOD Research articles on the relationship between IBD and CRC published from 2000 to 2023 and in English were selected from the Web of Science Core Collection (Woscc) database. The articles were downloaded as "full record and references". CiteSpace was used to conduct cooperative, cluster, co-citation, and burst analyses. RESULTS The literature search revealed 4244 articles; of which, 5 duplicates were removed, resulting in the inclusion of 4239 articles in this study. The United States of America had the highest number of publications, with Mayo Clinic and Harvard University being the most active institutions, and Bas Oldenburg being the most active author. Collaboration among core authors was inadequate. JA Eaden was the most cited author, and CRC was the most common keyword. Burst analysis indicated that Sun Yat-sen University might be one of the institutions with a large contribution to this research field in the future. Cluster analysis showed that earlier research focused more on microsatellite instability, whereas "gut microbiota" and "oxidative stress" are considered current research hotspots and trends. CONCLUSION At present, the primary focus areas of research are "gut microbiota" and "oxidative stress". With the improvement of healthcare policies and standards, regular endoscopic monitoring of patients with IBD has become an indispensable diagnostic and therapeutic practice. More drugs will be developed to reduce the risk of progression from IBD to CRC. The findings of this study provide valuable insights into the relationship between IBD and CRC for researchers in the same field.
Collapse
Affiliation(s)
- Hao Zhang
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, 475000, China
| | - Huiru Xin
- Department of Cardiothoracic Surgery, Huaihe Hospital of Henan University, Kaifeng, 475000, China
| | - Mengqi Zhao
- Department of Gastroenterology, Huaihe Hospital of Henan University, Kaifeng, 475000, China
| | - Chenyang Bi
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, 475000, China
| | - Yafei Xiao
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, 475000, China
| | - Yifan Li
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, 475000, China
| | - Changjiang Qin
- Department of General Surgery, Huaihe Hospital of Henan University, Kaifeng, 475000, China.
| |
Collapse
|
|
5
|
Nasreddin N, Jansen M, Loughrey MB, Wang LM, Koelzer VH, Rodriguez-Justo M, Novelli M, Fisher J, Brown MW, Al Bakir I, Hart AL, Dunne P, Graham TA, Leedham SJ. Poor Diagnostic Reproducibility in the Identification of Nonconventional Dysplasia in Colitis Impacts the Application of Histologic Stratification Tools. Mod Pathol 2024; 37:100419. [PMID: 38158125 DOI: 10.1016/j.modpat.2023.100419] [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: 07/06/2023] [Revised: 12/10/2023] [Accepted: 12/19/2023] [Indexed: 01/03/2024]
Abstract
Due to their increased cancer risk, patients with longstanding inflammatory bowel disease are offered endoscopic surveillance with concomitant histopathologic assessments, aimed at identifying dysplasia as a precursor lesion of colitis-associated colorectal cancer. However, this strategy is beset with difficulties and limitations. Recently, a novel classification criterion for colitis-associated low-grade dysplasia has been proposed, and an association between nonconventional dysplasia and progression was reported, suggesting the possibility of histology-based stratification of patients with colitis-associated lesions. Here, a cohort of colitis-associated lesions was assessed by a panel of 6 experienced pathologists to test the applicability of the published classification criteria and try and validate the association between nonconventional dysplasia and progression. While confirming the presence of different morphologic patterns of colitis-associated dysplasia, the study demonstrated difficulties concerning diagnostic reproducibility between pathologists and was unable to validate the association of nonconventional dysplasia with cancer progression. Our study highlights the overall difficulty of using histologic assessment of precursor lesions for cancer risk prediction in inflammatory bowel disease patients and suggests the need for a different diagnostic strategy that can objectively identify high-risk phenotypes.
Collapse
Affiliation(s)
- Nadia Nasreddin
- Wellcome Centre Human Genetics, Roosevelt Drive, University of Oxford, Oxford, United Kingdom
| | - Marnix Jansen
- Department of Pathology, UCL Cancer Institute, University College London, London, United Kingdom
| | - Maurice B Loughrey
- Department of Cellular Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland; Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland
| | - Lai Mun Wang
- Department of Laboratory Medicine, Changi General Hospital, Singapore, Singapore
| | - Viktor H Koelzer
- Department of Pathology and Molecular Pathology, University and University Hospital Zürich, Zürich, Switzerland
| | - Manuel Rodriguez-Justo
- Department of Pathology, UCL Cancer Institute, University College London, London, United Kingdom
| | - Marco Novelli
- Department of Pathology, UCL Cancer Institute, University College London, London, United Kingdom
| | - Jennifer Fisher
- Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom
| | - Matthew W Brown
- Wellcome Centre Human Genetics, Roosevelt Drive, University of Oxford, Oxford, United Kingdom
| | | | - Ailsa L Hart
- IBD Unit, St Mark's Hospital, Harrow, London, United Kingdom
| | - Philip Dunne
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, United Kingdom
| | - Trevor A Graham
- Centre for Evolution and Cancer, Institute of Cancer Research, London, United Kingdom
| | - Simon J Leedham
- Wellcome Centre Human Genetics, Roosevelt Drive, University of Oxford, Oxford, United Kingdom.
| |
Collapse
|
|
6
|
Takeuchi C, Yamashita S, Liu YY, Takeshima H, Sasaki A, Fukuda M, Hashimoto T, Naka T, Ishizu K, Sekine S, Yoshikawa T, Hamada A, Yamamichi N, Fujishiro M, Ushijima T. Precancerous nature of intestinal metaplasia with increased chance of conversion and accelerated DNA methylation. Gut 2024; 73:255-267. [PMID: 37751933 DOI: 10.1136/gutjnl-2023-329492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 08/31/2023] [Indexed: 09/28/2023]
Abstract
OBJECTIVE The presence of intestinal metaplasia (IM) is a risk factor for gastric cancer. However, it is still controversial whether IM itself is precancerous or paracancerous. Here, we aimed to explore the precancerous nature of IM by analysing epigenetic alterations. DESIGN Genome-wide DNA methylation analysis was conducted by EPIC BeadArray using IM crypts isolated by Alcian blue staining. Chromatin immunoprecipitation sequencing for H3K27ac and single-cell assay for transposase-accessible chromatin by sequencing were conducted using IM mucosa. NOS2 was induced using Tet-on gene expression system in normal cells. RESULTS IM crypts had a methylation profile unique from non-IM crypts, showing extensive DNA hypermethylation in promoter CpG islands, including those of tumour-suppressor genes. Also, the IM-specific methylation profile, namely epigenetic footprint, was present in a fraction of gastric cancers with a higher frequency than expected, and suggested to be associated with good overall survival. IM organoids had remarkably high NOS2 expression, and NOS2 induction in normal cells led to accelerated induction of aberrant DNA methylation, namely epigenetic instability, by increasing DNA methyltransferase activity. IM mucosa showed dynamic enhancer reprogramming, including the regions involved in higher NOS2 expression. NOS2 had open chromatin in IM cells but not in gastric cells, and IM cells had frequent closed chromatin of tumour-suppressor genes, indicating their methylation-silencing. NOS2 expression in IM-derived organoids was upregulated by interleukin-17A, a cytokine secreted by extracellular bacterial infection. CONCLUSIONS IM cells were considered to have a precancerous nature potentially with an increased chance of converting into cancer cells, and an accelerated DNA methylation induction due to abnormal NOS2 expression.
Collapse
Affiliation(s)
- Chihiro Takeuchi
- Division of Epigenomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Shinagawa-ku, Tokyo, Japan
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Satoshi Yamashita
- Division of Epigenomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
- Department of Biotechnology, Maebashi Institute of Technology, Maebashi, Gunma, Japan
| | - Yu-Yu Liu
- Division of Epigenomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Shinagawa-ku, Tokyo, Japan
| | - Hideyuki Takeshima
- Division of Epigenomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Shinagawa-ku, Tokyo, Japan
| | - Akiko Sasaki
- Division of Epigenomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
- Gastroenterology Medicine Center, Shonan Kamakura General Hospital, Kamakura, Kanagawa, Japan
| | - Masahide Fukuda
- Division of Epigenomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
- Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Oita, Japan
| | - Taiki Hashimoto
- Department of Diagnostic Pathology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Tomoaki Naka
- Department of Diagnostic Pathology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Kenichi Ishizu
- Department of Gastric Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Shigeki Sekine
- Department of Diagnostic Pathology, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Takaki Yoshikawa
- Department of Gastric Surgery, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
| | - Akinobu Hamada
- Division of Molecular Pharmacology, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
| | - Nobutake Yamamichi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
- Center for Epidemiology and Preventive Medicine, The University of Tokyo Hospital, Bunkyo-ku, Tokyo, Japan
| | - Mitsuhiro Fujishiro
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan
- Department of Epigenomics, Institute for Advanced Life Sciences, Hoshi University, Shinagawa-ku, Tokyo, Japan
| |
Collapse
|
|
7
|
Musulen E, Gené M, Cuatrecasas M, Amat I, Veiga JA, Fernández-Aceñero MJ, Chimisana VF, Tarragona J, Jurado I, Fernández-Victoria R, Martínez-Ciarpaglini C, Alenda González C, Zac C, Fernández-Figueras MT, Esteller M. Gastric metaplasia as a precursor of nonconventional dysplasia in inflammatory bowel disease. Hum Pathol 2024; 143:50-61. [PMID: 38000679 DOI: 10.1016/j.humpath.2023.11.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 10/18/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023]
Abstract
Gastric metaplasia in colonic mucosa with inflammatory bowel disease (IBD) develops as an adaptation mechanism. The association between gastric metaplasia and nonconventional and/or conventional dysplasia as precursors of colitis-associated colorectal cancer is unknown. To address this question, we retrospectively reviewed a series of 33 IBD colectomies to identify gastric metaplasia in 76 precursor lesions. We obtained 61 nonconventional and 15 conventional dysplasias. Among nonconventional dysplasia, 31 (50.8 %) were low-grade (LGD), 4 (6.5 %) were high-grade (HGD), 9 (14.8 %) had both LGD and HGD, and 17 (27.9 %) had no dysplasia (ND), while 14 (93 %) conventional dysplasias had LGD, and 1 (7 %) had LGD and HGD. Gastric metaplasia was assessed by concomitant immunoexpression of MUC5AC and loss of CDX2 staining. Expression of a p53-mut pattern was considered as a surrogate for gene mutation, and complete loss of MLH1 staining as presence of MLH1 hypermethylation. In nonconventional dysplasia, MUC5AC immunoexpression decreased as the degree of dysplasia increased, being 78 % in LGD and 39 % in HGD (p = 0.006). CDX2 was lost in epithelial glands with high expression of MUC5AC (p < 0.001). The p53-mut pattern was observed in 77 % HGD, 45 % LGD, and in 6 % with ND (p < 0.001). Neither nonconventional nor conventional dysplasia showed complete loss of MLH1 staining. Gastric metaplasia was also present in mucosa adjacent to nonconventional dysplasia with chronic changes or active inflammation. Our results show that gastric metaplasia appears in IBD-inflamed colon mucosa, it is the substrate of most nonconventional dysplasia and occurs prior to p53 alterations.
Collapse
Affiliation(s)
- Eva Musulen
- Pathology Department, Hospital Universitari General de Catalunya-Grupo QuironSalud, 08915 Sant Cugat Del Vallès, Barcelona, Spain; Institut de Recerca Contra La Leucèmia Josep Carreras (IJC), 08916 Badalona, Barcelona, Spain.
| | - Míriam Gené
- Pathology Department, Hospital Universitari Joan XXIII, 43005 Tarragona, Spain; Surgery Department, Programme of Surgery and Morphological Sciences, Universitat Autònoma de Barcelona (UAB), 08193 Cerdanyola Del Vallès, Spain
| | - Míriam Cuatrecasas
- Pathology Department, Hospital Clínic, 08036 Barcelona, Spain; Department of Basic Clinical Practice, University of Barcelona (UB), 08036 Barcelona, Spain
| | - Irene Amat
- Pathology Department, Complejo Hospitalario de Navarra, 31008 Navarra, Spain
| | - Jesús Alberto Veiga
- Pathology Department, Complejo Hospitalario Universitario de Ferrol, 15405 Ferrol, Spain
| | | | | | - Jordi Tarragona
- Pathology Department, Hospital Universitari Arnau de Vilanova, 25198 Lleida, Spain
| | - Ismael Jurado
- Pathology Department, Consorci Sanitari de Terrassa, 08227 Terrassa, Spain
| | | | - Carolina Martínez-Ciarpaglini
- Pathology Department, Hospital Clínico Universitario de Valencia, INCLIVA- Instituto de Investigación Sanitaria, Universidad de Valencia, 46010 Valencia, Spain
| | - Cristina Alenda González
- Pathology Department, Hospital General Universitario Dr. Balmis, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), 031010 Alicante, Spain
| | - Carlos Zac
- Pathology Department, Hospital Universitari I Politècnic La Fe, 46026 Valencia, Spain
| | - María Teresa Fernández-Figueras
- Pathology Department, Hospital Universitari General de Catalunya-Grupo QuironSalud, 08915 Sant Cugat Del Vallès, Barcelona, Spain; School of Medicine, Campus Sant Cugat Del Vallès, Universitat Internacional de Catalunya (UIC), 08917 Sant Cugat Del Vallès, Spain
| | - Manel Esteller
- Institut de Recerca Contra La Leucèmia Josep Carreras (IJC), 08916 Badalona, Barcelona, Spain; Institució Catalana de Recerca I Estudis Avançats (ICREA), 08010 Barcelona, Spain; Faculty of Medicine and Health Sciences, Department of Physiological Sciences, Universitat de Barcelona (UB), 08007 Barcelona, Spain; Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
| |
Collapse
|
|
8
|
Liu CY, Girish N, Gomez ML, Kalski M, Bernard JK, Simons BD, Polk DB. Wound-healing plasticity enables clonal expansion of founder progenitor cells in colitis. Dev Cell 2023; 58:2309-2325.e7. [PMID: 37652012 PMCID: PMC10872951 DOI: 10.1016/j.devcel.2023.08.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 05/30/2023] [Accepted: 08/05/2023] [Indexed: 09/02/2023]
Abstract
Chronic colonic injury and inflammation pose high risks for field cancerization, wherein injury-associated mutations promote stem cell fitness and gradual clonal expansion. However, the long-term stability of some colitis-associated mutational fields could suggest alternate origins. Here, studies of acute murine colitis reveal a punctuated mechanism of massive, neutral clonal expansion during normal wound healing. Through three-dimensional (3D) imaging, quantitative fate mapping, and single-cell transcriptomics, we show that epithelial wound repair begins with the loss of structural constraints on regeneration, forming fused labyrinthine channels containing epithelial cells reprogrammed to a non-proliferative plastic state. A small but highly proliferative set of epithelial founder progenitor cells (FPCs) subsequently emerges and undergoes extensive cell division, enabling fluid-like lineage mixing and spreading across the colonic surface. Crypt budding restores the glandular organization, imprinting the pattern of clonal expansion. The emergence and functions of FPCs within a critical window of plasticity represent regenerative targets with implications for preneoplasia.
Collapse
Affiliation(s)
- Cambrian Y Liu
- Department of Medicine, The University of Chicago, Chicago, IL 60637, USA; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
| | - Nandini Girish
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA; Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA
| | - Marie L Gomez
- Program in Biomedical and Biological Sciences, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA
| | - Martin Kalski
- Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
| | - Jessica K Bernard
- Program in Craniofacial Biology, Herman Ostrow School of Dentistry of the University of Southern California, Los Angeles, CA 90033, USA
| | - Benjamin D Simons
- Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK; Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge CB3 0WA, UK; Wellcome Trust, Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge CB2 0AW, UK
| | - D Brent Polk
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA; Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA 92093, USA; Department of Biochemistry and Molecular Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Rady Children's Hospital, San Diego, CA 92123, USA.
| |
Collapse
|
|
9
|
Zhou RW, Harpaz N, Itzkowitz SH, Parsons RE. Molecular mechanisms in colitis-associated colorectal cancer. Oncogenesis 2023; 12:48. [PMID: 37884500 PMCID: PMC10603140 DOI: 10.1038/s41389-023-00492-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/30/2023] [Accepted: 09/11/2023] [Indexed: 10/28/2023] Open
Abstract
Sustained chronic inflammation of the large intestine leads to tissue damage and repair, which is associated with an increased incidence of colitis-associated colorectal cancer (CAC). The genetic makeup of CAC is somewhat similar to sporadic colorectal carcinoma (sCRC), but there are differences in the sequence and timing of alterations in the carcinogenesis process. Several models have been developed to explain the development of CAC, particularly the "field cancerization" model, which proposes that chronic inflammation accelerates mutagenesis and selects for the clonal expansion of phenotypically normal, pro-tumorigenic cells. In contrast, the "Big Bang" model posits that tumorigenic clones with multiple driver gene mutations emerge spontaneously. The details of CAC tumorigenesis-and how they differ from sCRC-are not yet fully understood. In this Review, we discuss recent genetic, epigenetic, and environmental findings related to CAC pathogenesis in the past five years, with a focus on unbiased, high-resolution genetic profiling of non-dysplastic field cancerization in the context of inflammatory bowel disease (IBD).
Collapse
Affiliation(s)
- Royce W Zhou
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Molecular Medicine Program, Internal Medicine Residency Program, Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Noam Harpaz
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Steven H Itzkowitz
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Ramon E Parsons
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| |
Collapse
|
|
10
|
Gené M, Cuatrecasas M, Amat I, Veiga JA, Fernández Aceñero MJ, Fusté Chimisana V, Tarragona J, Jurado I, Fernández-Victoria R, Martínez Ciarpaglini C, Alenda González C, Zac C, Ortega de la Obra P, Fernández-Figueras MT, Esteller M, Musulen E. Alterations in p53, Microsatellite Stability and Lack of MUC5AC Expression as Molecular Features of Colorectal Carcinoma Associated with Inflammatory Bowel Disease. Int J Mol Sci 2023; 24:ijms24108655. [PMID: 37240002 DOI: 10.3390/ijms24108655] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/07/2023] [Accepted: 05/08/2023] [Indexed: 05/28/2023] Open
Abstract
Colitis-associated colorectal carcinoma (CAC) occurs in inflammatory bowel disease (IBD) because of the "chronic inflammation-dysplasia-cancer" carcinogenesis pathway characterized by p53 alterations in the early stages. Recently, gastric metaplasia (GM) has been described as the initial event of the serrated colorectal cancer (CRC) process, resulting from chronic stress on the colon mucosa. The aim of the study is to characterize CAC analyzing p53 alterations and microsatellite instability (MSI) to explore their relationship with GM using a series of CRC and the adjacent intestinal mucosa. Immunohistochemistry was performed to assess p53 alterations, MSI and MUC5AC expression as a surrogate for GM. The p53 mut-pattern was found in more than half of the CAC, most frequently stable (MSS) and MUC5AC negative. Only six tumors were unstable (MSI-H), being with p53 wt-pattern (p = 0.010) and MUC5AC positive (p = 0.005). MUC5AC staining was more frequently observed in intestinal mucosa, inflamed or with chronic changes, than in CAC, especially in those with p53 wt-pattern and MSS. Based on our results, we conclude that, as in the serrated pathway of CRC, in IBD GM occurs in inflamed mucosa, persists in those with chronic changes and disappears with the acquisition of p53 mutations.
Collapse
Affiliation(s)
- Míriam Gené
- Pathology Department, Hospital Universitari Joan XXIII, 43005 Tarragona, Spain
- Surgery Department, Programme of Surgery and Morphological Sciences, Universitat Autònoma de Barcelona (UAB), 08193 Barcelona, Spain
| | - Míriam Cuatrecasas
- Pathology Department, Hospital Clínic de Barcelona, Universitat de Barcelona (UB), 08007 Barcelona, Spain
- School of Medicine, Campus Clínic, Universitat de Barcelona (UB), 08036 Barcelona, Spain
| | - Irene Amat
- Pathology Department, Complejo Hospitalario de Navarra, 31008 Navarra, Spain
| | - Jesús Alberto Veiga
- Pathology Department, Complejo Hospitalario Universitario de Ferrol, 15405 Ferrol, Spain
| | | | | | - Jordi Tarragona
- Pathology Department, Hospital Universitari Arnau de Vilanova, 25198 Lleida, Spain
| | - Ismael Jurado
- Pathology Department, Consorci Sanitari de Terrassa, 08227 Terrassa, Spain
| | | | - Carolina Martínez Ciarpaglini
- Pathology Department, Hospital Clínico Universitario de Valencia, Valencia INCLIVA-Instituto de Investigación Sanitaria, Universidad de Valencia, 46010 Valencia, Spain
| | - Cristina Alenda González
- Pathology Department, Hospital General Universitario Dr. Balmis, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), 03010 Alicante, Spain
| | - Carlos Zac
- Pathology Department, Hospital Universitari i Politècnic La Fe, 46026 Valencia, Spain
| | | | - María Teresa Fernández-Figueras
- Pathology Department, Hospital Universitari General de Catalunya-Grupo QuironSalud, Sant Cugat del Vallès, 08195 Barcelona, Spain
- School of Medicine, Campus Sant Cugat del Vallès, Universitat Internacional de Catalunya (UIC), Sant Cugat del Vallès, 08017 Barcelona, Spain
| | - Manel Esteller
- Institut de Recerca contra la Leucèmia Josep Carreras (IJC), Badalona, 08916 Barcelona, Spain
- Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain
- Faculty of Medicine and Health Sciences, Department of Physiological Sciences, Universitat de Barcelona (UB), 08007 Barcelona, Spain
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Eva Musulen
- Pathology Department, Hospital Universitari General de Catalunya-Grupo QuironSalud, Sant Cugat del Vallès, 08195 Barcelona, Spain
- Institut de Recerca contra la Leucèmia Josep Carreras (IJC), Badalona, 08916 Barcelona, Spain
| |
Collapse
|
|
11
|
Rubio CA, Lang-Schwarz C, Vieth M. Crypt-rings in tandem detected in infectious colitis, in IBD and in IBD-associated noninvasive neoplasia. Pathol Res Pract 2023; 245:154466. [PMID: 37075640 DOI: 10.1016/j.prp.2023.154466] [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: 02/01/2023] [Revised: 04/13/2023] [Accepted: 04/14/2023] [Indexed: 04/21/2023]
Abstract
AIMS Recently, eight novel histologic structures in colon mucosa with inflammation were described. Here, we assessed the frequency of one of them: crypt rings in tandem (CRT), in patients with infectious colitis (IC), IBD (ulcerative colitis; UC or Crohn colitis; CrC) and UC in remission (UCR). In addition, the frequency of dysplastic CRT (DCRT) in IBD-associated noninvasive neoplasia (IBDNIN) were also calculated. METHODS Colon biopsies in 578 cases were reviewed: 42 cases with IC, 280 with IBD (180 UC and 100 CrC), 100 UCR and the remaining 156, IBDNIN. RESULTS The proportions of CRT in IC was 16.7%, in IBD 14.3% %, in UCR 3%, and of DCRT in IBDNIN, 20%. No differences were recorded between the proportions of CRT in IC, UC and CrC. Conversely, the difference in CRT frequency between UC and UCR, and between CRT and DCRT were significant (P = 0.006, and p = 0.05, respectively). CONCLUSIONS CRT evolved in IC and in IBD. The finding of CRT in IC strongly suggest that those characteristic crypts were shaped at the early stages of mucosal inflammation. CRT persisted in IBD with protracted inflammation but plummeted in UCR, that is when the mucosal inflammation waned. The proportion of DCRT was significantly higher than that of CRT. It is submitted that DCRT might had developed in IBDNIN using CRT as scaffolds. This is the first study in which a characteristic pathologic aberration of cryptogenesis was tracked in colon biopsies from patients with IBD and with IBD-associated neoplastic transformation.
Collapse
Affiliation(s)
- Carlos A Rubio
- Department of Pathology, Karolinska Institute and University Hospital, Stockholm, Sweden.
| | - Corinna Lang-Schwarz
- Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg, Klinikum Bayreuth, Bayreuth, Germany
| | - Michael Vieth
- Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg, Klinikum Bayreuth, Bayreuth, Germany
| |
Collapse
|
|
12
|
Collin G, Foy JP, Aznar N, Rama N, Wierinckx A, Saintigny P, Puisieux A, Ansieau S. Intestinal Epithelial Cells Adapt to Chronic Inflammation through Partial Genetic Reprogramming. Cancers (Basel) 2023; 15:cancers15030973. [PMID: 36765930 PMCID: PMC9913703 DOI: 10.3390/cancers15030973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 01/30/2023] [Accepted: 02/01/2023] [Indexed: 02/05/2023] Open
Abstract
Reactive oxygen species (ROS) are considered to be the main drivers of inflammatory bowel disease. We investigated whether this permanent insult compels intestinal stem cells to develop strategies to dampen the deleterious effects of ROS. As an adverse effect, this adaptation process may increase their tolerance to oncogenic insults and facilitate their neoplastic transformation. We submitted immortalized human colonic epithelial cells to either a mimic of chronic inflammation or to a chemical peroxide, analyzed how they adapted to stress, and addressed the biological relevance of these observations in databases. We demonstrated that cells adapt to chronic-inflammation-associated oxidative stress in vitro through a partial genetic reprogramming. Through a gene set enrichment analysis, we showed that this program is recurrently active in the intestinal mucosae of Crohn's and ulcerative colitis disease patients and evolves alongside disease progression. Based on a previously reported characterization of intestinal stem and precursor cells using tracing experiments, we lastly confirmed the activation of the program in intestinal precursor cells during murine colorectal cancer development. This adaptive process is thus likely to play a role in the progression of Crohn's and ulcerative disease, and potentially in the initiation of colorectal cancer.
Collapse
Affiliation(s)
- Guillaume Collin
- Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université Lyon1, 69008 Lyon, France
| | - Jean-Philippe Foy
- Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université Lyon1, 69008 Lyon, France
| | - Nicolas Aznar
- Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université Lyon1, 69008 Lyon, France
| | - Nicolas Rama
- Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université Lyon1, 69008 Lyon, France
| | | | - Pierre Saintigny
- Department of Medical Oncology, Centre Léon Bérard, 69008 Lyon, France
| | - Alain Puisieux
- Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université Lyon1, 69008 Lyon, France
| | - Stéphane Ansieau
- Centre de Recherche en Cancérologie de Lyon, INSERM U1052, CNRS UMR 5286, Centre Léon Bérard, Université Lyon1, 69008 Lyon, France
- Correspondence: ; Tel.: +33-(0)469-166-680
| |
Collapse
|
|
13
|
Matsuno T, Mikami T, Hayashi H, Funahashi K, Okazumi S, Hiruta N, Shibuya K, Igarashi Y. Estrogen receptor beta expression in colitis-associated carcinoma in comparison with sporadic colonic tumor: An immunohistochemical study. JGH Open 2023; 7:110-117. [PMID: 36852140 PMCID: PMC9958341 DOI: 10.1002/jgh3.12859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/14/2022] [Accepted: 12/22/2022] [Indexed: 01/06/2023]
Abstract
Background and Aim The rate of ulcerative colitis (UC)-related colorectal cancer (colitis-associated carcinoma) is increasing. Estrogen receptor (ER) beta expression has been studied separately in patients with sporadic colorectal cancer and those with colitis-associated carcinoma. However, no study has compared the expression in both of these cancer types. The present study aimed to evaluate the relationship between colitis-associated carcinoma and ERs and assess whether the expression of ER beta influences cell proliferation. Methods This study included 45 surgically operated colitis-associated carcinomas, 43 high-grade dysplasias, 34 low-grade dysplasias, 36 sporadic colorectal cancers, 44 high-grade adenomas, and 34 low-grade adenomas. ER beta expression was evaluated with immunohistochemistry. Results Colitis-associated carcinoma showed significantly lower ER beta immunoexpression than sporadic colorectal lesions and high- and low-grade dysplasia. In seven colitis-associated carcinoma harboring both intensity score 3 (strong immunoexpression) and score 1 (weak immunoexpression) areas, the correlation among ER beta intensity, Ki-67, and p21 labeling index was assessed; an area with an ER beta intensity score of 3 showed a higher Ki-67 labeling index than that with score 1. In four out of the seven lesions, p21 labeling index was higher in the area of ER beta score 1 than in that of ER beta score 3. Conclusions The data suggest that ER beta expression is an accelerating factor in colorectal tumors. This association may be lower in colitis-associated carcinoma than in sporadic colorectal cancer.
Collapse
Affiliation(s)
- Takahisa Matsuno
- Division of Gastroenterology and Hepatology, Department of Internal MedicineToho University Omori Medical CenterTokyoJapan
| | - Tetuo Mikami
- Department of PathologyToho University School of MedicineTokyoJapan
| | - Hiroyuki Hayashi
- Department of PathologyYokohama Municipal Citizen's HospitalYokohamaJapan
| | | | - Shinichi Okazumi
- Department of SurgeryToho University Sakura Medical CenterSakuraJapan
| | - Nobuyuki Hiruta
- Department of Surgical PathologyToho University Sakura Medical CenterSakuraJapan
| | - Kazutoshi Shibuya
- Department of Surgical PathologyToho University School of MedicineTokyoJapan
| | - Yoshinori Igarashi
- Division of Gastroenterology and Hepatology, Department of Internal MedicineToho University Omori Medical CenterTokyoJapan
| |
Collapse
|
|
14
|
Volovat SR, Augustin I, Zob D, Boboc D, Amurariti F, Volovat C, Stefanescu C, Stolniceanu CR, Ciocoiu M, Dumitras EA, Danciu M, Apostol DGC, Drug V, Shurbaji SA, Coca LG, Leon F, Iftene A, Herghelegiu PC. Use of Personalized Biomarkers in Metastatic Colorectal Cancer and the Impact of AI. Cancers (Basel) 2022; 14:4834. [PMID: 36230757 PMCID: PMC9562853 DOI: 10.3390/cancers14194834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2022] [Revised: 09/18/2022] [Accepted: 09/29/2022] [Indexed: 12/09/2022] Open
Abstract
Colorectal cancer is a major cause of cancer-related death worldwide and is correlated with genetic and epigenetic alterations in the colonic epithelium. Genetic changes play a major role in the pathophysiology of colorectal cancer through the development of gene mutations, but recent research has shown an important role for epigenetic alterations. In this review, we try to describe the current knowledge about epigenetic alterations, including DNA methylation and histone modifications, as well as the role of non-coding RNAs as epigenetic regulators and the prognostic and predictive biomarkers in metastatic colorectal disease that can allow increases in the effectiveness of treatments. Additionally, the intestinal microbiota's composition can be an important biomarker for the response to strategies based on the immunotherapy of CRC. The identification of biomarkers in mCRC can be enhanced by developing artificial intelligence programs. We present the actual models that implement AI technology as a bridge connecting ncRNAs with tumors and conducted some experiments to improve the quality of the model used as well as the speed of the model that provides answers to users. In order to carry out this task, we implemented six algorithms: the naive Bayes classifier, the random forest classifier, the decision tree classifier, gradient boosted trees, logistic regression and SVM.
Collapse
Affiliation(s)
- Simona-Ruxandra Volovat
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Iolanda Augustin
- Department of Medical Oncology, AI.Trestioreanu Institute of Oncology, 022328 Bucharest, Romania
| | - Daniela Zob
- Department of Medical Oncology, AI.Trestioreanu Institute of Oncology, 022328 Bucharest, Romania
| | - Diana Boboc
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Florin Amurariti
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Constantin Volovat
- Department of Medical Oncology, “Euroclinic” Center of Oncology, 2 Vasile Conta Str., 700106 Iasi, Romania
| | - Cipriana Stefanescu
- Department of Biophysics and Medical Physics-Nuclear Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Cati Raluca Stolniceanu
- Department of Biophysics and Medical Physics-Nuclear Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
| | - Manuela Ciocoiu
- Department of Pathophysiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Eduard Alexandru Dumitras
- Department of Pathophysiology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
- Department of Anesthesiology and Intensive Care, Regional Institute of Oncology, 700115 Iasi, Romania
| | - Mihai Danciu
- Pathology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | | | - Vasile Drug
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, 16 University Str., 700115 Iasi, Romania
- Gastroenterology Clinic, Institute of Gastroenterology and Hepatology, ‘St. Spiridon’ Clinical Hospital, 700115 Iasi, Romania
| | - Sinziana Al Shurbaji
- Gastroenterology Clinic, Institute of Gastroenterology and Hepatology, ‘St. Spiridon’ Clinical Hospital, 700115 Iasi, Romania
| | - Lucia-Georgiana Coca
- Faculty of Computer Science, Alexandru Ioan Cuza University, 700115 Iasi, Romania
| | - Florin Leon
- Faculty of Automatic Control and Computer Engineering, Gheorghe Asachi Technical University, 700115 Iasi, Romania
| | - Adrian Iftene
- Faculty of Computer Science, Alexandru Ioan Cuza University, 700115 Iasi, Romania
| | - Paul-Corneliu Herghelegiu
- Faculty of Automatic Control and Computer Engineering, Gheorghe Asachi Technical University, 700115 Iasi, Romania
| |
Collapse
|
|
15
|
Kasuga S, Anzai H, Makise N, Sonoda H, Nagai Y, Abe S, Yokoyama Y, Ozawa T, Emoto S, Murono K, Sasaki K, Kawai K, Nozawa H, Ushiku T, Ishihara S. Giant filiform polyposis with high-grade dysplasia: A case report and review of the literature. Ann Med Surg (Lond) 2022; 82:104433. [PMID: 36268352 PMCID: PMC9577439 DOI: 10.1016/j.amsu.2022.104433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 08/01/2022] [Accepted: 08/12/2022] [Indexed: 11/28/2022] Open
Affiliation(s)
- So Kasuga
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
- Corresponding author. Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
| | - Hiroyuki Anzai
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Naohiro Makise
- Department of Pathology, The University of Tokyo, Tokyo, Japan
| | - Hirofumi Sonoda
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Yuzo Nagai
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Shinya Abe
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Yuichiro Yokoyama
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Tsuyoshi Ozawa
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Shigenobu Emoto
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Koji Murono
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Kazuhito Sasaki
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Kazushige Kawai
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Hiroaki Nozawa
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, The University of Tokyo, Tokyo, Japan
| | - Soichiro Ishihara
- Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
16
|
Noguchi T, Ando T, Emoto S, Nozawa H, Kawai K, Sasaki K, Murono K, Kishikawa J, Ishi H, Yokoyama Y, Abe S, Nagai Y, Anzai H, Sonoda H, Hata K, Sasaki T, Ishihara S. Artificial Intelligence Program to Predict p53 Mutations in Ulcerative Colitis-Associated Cancer or Dysplasia. Inflamm Bowel Dis 2022; 28:1072-1080. [PMID: 35278081 DOI: 10.1093/ibd/izab350] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Indexed: 12/26/2022]
Abstract
BACKGROUND The diagnosis of colitis-associated cancer or dysplasia is important in the treatment of ulcerative colitis. Immunohistochemistry of p53 along with hematoxylin and eosin (H&E) staining is conventionally used to accurately diagnose the pathological conditions. However, evaluation of p53 immunohistochemistry in all biopsied specimens is expensive and time-consuming for pathologists. In this study, we aimed to develop an artificial intelligence program using a deep learning algorithm to investigate and predict p53 immunohistochemical staining from H&E-stained slides. METHODS We cropped 25 849 patches from whole-slide images of H&E-stained slides with the corresponding p53-stained slides. These slides were prepared from samples of 12 patients with colitis-associated neoplasia who underwent total colectomy. We annotated all glands in the whole-slide images of the H&E-stained slides and grouped them into 3 classes: p53 positive, p53 negative, and p53 null. We used 80% of the patches for training a convolutional neural network (CNN), 10% for validation, and 10% for final testing. RESULTS The trained CNN glands were classified into 2 or 3 classes according to p53 positivity, with a mean average precision of 0.731 to 0.754. The accuracy, sensitivity (recall), specificity, positive predictive value (precision), and F-measure of the prediction of p53 immunohistochemical staining of the glands detected by the trained CNN were 0.86 to 0.91, 0.73 to 0.83, 0.91 to 0.92, 0.82 to 0.89, and 0.77 to 0.86, respectively. CONCLUSIONS Our trained CNN can be used as a reasonable alternative to conventional p53 immunohistochemical staining in the pathological diagnosis of colitis-associated neoplasia, which is accurate, saves time, and is cost-effective.
Collapse
Affiliation(s)
- Tatsuki Noguchi
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
| | - Takumi Ando
- Department of Pathology, University of Tokyo, Tokyo, Japan.,Department of Next-Generation Pathology Information Networking, University of Tokyo, Tokyo, Japan
| | - Shigenobu Emoto
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
| | - Hiroaki Nozawa
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
| | - Kazushige Kawai
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
| | - Kazuhito Sasaki
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
| | - Koji Murono
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
| | - Junko Kishikawa
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
| | - Hiroaki Ishi
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
| | | | - Shinya Abe
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
| | - Yuzo Nagai
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
| | - Hiroyuki Anzai
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
| | - Hirofumi Sonoda
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
| | - Keisuke Hata
- Department of Surgical Oncology, University of Tokyo, Tokyo, Japan
| | - Takeshi Sasaki
- Department of Pathology, University of Tokyo, Tokyo, Japan.,Department of Next-Generation Pathology Information Networking, University of Tokyo, Tokyo, Japan
| | | |
Collapse
|
|
17
|
Cancer evolution: special focus on the immune aspect of cancer. Semin Cancer Biol 2022; 86:420-435. [PMID: 35589072 DOI: 10.1016/j.semcancer.2022.05.006] [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: 12/15/2021] [Revised: 04/18/2022] [Accepted: 05/12/2022] [Indexed: 11/20/2022]
Abstract
Cancer is an evolutionary disease. Intra-tumor heterogeneity (ITH), which describes the diversity within individual tumors, sets the foundation for evolution. The fitness of tumor cells is determined by their microenvironment, which exerts intense selection pressure that generally favors cells with survival and proliferation advantages. It has been revealed that host immunity dramatically influences the evolutionary trajectory of cancer. As technologies advance, a refined map of the immune system's involvement in cancer evolution has gradually come to our knowledge. Here we specifically view cancer through the lens of evolutionary immunological biology. We will cover the neoplastic evolution under immunosurveillance, including how the host immunity shapes the tumor evolutionary trajectory and how progressive tumors modulate the host immunity to survive. A comprehensive understanding of the interplay between cancer evolution and cancer immunity provides clues to combating cancer strategically.
Collapse
|
|
18
|
de Krijger M, Carvalho B, Rausch C, Bolijn AS, Delis-van Diemen PM, Tijssen M, van Engeland M, Mostafavi N, Bogie RMM, Dekker E, Masclee AAM, Verheij J, Meijer GA, Ponsioen CY. Genetic Profiling of Colorectal Carcinomas of Patients with Primary Sclerosing Cholangitis and Inflammatory Bowel Disease. Inflamm Bowel Dis 2022; 28:1309-1320. [PMID: 35554535 PMCID: PMC9434447 DOI: 10.1093/ibd/izac087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Patients with primary sclerosing cholangitis (PSC) and inflammatory bowel disease (IBD) run a 10-fold increased risk of developing colorectal cancer (CRC) compared to patients with IBD only. The aim of this study was to perform an extensive screen of known carcinogenic genomic alterations in patients with PSC-IBD, and to investigate whether such changes occur already in nondysplastic mucosa. METHODS Archival cancer tissue and nondysplastic mucosa from resection specimens of 19 patients with PSC-IBD-CRC were characterized, determining DNA copy-number variations, microsatellite instability (MSI), mutations on 48 cancer genes, and CpG island methylator phenotype (CIMP). Genetic profiles were compared with 2 published cohorts of IBD-associated CRC (IBD-CRC; n = 11) and sporadic CRC (s-CRC; n = 100). RESULTS Patterns of chromosomal aberrations in PSC-IBD-CRC were similar to those observed in IBD-CRC and s-CRC, MSI occurred only once. Mutation frequencies were comparable between the groups, except for mutations in KRAS, which were less frequent in PSC-IBD-CRC (5%) versus IBD-CRC (38%) and s-CRC (31%; P = .034), and in APC, which were less frequent in PSC-IBD-CRC (5%) and IBD-CRC (0%) versus s-CRC (50%; P < .001). Cases of PSC-IBD-CRC were frequently CIMP positive (44%), at similar levels to cases of s-CRC (34%; P = .574) but less frequent than in cases with IBD-CRC (90%; P = .037). Similar copy number aberrations and mutations were present in matched cancers and adjacent mucosa in 5/15 and 7/11 patients, respectively. CONCLUSIONS The excess risk of CRC in patients with PSC-IBD was not explained by copy number aberrations, mutations, MSI, nor CIMP status, in cancer tissue, nor in adjacent mucosa. These findings set the stage for further exome-wide and epigenetic studies.
Collapse
Affiliation(s)
- Manon de Krijger
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands,Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Beatriz Carvalho
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Christian Rausch
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Anne S Bolijn
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | | | - Marianne Tijssen
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Manon van Engeland
- Department of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Nahid Mostafavi
- Biostatistics Unit of Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Roel M M Bogie
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Evelien Dekker
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Ad A M Masclee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Joanne Verheij
- Department of Pathology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Gerrit A Meijer
- Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Cyriel Y Ponsioen
- Address Correspondence to: Cyriel Y. Ponsioen, MD, PhD, Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands ()
| |
Collapse
|
|
19
|
Gabbutt C, Schenck RO, Weisenberger DJ, Kimberley C, Berner A, Househam J, Lakatos E, Robertson-Tessi M, Martin I, Patel R, Clark SK, Latchford A, Barnes CP, Leedham SJ, Anderson ARA, Graham TA, Shibata D. Fluctuating methylation clocks for cell lineage tracing at high temporal resolution in human tissues. Nat Biotechnol 2022; 40:720-730. [PMID: 34980912 PMCID: PMC9110299 DOI: 10.1038/s41587-021-01109-w] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 09/28/2021] [Indexed: 02/07/2023]
Abstract
Molecular clocks that record cell ancestry mutate too slowly to measure the short-timescale dynamics of cell renewal in adult tissues. Here, we show that fluctuating DNA methylation marks can be used as clocks in cells where ongoing methylation and demethylation cause repeated 'flip-flops' between methylated and unmethylated states. We identify endogenous fluctuating CpG (fCpG) sites using standard methylation arrays and develop a mathematical model to quantitatively measure human adult stem cell dynamics from these data. Small intestinal crypts were inferred to contain slightly more stem cells than the colon, with slower stem cell replacement in the small intestine. Germline APC mutation increased the number of replacements per crypt. In blood, we measured rapid expansion of acute leukemia and slower growth of chronic disease. Thus, the patterns of human somatic cell birth and death are measurable with fluctuating methylation clocks (FMCs).
Collapse
Affiliation(s)
- Calum Gabbutt
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Department of Cell and Developmental Biology, University College London, London, UK
- London Interdisciplinary Doctoral Training Programme (LIDo), London, UK
| | - Ryan O Schenck
- Integrated Mathematical Oncology Department, Moffitt Cancer Center, Tampa, FL, USA
- Intestinal Stem Cell Biology Lab, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Daniel J Weisenberger
- Department of Biochemistry and Molecular Medicine, University of Southern California, Los Angeles, CA, USA
| | - Christopher Kimberley
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Alison Berner
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Jacob Househam
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Eszter Lakatos
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Mark Robertson-Tessi
- Integrated Mathematical Oncology Department, Moffitt Cancer Center, Tampa, FL, USA
| | - Isabel Martin
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- St. Mark's Hospital, Harrow, London, UK
| | - Roshani Patel
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- St. Mark's Hospital, Harrow, London, UK
| | - Susan K Clark
- St. Mark's Hospital, Harrow, London, UK
- Department of Surgery and Cancer, Imperial College, London, UK
| | - Andrew Latchford
- St. Mark's Hospital, Harrow, London, UK
- Department of Surgery and Cancer, Imperial College, London, UK
| | - Chris P Barnes
- Department of Cell and Developmental Biology, University College London, London, UK
| | - Simon J Leedham
- Intestinal Stem Cell Biology Lab, Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
| | | | - Trevor A Graham
- Evolution and Cancer Laboratory, Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
| | - Darryl Shibata
- Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
| |
Collapse
|
|
20
|
Krugliak Cleveland N, Torres J, Rubin DT. What Does Disease Progression Look Like in Ulcerative Colitis, and How Might It Be Prevented? Gastroenterology 2022; 162:1396-1408. [PMID: 35101421 DOI: 10.1053/j.gastro.2022.01.023] [Citation(s) in RCA: 82] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 02/08/2023]
Abstract
Ulcerative colitis (UC) has been characterized by inflammation limited to the mucosa. Although sustained and durable remission has been associated with mucosal healing, the recurrent phenomenon of persistent clinical disease activity despite mucosal healing has been observed in clinical practice and across pivotal trials. Over time, UC appears to confer an increased risk of progression, defined as changes of disease phenotype; adverse transmural effects on the bowel wall; increased risk of neoplasia development; worsening colorectal function; and increased risk of colectomy, hospitalizations, and other extraintestinal comorbidities. Although the treatment paradigm for Crohn's disease has shifted toward early aggressive intervention to prevent disease progression and irreversible bowel damage, such urgency in efforts to halt disease progression in UC have been largely overlooked. This review summarizes the multiple facets of UC contributing to a modified perception of the disease as a progressive one. We propose further study of the natural history and priorities for further treatment goals that include these considerations.
Collapse
Affiliation(s)
| | - Joana Torres
- Gastroenterology Division, Hospital Beatriz Ângelo, Loures, Lisbon, Portugal; Division of Gastroenterology, Hospital da Luz, Lisbon, Portugal
| | - David T Rubin
- University of Chicago Medicine Inflammatory Bowel Disease Center, Chicago, Illinois.
| |
Collapse
|
|
21
|
Kumagai K, Shimizu T, Takai A, Kakiuchi N, Takeuchi Y, Hirano T, Takeda H, Mizuguchi A, Teramura M, Ito T, Iguchi E, Nikaido M, Eso Y, Takahashi K, Ueda Y, Miyamoto SI, Obama K, Ogawa S, Marusawa H, Seno H. Expansion of gastric intestinal metaplasia with copy number aberrations contributes to field cancerization. Cancer Res 2022; 82:1712-1723. [PMID: 35363856 DOI: 10.1158/0008-5472.can-21-1523] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 09/14/2021] [Accepted: 03/07/2022] [Indexed: 12/09/2022]
Abstract
Intestinal metaplasia (IM) is a risk factor for gastric cancer following infection with Helicobacter pylori. To explore the susceptibility of pure gastric IM to cancer development, we investigated genetic alterations in single IM gastric glands. We isolated 50 single IM or non-IM glands from the inflamed gastric mucosa of 11 patients with intramucosal gastric carcinoma (IGC) and 4 patients without IGC; nineteen single glands in the non-inflamed gastric mucosa of 11 individuals from our cohort and previous dataset were also included as controls. Whole exome sequencing of single glands revealed significantly higher accumulation of somatic mutations in various genes within IM glands compared with non-IM glands. Clonal ordering analysis showed that IM glands expanded to form clusters with shared mutations. Additionally, targeted-capture deep sequencing and copy number (CN) analyses were performed in 96 clustered IM or non-IM gastric glands from 26 patients with IGC. CN analyses were also performed on 41 IGC samples and the Cancer Genome Atlas-Stomach Adenocarcinoma datasets. These analyses revealed that polyclonally expanded IM commonly acquired copy number aberrations (CNA), including amplification of chromosomes 8, 20, and 2. A large portion of clustered IM glands typically consisted of common CNAs rather than other cancer-related mutations. Moreover, the CNA patterns of clustered IM glands were similar to those of IGC, indicative of precancerous conditions. Taken together, these findings suggest that, in the gastric mucosa inflamed with H. pylori infection, IM glands expand via acquisition of CNAs comparable to those of IGC, contributing to field cancerization.
Collapse
Affiliation(s)
- Ken Kumagai
- Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
| | | | - Atsushi Takai
- Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | | | | | - Haruhiko Takeda
- Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
| | - Aya Mizuguchi
- Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
| | - Mari Teramura
- Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
| | - Takahiko Ito
- Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
| | | | | | - Yuji Eso
- Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Ken Takahashi
- Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
| | - Yoshihide Ueda
- Graduate School of Medicine, Kyoto University, Kyoto, Kyoto, Japan
| | | | - Kazutaka Obama
- Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | | | | | - Hiroshi Seno
- Graduate School of Medicine, Kyoto University, Kyoto, Japan
| |
Collapse
|
|
22
|
Philipovskiy A, Ghafouri R, Dwivedi AK, Alvarado L, McCallum R, Maegawa F, Konstantinidis IT, Hakim N, Shurmur S, Awasthi S, Gaur S, Corral J. Association Between Tumor Mutation Profile and Clinical Outcomes Among Hispanic-Latino Patients With Metastatic Colorectal Cancer. Front Oncol 2022; 11:772225. [PMID: 35141142 PMCID: PMC8819001 DOI: 10.3389/fonc.2021.772225] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 12/13/2021] [Indexed: 11/23/2022] Open
Abstract
In the United States, CRC is the third most common type of cancer and the second leading cause of cancer-related death. Although the incidence of CRC among the Hispanic population has been declining, recently, a dramatic increase in CRC incidents among HL younger than 50 years of age has been reported. The incidence of early-onset CRC is more significant in HL population (45%) than in non-Hispanic Whites (27%) and African-Americans (15%). The reason for these racial disparities and the biology of CRC in the HL are not well understood. We performed this study to understand the biology of the disease in HL patients. We analyzed formalin-fixed paraffin-embedded tumor tissue samples from 52 HL patients with mCRC. We compared the results with individual patient clinical histories and outcomes. We identified commonly altered genes in HL patients (APC, TP53, KRAS, GNAS, and NOTCH). Importantly, mutation frequencies in the APC gene were significantly higher among HL patients. The combination of mutations in the APC, NOTCH, and KRAS genes in the same tumors was associated with a higher risk of progression after first-line of chemotherapy and overall survival. Our data support the notion that the molecular drivers of CRC might be different in HL patients.
Collapse
Affiliation(s)
- Alexander Philipovskiy
- Department of Internal Medicine, Division of Hematology-Oncology, Texas Tech University Health Sciences Center Lubbock, Lubbock, TX, United States
- *Correspondence: Alexander Philipovskiy,
| | - Reshad Ghafouri
- Department of Internal Medicine, Division of Hematology-Oncology, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Alok Kumar Dwivedi
- Department of Molecular and Translational Medicine, Division of Biostatistics & Epidemiology, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Luis Alvarado
- Department of Molecular and Translational Medicine, Division of Biostatistics & Epidemiology, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Richard McCallum
- Department of Internal Medicine, Division of Gastroenterology, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Felipe Maegawa
- Department of Surgery, Southern Arizona VA Health Care System, University of Arizona, Tucson, AZ, United States
| | - Ioannis T. Konstantinidis
- Department of Surgery, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Nawar Hakim
- Department of Pathology, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Scott Shurmur
- Department of Internal Medicine, Division of Hematology-Oncology, Texas Tech University Health Sciences Center Lubbock, Lubbock, TX, United States
| | - Sanjay Awasthi
- Department of Internal Medicine, Division of Hematology-Oncology, Texas Tech University Health Sciences Center Lubbock, Lubbock, TX, United States
| | - Sumit Gaur
- Department of Internal Medicine, Division of Hematology-Oncology, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| | - Javier Corral
- Department of Internal Medicine, Division of Hematology-Oncology, Texas Tech University Health Sciences Center El Paso, El Paso, TX, United States
| |
Collapse
|
|
23
|
Cherkasova V, Kovalchuk O, Kovalchuk I. Cannabinoids and Endocannabinoid System Changes in Intestinal Inflammation and Colorectal Cancer. Cancers (Basel) 2021; 13:4353. [PMID: 34503163 PMCID: PMC8430689 DOI: 10.3390/cancers13174353] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 08/25/2021] [Indexed: 01/02/2023] Open
Abstract
Despite the multiple preventive measures and treatment options, colorectal cancer holds a significant place in the world's disease and mortality rates. The development of novel therapy is in critical need, and based on recent experimental data, cannabinoids could become excellent candidates. This review covered known experimental studies regarding the effects of cannabinoids on intestinal inflammation and colorectal cancer. In our opinion, because colorectal cancer is a heterogeneous disease with different genomic landscapes, the choice of cannabinoids for tumor prevention and treatment depends on the type of the disease, its etiology, driver mutations, and the expression levels of cannabinoid receptors. In this review, we describe the molecular changes of the endocannabinoid system in the pathologies of the large intestine, focusing on inflammation and cancer.
Collapse
Affiliation(s)
| | - Olga Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 7X8, Canada;
| | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 7X8, Canada;
| |
Collapse
|
|
24
|
Geospatial Assessments of DNA Adducts in the Human Stomach: A Model of Field Cancerization. Cancers (Basel) 2021; 13:cancers13153728. [PMID: 34359626 PMCID: PMC8345122 DOI: 10.3390/cancers13153728] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2021] [Revised: 07/21/2021] [Accepted: 07/22/2021] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Field cancerization is a popular concept regarding where cancer cells arise in a plane, such as the opened-up gastrointestinal mucosa. The geospatial distribution of DNA adducts, some of which are believed to initiate mutation, may be a clue to understanding the landscape of the preferred occurrence of gastric cancer in the human stomach, such that the occurrence is much more frequent in the lesser curvature than in the greater curvature. METHODS Seven DNA adducts, C5-methyl-2'-deoxycytidine, 2'-deoxyinosine, C5-hydroxymethyl-2'-deoxycytidine, N6-methyl-2'-deoxyadenosine, 1,N6-etheno-2'-deoxyadenosine, N6-hydroxymethyl-2'-deoxyadenosine, and C8-oxo-2'-deoxyguanosine, from different points and zones of the human stomach were semi quantitatively measured by liquid chromatography/tandem mass spectrometry. The differences in the quantity of these DNA adducts from the lesser and greater curvature, the upper, middle and lower third zones, the anterior and posterior wall of the stomach, and the mucosae distant from and near the tumor were compared to determine whether the location preference of cancer in the stomach could be explained by the distribution of these DNA adducts. Comparisons were conducted considering the tumor locations and operation methods. CONCLUSIONS Regarding the DNA adducts investigated, significant differences in quantities and locations in the whole stomach were not noted; thus, these DNA adducts do not explain the preferential occurrence of cancer in particular locations of the human stomach.
Collapse
|
|
25
|
Kumar R, Harilal S, Carradori S, Mathew B. A Comprehensive Overview of Colon Cancer- A Grim Reaper of the 21st Century. Curr Med Chem 2021; 28:2657-2696. [PMID: 33106132 DOI: 10.2174/0929867327666201026143757] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 09/18/2020] [Accepted: 09/18/2020] [Indexed: 12/09/2022]
Abstract
A few decades ago, the incidence of colorectal cancer (CRC) was low and is now the fourth in the list of deadly cancers producing nearly a million deaths annually. A population that is aging along with risk factors such as smoking, obesity, sedentary lifestyle with little or no physical activity, and non-healthy food habits of developed countries can increase the risk of colorectal cancer. The balance in gut microbiota and the metabolites produced during bacterial fermentation within the host plays a significant role in regulating intestinal diseases as well as colorectal cancer development. Recent progress in the understanding of illness resulted in multiple treatment options such as surgery, radiation, and chemotherapy, including targeted therapy and multitherapies. The treatment plan for CRC depends on the location, stage and grade of cancer as well as genomic biomarker tests. Despite all the advancements made in the genetic and molecular aspects of the disease, the knowledge seems inadequate as the drug action as well as the wide variation in drug response did not appear strongly correlated with the individual molecular and genetic characteristics, which suggests the requirement of comprehensive molecular understanding of this complex heterogeneous disease. Furthermore, multitherapies or a broad spectrum approach, which is an amalgamation of the various promising as well as effective therapeutic strategies that can tackle heterogeneity and act on several targets of the disease, need to be validated in clinical studies. The latest treatment options have significantly increased the survival of up to three years in the case of advanced disease. The fact that colorectal cancer is developed from a polypoid precursor, as well as the symptoms of the disease that occur at an advanced stage, underlines how screening programs can help early detection and decrease mortality as well as morbidity from CRC.
Collapse
Affiliation(s)
- Rajesh Kumar
- Department of Pharmacy, Kerala University of Health Sciences, Thrissur, Kerala, India
| | - Seetha Harilal
- Department of Pharmacy, Kerala University of Health Sciences, Thrissur, Kerala, India
| | - Simone Carradori
- Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, via dei Vestini 31, 66100 Chieti, Italy
| | - Bijo Mathew
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Sciences Campus, Kochi-682 041, India
| |
Collapse
|
|
26
|
Yalchin M, Baker AM, Graham TA, Hart A. Predicting Colorectal Cancer Occurrence in IBD. Cancers (Basel) 2021; 13:2908. [PMID: 34200768 PMCID: PMC8230430 DOI: 10.3390/cancers13122908] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 05/27/2021] [Accepted: 06/01/2021] [Indexed: 12/13/2022] Open
Abstract
Patients with colonic inflammatory bowel disease (IBD) are at an increased risk of developing colorectal cancer (CRC), and are therefore enrolled into a surveillance programme aimed at detecting dysplasia or early cancer. Current surveillance programmes are guided by clinical, endoscopic or histological predictors of colitis-associated CRC (CA-CRC). We have seen great progress in our understanding of these predictors of disease progression, and advances in endoscopic technique and management, along with improved medical care, has been mirrored by the falling incidence of CA-CRC over the last 50 years. However, more could be done to improve our molecular understanding of CA-CRC progression and enable better risk stratification for patients with IBD. This review summarises the known risk factors associated with CA-CRC and explores the molecular landscape that has the potential to complement and optimise the existing IBD surveillance programme.
Collapse
Affiliation(s)
- Mehmet Yalchin
- Inflammatory Bowel Disease Department, St. Mark’s Hospital, Watford R.d., Harrow HA1 3UJ, UK
- Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse S.q., London EC1M 6BQ, UK; (A.-M.B.); (T.A.G.)
| | - Ann-Marie Baker
- Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse S.q., London EC1M 6BQ, UK; (A.-M.B.); (T.A.G.)
| | - Trevor A. Graham
- Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse S.q., London EC1M 6BQ, UK; (A.-M.B.); (T.A.G.)
| | - Ailsa Hart
- Inflammatory Bowel Disease Department, St. Mark’s Hospital, Watford R.d., Harrow HA1 3UJ, UK
| |
Collapse
|
|
27
|
Yum MK, Han S, Fink J, Wu SHS, Dabrowska C, Trendafilova T, Mustata R, Chatzeli L, Azzarelli R, Pshenichnaya I, Lee E, England F, Kim JK, Stange DE, Philpott A, Lee JH, Koo BK, Simons BD. Tracing oncogene-driven remodelling of the intestinal stem cell niche. Nature 2021; 594:442-447. [PMID: 34079126 PMCID: PMC7614896 DOI: 10.1038/s41586-021-03605-0] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 04/30/2021] [Indexed: 02/06/2023]
Abstract
Interactions between tumour cells and the surrounding microenvironment contribute to tumour progression, metastasis and recurrence1-3. Although mosaic analyses in Drosophila have advanced our understanding of such interactions4,5, it has been difficult to engineer parallel approaches in vertebrates. Here we present an oncogene-associated, multicolour reporter mouse model-the Red2Onco system-that allows differential tracing of mutant and wild-type cells in the same tissue. By applying this system to the small intestine, we show that oncogene-expressing mutant crypts alter the cellular organization of neighbouring wild-type crypts, thereby driving accelerated clonal drift. Crypts that express oncogenic KRAS or PI3K secrete BMP ligands that suppress local stem cell activity, while changes in PDGFRloCD81+ stromal cells induced by crypts with oncogenic PI3K alter the WNT signalling environment. Together, these results show how oncogene-driven paracrine remodelling creates a niche environment that is detrimental to the maintenance of wild-type tissue, promoting field transformation dominated by oncogenic clones.
Collapse
Affiliation(s)
- Min Kyu Yum
- Wellcome Trust-Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Seungmin Han
- Wellcome Trust-Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Juergen Fink
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Szu-Hsien Sam Wu
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Vienna, Austria
- Vienna BioCenter PhD Program, Doctoral School at the University of Vienna and Medical University of Vienna, Vienna, Austria
| | - Catherine Dabrowska
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Teodora Trendafilova
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Roxana Mustata
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Lemonia Chatzeli
- Wellcome Trust-Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Roberta Azzarelli
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
- Department of Oncology, University of Cambridge, Hutchison-MRC Research Centre, Cambridge, UK
| | - Irina Pshenichnaya
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
| | - Eunmin Lee
- Department of New Biology, DGIST, Daegu, Republic of Korea
| | - Frances England
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | | | - Daniel E Stange
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Medical Faculty, Technische Universität Dresden, Dresden, Germany
| | - Anna Philpott
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
- Department of Oncology, University of Cambridge, Hutchison-MRC Research Centre, Cambridge, UK
| | - Joo-Hyeon Lee
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Bon-Kyoung Koo
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.
- Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter (VBC), Vienna, Austria.
| | - Benjamin D Simons
- Wellcome Trust-Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge, UK.
- Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge, UK.
| |
Collapse
|
|
28
|
Hirsch D, Hardt J, Sauer C, Heselmeyer-Hadded K, Witt SH, Kienle P, Ried T, Gaiser T. Molecular characterization of ulcerative colitis-associated colorectal carcinomas. Mod Pathol 2021; 34:1153-1166. [PMID: 33318582 PMCID: PMC8154647 DOI: 10.1038/s41379-020-00722-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 10/14/2020] [Accepted: 10/28/2020] [Indexed: 12/15/2022]
Abstract
Patients with ulcerative colitis (UC) are at increased risk for developing colorectal cancer (CRC). In contrast to sporadic colorectal tumorigenesis, TP53 mutations occur early in the progression from inflamed colonic epithelium to dysplasia to CRC, and are sometimes readily detectable in inflamed, (yet) non-dysplastic mucosa. Here, we analyzed formalin-fixed paraffin-embedded tissue samples from 19 patients with long-standing UC (median 18 years, range 3 to 34) who had developed CRC as a consequence of chronic inflammation of the large bowel. We performed microsatellite instability testing, copy number analysis by array-based comparative genomic hybridization, mutation analysis by targeted next generation sequencing (48-gene panel) and TP53 immunostaining. The results were compared to The Cancer Genome Atlas (TCGA) data on sporadic CRC. All UC-CRC lesions in our cohort were microsatellite stable. Overall, genomic imbalances of UC-CRCs showed patterns of chromosomal aneuploidies characteristic for sporadic CRC with the exception of gains of chromosome arm 5p (12 of 23 UC-CRC, 52%), which are rare in sporadic CRCs from TCGA (21 of 144, 15%; FDR adjusted P = 0.006). UC-CRCs showed a predilection for TP53 alterations, which was the most frequently mutated gene in our cohort (20 of 23, 87%). Interestingly, spatially separated tumor lesions from individual patients tended to harbor distinct TP53 mutations. Similar to CRCs arising in a background of Crohn's colitis, the genetic landscape of UC-CRCs was characterized by TP53 mutations and chromosomal aneuploidies including gains of chromosome arm 5p. Both alterations harbor the potential for early detection in precursor lesions, thus complementing morphologic diagnosis.
Collapse
Affiliation(s)
- Daniela Hirsch
- Institute of Pathology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
- Cancer Genomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Julia Hardt
- Department of Surgery, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Christian Sauer
- Institute of Pathology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Kerstin Heselmeyer-Hadded
- Cancer Genomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Stephanie H Witt
- Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Peter Kienle
- General and Visceral Surgery, Theresienkrankenhaus and St. Hedwig-Klinik GmbH, Mannheim, Germany
| | - Thomas Ried
- Cancer Genomics Section, Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Timo Gaiser
- Institute of Pathology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| |
Collapse
|
|
29
|
Nakanishi R, Shimizu T, Kumagai K, Takai A, Marusawa H. Genetic Pathogenesis of Inflammation-Associated Cancers in Digestive Organs. Pathogens 2021; 10:453. [PMID: 33918902 PMCID: PMC8069378 DOI: 10.3390/pathogens10040453] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/12/2021] [Accepted: 04/08/2021] [Indexed: 12/20/2022] Open
Abstract
Epidemiological, clinical, and biological studies convincingly demonstrate that chronic inflammation predisposes to the development of human cancers. In digestive organs, inflammation-associated cancers include colitis-associated colorectal cancers, Helicobacter pylori-associated gastric cancer, as well as Barrett's esophagus and esophageal adenocarcinoma associated with chronic duodenogastric-esophageal reflux. Cancer is a genomic disease, and stepwise accumulation of genetic and epigenetic alterations of tumor-related genes leads to the development of tumor cells. Recent genome analyses show that genetic alterations, which are evoked by inflammation, are latently accumulated in inflamed epithelial cells of digestive organs. Production of reactive oxygen and aberrant expression of activation-induced cytidine deaminase, a nucleotide-editing enzyme, could be induced in inflamed gastrointestinal epithelial cells and play a role as a genomic modulator of inflammation-associated carcinogenesis. Understanding the molecular linkage between inflammation and genetic alterations will open up a new field of tumor biology and provide a novel strategy for the prevention of inflammation-associated tumorigenesis.
Collapse
Affiliation(s)
- Risa Nakanishi
- Department of Gastroenterology, Red Cross Osaka Hospital, Osaka 543-8555, Japan;
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; (T.S.); (K.K.); (A.T.)
| | - Takahiro Shimizu
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; (T.S.); (K.K.); (A.T.)
| | - Ken Kumagai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; (T.S.); (K.K.); (A.T.)
| | - Atsushi Takai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan; (T.S.); (K.K.); (A.T.)
| | - Hiroyuki Marusawa
- Department of Gastroenterology, Red Cross Osaka Hospital, Osaka 543-8555, Japan;
| |
Collapse
|
|
30
|
Abstract
Cancer is a clonal disorder derived from a single ancestor cell and its progenies that are positively selected by acquisition of 'driver mutations'. However, the evolution of positively selected clones does not necessarily imply the presence of cancer. On the contrary, it has become clear that expansion of these clones in phenotypically normal or non-cancer tissues is commonly seen in association with ageing and/or in response to environmental insults and chronic inflammation. Recent studies have reported expansion of clones harbouring mutations in cancer driver genes in the blood, skin, oesophagus, bronchus, liver, endometrium and bladder, where the expansion could be so extensive that tissues undergo remodelling of an almost entire tissue. The presence of common cancer driver mutations in normal tissues suggests a strong link to cancer development, providing an opportunity to understand early carcinogenic processes. Nevertheless, some driver mutations are unique to normal tissues or have a mutation frequency that is much higher in normal tissue than in cancer, indicating that the respective clones may not necessarily be destined for evolution to cancer but even negatively selected for carcinogenesis depending on the mutated gene. Moreover, tissues that are remodelled by genetically altered clones might define functionalities of aged tissues or modified inflammatory processes. In this Review, we provide an overview of major findings on clonal expansion in phenotypically normal or non-cancer tissues and discuss their biological significance not only in cancer development but also in ageing and inflammatory diseases.
Collapse
Affiliation(s)
- Nobuyuki Kakiuchi
- Department of Pathology and Tumour Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Seishi Ogawa
- Department of Pathology and Tumour Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
- Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto, Japan.
- Department of Medicine, Centre for Haematology and Regenerative Medicine, Karolinska Institute, Stockholm, Sweden.
| |
Collapse
|
|
31
|
Singhi AD, Waters KM, Makhoul EP, Parian A, Lazarev MG, Proksell SS, Dueker JM, Schwartz MB, Wald AI, Nikiforova MN, Montgomery EA. Targeted next-generation sequencing supports serrated epithelial change as an early precursor to inflammatory bowel disease-associated colorectal neoplasia. Hum Pathol 2021; 112:9-19. [PMID: 33727167 PMCID: PMC10113803 DOI: 10.1016/j.humpath.2021.03.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 02/28/2021] [Accepted: 03/02/2021] [Indexed: 12/12/2022]
Abstract
Serrated epithelial change (SEC) manifests in patients with long-standing inflammatory bowel disease (IBD) and is characterized by disorganized crypt architecture, irregular serrations, and goblet cell-rich epithelium. The serrated nature of SEC is reminiscent of serrated colorectal polyps, which frequently harbor KRAS/BRAF mutations. SEC is, however, not only histologically distinct from sporadic serrated polyps but also associated with colorectal neoplasia. Whether SEC is a precursor to IBD-associated neoplasia remains unclear. To further define the relationship of SEC with serrated colorectal polyps and IBD-associated neoplasia, we performed targeted next-generation sequencing on colorectal specimens to include the following: SEC without dysplasia/neoplasia (n = 10), SEC with separate foci of associated dysplasia/adenocarcinoma from the same patients (n = 17), and uninvolved mucosa (n = 10) from 14 patients. In addition, we molecularly profiled sessile serrated lesion (SSL)-like or serrated lesion, not otherwise specified (SL-NOS), specimens, from 11 patients who also had IBD. This control cohort included SSL-like/SL-NOS without dysplasia/neoplasia (n = 11), SSL-like/SL-NOS with associated low-grade dysplasia (n = 2), and uninvolved mucosa (n = 8). By next-generation sequencing, the most frequently mutated gene in SEC without neoplasia and associated dysplasia/adenocarcinoma from separate foci in the same patients was TP53. Recurrent TP53 mutations were present in 50% of SEC specimens without dysplasia/neoplasia. In addition, alterations in TP53 were detected at a prevalence of 71% in low-grade dysplasia, 83% in high-grade dysplasia, and 100% in adenocarcinoma. Paired sequencing of SEC and associated neoplasia revealed identical TP53 missense mutations for 3 patients. In contrast, 91% of SSL-like/SL-NOS specimens without dysplasia/neoplasia harbored KRAS/BRAF mutations, which were conserved in associated low-grade dysplasia. No genomic alterations were found in uninvolved mucosa from either patients with SEC or patients with SSL-like/SL-NOS. Based on our findings, we conclude SEC is distinct from SSL-like serrated colorectal lesions in patients with IBD and an early precursor to IBD-associated neoplasia that warrants colonoscopic surveillance.
Collapse
Affiliation(s)
- Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Kevin M Waters
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Elias P Makhoul
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Alyssa Parian
- Department of Medicine, Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - Mark G Lazarev
- Department of Medicine, Division of Gastroenterology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA
| | - Siobhan S Proksell
- Department of Medicine, Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Jeffrey M Dueker
- Department of Medicine, Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Marc B Schwartz
- Department of Medicine, Division of Gastroenterology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Abigail I Wald
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Marina N Nikiforova
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, 15213, USA
| | - Elizabeth A Montgomery
- Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, 21205, USA; Department of Pathology, University of Miami Miller School of Medicine, Miami, FL, 33136, USA.
| |
Collapse
|
|
32
|
Iwama T, Fujiya M, Konishi H, Tanaka H, Murakami Y, Kunogi T, Sasaki T, Takahashi K, Ando K, Ueno N, Kashima S, Moriichi K, Tanabe H, Okumura T. Bacteria-derived ferrichrome inhibits tumor progression in sporadic colorectal neoplasms and colitis-associated cancer. Cancer Cell Int 2021; 21:21. [PMID: 33407519 PMCID: PMC7789586 DOI: 10.1186/s12935-020-01723-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Accepted: 12/19/2020] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND Colorectal cancers develop through several pathways, including the adenoma-carcinoma sequence and colitis-associated carcinogenesis. An altered intestinal microflora has been reported to be associated with the development and progression of colorectal cancer via these pathways. We identified Lactobacillus casei-derived ferrichrome as a mediator of the bacterial anti-tumor effect of colorectal cancer cells through the upregulation of DDIT3. In this study, we investigated the anti-tumor effects of ferrichrome on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. METHODS SRB and MTT assays were performed to assess growth inhibition in vitro. Eighteen organoids were prepared from biopsy specimens obtained by colonoscopy. An AOM-DSS carcinogenesis model and xenograft model of colorectal cancer cells were generated for the assessment of the tumor suppressive effect of ferrichrome in vivo. RESULTS Ferrichrome inhibited the cell growth of colorectal cancer cells in vitro and in in vivo xenograft models. Ferrichrome exerted a strong tumor-suppressive effect that was superior to that of currently available anti-tumor agents, including 5-FU and cisplatin, both in vitro and in vivo. The tumor-suppressive effect of the combination of ferrichrome and 5-FU was superior to that of single treatment with either drug. The tumor suppressive effects of ferrichrome were confirmed through the upregulation of DDIT3 in patient-derived organoids of adenoma and carcinoma. Ferrichrome inhibited the tumor progression in the AOM-DSS model while exhibiting no anti-inflammatory effect in the DSS-colitis model, suggesting that ferrichrome inhibited cancer cells, but not a precancerous condition, via the colitis-associated pathway. CONCLUSIONS Ferrichrome exerts a tumor suppressive effect on precancerous conditions and cancer cells associated with sporadic as well as colitis-associated colorectal cancer. The anti-tumor effect of ferrichrome was mediated by the upregulation of DDIT3, and was superior to that of 5-FU or cisplatin. These results suggest that Lactobacillus brevis-derived ferrichrome may be a candidate anti-tumor drug for the treatment of colorectal neoplasms.
Collapse
Affiliation(s)
- Takuya Iwama
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Hokkaido, 078-8510, Asahikawa, Japan
| | - Mikihiro Fujiya
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Hokkaido, 078-8510, Asahikawa, Japan.
| | - Hiroaki Konishi
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Hokkaido, 078-8510, Asahikawa, Japan
| | - Hiroki Tanaka
- Department of Legal Medicine, Asahikawa Medical University, Asahikawa, Japan
| | - Yuki Murakami
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Hokkaido, 078-8510, Asahikawa, Japan
| | - Takehito Kunogi
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Hokkaido, 078-8510, Asahikawa, Japan
| | - Takahiro Sasaki
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Hokkaido, 078-8510, Asahikawa, Japan
| | - Keitaro Takahashi
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Hokkaido, 078-8510, Asahikawa, Japan
| | - Katsuyoshi Ando
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Hokkaido, 078-8510, Asahikawa, Japan
| | - Nobuhiro Ueno
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Hokkaido, 078-8510, Asahikawa, Japan
| | - Shin Kashima
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Hokkaido, 078-8510, Asahikawa, Japan
| | - Kentaro Moriichi
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Hokkaido, 078-8510, Asahikawa, Japan
| | - Hiroki Tanabe
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Hokkaido, 078-8510, Asahikawa, Japan
| | - Toshikatsu Okumura
- Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, 2-1-1-1, Midorigaoka, Hokkaido, 078-8510, Asahikawa, Japan
| |
Collapse
|
|
33
|
Lin L, Cheng X, Yin D. Aberrant DNA Methylation in Esophageal Squamous Cell Carcinoma: Biological and Clinical Implications. Front Oncol 2020; 10:549850. [PMID: 33194605 PMCID: PMC7645039 DOI: 10.3389/fonc.2020.549850] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 09/18/2020] [Indexed: 12/20/2022] Open
Abstract
Almost all cancer cells possess multiple epigenetic abnormalities, which cooperate with genetic alterations to enable the acquisition of cancer hallmarks during tumorigenesis. As the most frequently found epigenetic change in human cancers, aberrant DNA methylation manifests at two major forms: global genomic DNA hypomethylation and locus-specific promoter region hypermethylation. It has been recognized as a critical contributor to esophageal squamous cell carcinoma (ESCC) malignant transformation. In ESCC, DNA methylation alterations affect genes involved in cell cycle regulation, DNA damage repair, and cancer-related signaling pathways. Aberrant DNA methylation patterns occur not only in ESCC tumors but also in precursor lesions. It adds another layer of complexity to the ESCC heterogeneity and may serve as early diagnostic, prognostic, and chemo-sensitive markers. Characterization of the DNA methylome in ESCC could help better understand its pathogenesis and develop improved therapies. We herein summarize the current research and knowledge about DNA methylation in ESCC and its clinical significance in diagnosis, prognosis, and treatment.
Collapse
Affiliation(s)
- Lehang Lin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xu Cheng
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Dong Yin
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| |
Collapse
|
|
34
|
Alison MR. The cellular origins of cancer with particular reference to the gastrointestinal tract. Int J Exp Pathol 2020; 101:132-151. [PMID: 32794627 PMCID: PMC7495846 DOI: 10.1111/iep.12364] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 06/11/2020] [Accepted: 06/13/2020] [Indexed: 12/18/2022] Open
Abstract
Stem cells or their closely related committed progenitor cells are the likely founder cells of most neoplasms. In the continually renewing and hierarchically organized epithelia of the oesophagus, stomach and intestine, homeostatic stem cells are located at the beginning of the cell flux, in the basal layer of the oesophagus, the isthmic region of gastric oxyntic glands and at the bottom of gastric pyloric-antral glands and colonic crypts. The introduction of mutant oncogenes such as KrasG12D or loss of Tp53 or Apc to specific cell types expressing the likes of Lgr5 and Mist1 can be readily accomplished in genetically engineered mouse models to initiate tumorigenesis. Other origins of cancer are discussed including 'reserve' stem cells that may be activated by damage or through disruption of morphogen gradients along the crypt axis. In the liver and pancreas, with little cell turnover and no obvious stem cell markers, the importance of regenerative hyperplasia associated with chronic inflammation to tumour initiation is vividly apparent, though inflammatory conditions in the renewing populations are also permissive for tumour induction. In the liver, hepatocytes, biliary epithelial cells and hepatic progenitor cells are embryologically related, and all can give rise to hepatocellular carcinoma and cholangiocarcinoma. In the exocrine pancreas, both acinar and ductal cells can give rise to pancreatic ductal adenocarcinoma (PDAC), although the preceding preneoplastic states are quite different: acinar-ductal metaplasia gives rise to pancreatic intraepithelial neoplasia culminating in PDAC, while ducts give rise to PDAC via. mucinous cell metaplasia that may have a polyclonal origin.
Collapse
Affiliation(s)
- Malcolm R. Alison
- Centre for Tumour BiologyBarts Cancer Institute, Charterhouse SquareBarts and The London School of Medicine and DentistryLondonUK
| |
Collapse
|
|
35
|
Rubio CA, Schmidt PT. Preliminary Report: Asymmetric Crypt Fission in Biopsies from Patients With Ulcerative Colitis. In Vivo 2020; 34:2693-2695. [PMID: 32871801 PMCID: PMC7652456 DOI: 10.21873/invivo.12089] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 05/08/2020] [Accepted: 05/11/2020] [Indexed: 02/03/2023]
Abstract
BACKGROUND Recently, we found crypts with asymmetric fission bordering ulcers in colectomy specimens from patients with ulcerative colitis (UC). Here, we report crypts with asymmetric fission found in biopsies from patients with UC. PATIENTS AND METHODS Sections from endoscopic biopsies from five patients with UC were reviewed. The number of transected (cut-across) crypts in symmetric and asymmetric fission was assessed in sections from three biopsies in each patient. RESULTS A total of 89 crypts in fission were recorded in the 15 biopsies; 36 (40.4%) were in symmetric fission and the remaining 53 (59.6%) in asymmetric fission. CONCLUSION A high frequency of asymmetric crypts in fission was demonstrated in endoscopic biopsies from patients with UC. It is suggested that this previously unaddressed histological parameter is included in pathological descriptions of endoscopic biopsies from patients with UC.
Collapse
Affiliation(s)
- Carlos A Rubio
- Gastrointestinal and Liver Research Laboratory, Department of Pathology, Karolinska Institute and University Hospital, Centre for Digestive Diseases, Stockholm, Sweden
| | - Peter T Schmidt
- Department of Medicine, Karolinska Institute and University Hospital, Centre for Digestive Diseases, Stockholm, Sweden
| |
Collapse
|
|
36
|
Kasi A, Handa S, Bhatti S, Umar S, Bansal A, Sun W. Molecular Pathogenesis and Classification of Colorectal Carcinoma. CURRENT COLORECTAL CANCER REPORTS 2020; 16:97-106. [PMID: 32905465 DOI: 10.1007/s11888-020-00458-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Purpose of review Molecular pathways in colorectal carcinogenesis involve several complex genetic and epigenetic modulations that cause normal colonic mucosa to metamorphose into a benign polyp and subsequently into a malignant tumor. Our purpose is to recapitulate historical and recent genomic research in order to augment the understanding of colorectal cancer pathogenesis. Recent Findings In 2015, the molecular classification for colorectal cancers was unified into one system with four distinct groups, also called as consensus molecular subtypes. This led to an enhanced understanding of molecular and immune signatures which has implications on predicting the clinical behavior as well as response to different therapeutic agents. Summary In this review, we expound on the current literature as well as draw on our own experience to present the important molecular pathogenesis pathways, key genetic mutations, differences in pathogenesis of left versus right sided tumors as well as the molecular classification of colorectal cancers.
Collapse
Affiliation(s)
- Anup Kasi
- Department of Medicine, Division of Medical Oncology, Kansas University Medical Center, Kansas City, KS, U.S.A
| | - Shivani Handa
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai West & Morningside, NY, NY
| | - Sajjad Bhatti
- Department of Medicine, Division of Medical Oncology, Kansas University Medical Center, Kansas City, KS, U.S.A
| | - Shahid Umar
- Department of Medicine, Division of Surgery, Kansas University Medical Center, Kansas City, KS, U.S.A
| | - Ajay Bansal
- Department of Medicine, Division of Gastroenterology, Kansas University Medical Center, Kansas City, KS, U.S.A
| | - Weijing Sun
- Department of Medicine, Division of Medical Oncology, Kansas University Medical Center, Kansas City, KS, U.S.A
| |
Collapse
|
|
37
|
Olafsson S, McIntyre RE, Coorens T, Butler T, Jung H, Robinson PS, Lee-Six H, Sanders MA, Arestang K, Dawson C, Tripathi M, Strongili K, Hooks Y, Stratton MR, Parkes M, Martincorena I, Raine T, Campbell PJ, Anderson CA. Somatic Evolution in Non-neoplastic IBD-Affected Colon. Cell 2020; 182:672-684.e11. [PMID: 32697969 PMCID: PMC7427325 DOI: 10.1016/j.cell.2020.06.036] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2020] [Revised: 05/01/2020] [Accepted: 06/24/2020] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease associated with increased risk of gastrointestinal cancers. We whole-genome sequenced 446 colonic crypts from 46 IBD patients and compared these to 412 crypts from 41 non-IBD controls from our previous publication on the mutation landscape of the normal colon. The average mutation rate of affected colonic epithelial cells is 2.4-fold that of healthy colon, and this increase is mostly driven by acceleration of mutational processes ubiquitously observed in normal colon. In contrast to the normal colon, where clonal expansions outside the confines of the crypt are rare, we observed widespread millimeter-scale clonal expansions. We discovered non-synonymous mutations in ARID1A, FBXW7, PIGR, ZC3H12A, and genes in the interleukin 17 and Toll-like receptor pathways, under positive selection in IBD. These results suggest distinct selection mechanisms in the colitis-affected colon and that somatic mutations potentially play a causal role in IBD pathogenesis.
Collapse
Affiliation(s)
| | | | - Tim Coorens
- Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK
| | - Timothy Butler
- Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK
| | - Hyunchul Jung
- Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK
| | - Philip S Robinson
- Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK; University of Cambridge, Department of Paediatrics, Cambridge CB2 0QQ, UK
| | - Henry Lee-Six
- Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK
| | - Mathijs A Sanders
- Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK; Department of Hematology, Erasmus University Medical Center, Postbus 2040, 3000 CA Rotterdam, the Netherlands
| | - Kenneth Arestang
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridgeshire CB2 0QQ, UK
| | - Claire Dawson
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridgeshire CB2 0QQ, UK
| | - Monika Tripathi
- Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridgeshire CB2 0QQ, UK
| | - Konstantina Strongili
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridgeshire CB2 0QQ, UK
| | - Yvette Hooks
- Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK
| | | | - Miles Parkes
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridgeshire CB2 0QQ, UK
| | | | - Tim Raine
- Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridgeshire CB2 0QQ, UK
| | | | - Carl A Anderson
- Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
| |
Collapse
|
|
38
|
Nakayama M, Oshima M. Mutant p53 in colon cancer. J Mol Cell Biol 2020; 11:267-276. [PMID: 30496442 PMCID: PMC6487790 DOI: 10.1093/jmcb/mjy075] [Citation(s) in RCA: 177] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 11/13/2018] [Accepted: 11/27/2018] [Indexed: 12/13/2022] Open
Abstract
The accumulation of genetic alterations in driver genes is responsible for the development and malignant progression of colorectal cancer. Comprehensive genome analyses have revealed the driver genes, including APC, KRAS, TGFBR2, and TP53, whose mutations are frequently found in human colorectal cancers. Among them, the p53 mutation is found in ~60% of colorectal cancers, and a majority of mutations are missense-type at ‘hot spots’, suggesting an oncogenic role of mutant p53 by ‘gain-of-function’ mechanisms. Mouse model studies have shown that one of these missense-type mutations, p53 R270H (corresponding to human R273H), causes submucosal invasion of intestinal tumors, while the loss of wild-type p53 has a limited effect on the invasion process. Furthermore, the same mutant p53 promotes metastasis when combined with Kras activation and TGF-β suppression. Importantly, either missense-type p53 mutation or loss of wild-type p53 induces NF-κB activation by a variety of mechanisms, such as increasing promoter accessibility by chromatin remodeling, which may contribute to progression to epithelial–mesenchymal transition. These results indicate that missense-type p53 mutations together with loss of wild-type p53 accelerate the late stage of colorectal cancer progression through the activation of both oncogenic and inflammatory pathways. Accordingly, the suppression of the mutant p53 function via the inhibition of nuclear accumulation is expected to be an effective strategy against malignant progression of colorectal cancer.
Collapse
Affiliation(s)
- Mizuho Nakayama
- Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.,WPI-Nano Life Science Institute, Kanazawa University, Kanazawa, Japan
| | - Masanobu Oshima
- Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.,WPI-Nano Life Science Institute, Kanazawa University, Kanazawa, Japan
| |
Collapse
|
|
39
|
Garcia PM, Moore J, Kahan D, Hong MY. Effects of Vitamin D Supplementation on Inflammation, Colonic Cell Kinetics, and Microbiota in Colitis: A Review. Molecules 2020; 25:molecules25102300. [PMID: 32422882 PMCID: PMC7288056 DOI: 10.3390/molecules25102300] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 05/06/2020] [Accepted: 05/12/2020] [Indexed: 02/06/2023] Open
Abstract
Vitamin D is widely known to regulate bone health, but there is increasing evidence that it may also ameliorate colitis through inflammation, cell proliferation and apoptosis, and the microbiota. The purpose of this review is to systematically examine the mechanisms by which vitamin D reduces colitis. PubMed and Web of Science were searched for articles published between 2008 and 2019 using key words such as "vitamin D," "colitis," "inflammatory bowel disease," "inflammation," "apoptosis," "cell proliferation," and "gut bacteria". Retrieved articles were further narrowed and it was determined whether their title and abstracts contained terminology pertaining to vitamin D in relation to colitis in human clinical trials, animal studies, and cell culture/biopsy studies, as well as selecting the best match sorting option in relation to the research question. In total, 30 studies met the established criteria. Studies consistently reported results showing that vitamin D supplementation can downregulate inflammatory pathways of COX-2, TNF-α, NF-κB, and MAPK, modify cell kinetics, and alter gut microbiome, all of which contribute to an improved state of colitis. Although vitamin D and vitamin D analogs have demonstrated positive effects against colitis, more randomized, controlled human clinical trials are needed to determine the value of vitamin D as a therapeutic agent in the treatment of colitis.
Collapse
|
|
40
|
Genetic and epigenetic factors interacting with clonal hematopoiesis resulting in chronic myelomonocytic leukemia. Curr Opin Hematol 2019; 27:2-10. [PMID: 31688455 DOI: 10.1097/moh.0000000000000553] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE OF REVIEW Since 2016, the WHO has recognized the significant phenotypic heterogeneity of chronic myelomonocytic leukemia (CMML) as a myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap disease. Although sharing many somatic mutations with MDS and MPN, the purpose of this review is to put recent biological findings of CMML in the context of evolutionary theory, highlighting it as a distinct evolutionary trajectory occurring in the context of clonal hematopoiesis. RECENT FINDINGS Clonal hematopoiesis of indeterminate potential (CHIP), with a mutational spectrum and prevalence correlated with age, has been defined. Enriched in DNMT3A, TET2, and ASXL1 mutations, clonal evolution can progress into various evolutionary trajectories including CMML. Impact of founder mutations (primarily TET2) on increased hematopoietic stem cell fitness has been well characterized. Epistatic interactions between mutations and epigenetic events have been explored, both in CMML and its pediatric counterpart juvenile myelomonocytic leukemia, including CMML transformation to acute myeloid leukemia. Together, these findings have contributed significantly toward CMML evolutionary dynamics. SUMMARY Despite relatively few 'driver' mutations in CMML, evolutionary development of chronic leukemia remains incompletely understood. Recent studies have shed light on the importance of studying epigenetic consequences of mutations and epistasis between key mutations to better understand clonal architecture and evolutionary dynamics.
Collapse
|
|
41
|
Guo M, Peng Y, Gao A, Du C, Herman JG. Epigenetic heterogeneity in cancer. Biomark Res 2019; 7:23. [PMID: 31695915 PMCID: PMC6824025 DOI: 10.1186/s40364-019-0174-y] [Citation(s) in RCA: 140] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 10/10/2019] [Indexed: 12/15/2022] Open
Abstract
Phenotypic and functional heterogeneity is one of the hallmarks of human cancers. Tumor genotype variations among tumors within different patients are known as interpatient heterogeneity, and variability among multiple tumors of the same type arising in the same patient is referred to as intra-patient heterogeneity. Subpopulations of cancer cells with distinct phenotypic and molecular features within a tumor are called intratumor heterogeneity (ITH). Since Nowell proposed the clonal evolution of tumor cell populations in 1976, tumor heterogeneity, especially ITH, was actively studied. Research has focused on the genetic basis of cancer, particularly mutational activation of oncogenes or inactivation of tumor-suppressor genes (TSGs). The phenomenon of ITH is commonly explained by Darwinian-like clonal evolution of a single tumor. Despite the monoclonal origin of most cancers, new clones arise during tumor progression due to the continuous acquisition of mutations. It is clear that disruption of the "epigenetic machinery" plays an important role in cancer development. Aberrant epigenetic changes occur more frequently than gene mutations in human cancers. The epigenome is at the intersection of the environment and genome. Epigenetic dysregulation occurs in the earliest stage of cancer. The current trend of epigenetic therapy is to use epigenetic drugs to reverse and/or delay future resistance to cancer therapies. A majority of cancer therapies fail to achieve durable responses, which is often attributed to ITH. Epigenetic therapy may reverse drug resistance in heterogeneous cancer. Complete understanding of genetic and epigenetic heterogeneity may assist in designing combinations of targeted therapies based on molecular information extracted from individual tumors.
Collapse
Affiliation(s)
- Mingzhou Guo
- 1Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, 40 Daxue Road, Zhengzhou, Henan 450052 China
| | - Yaojun Peng
- 1Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - Aiai Gao
- 1Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - Chen Du
- 1Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - James G Herman
- 3The Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Ave., Pittsburgh, PA 15213 USA
| |
Collapse
|
|
42
|
Mutaguchi M, Naganuma M, Sugimoto S, Fukuda T, Nanki K, Mizuno S, Hosoe N, Shimoda M, Ogata H, Iwao Y, Kanai T. Difference in the clinical characteristic and prognosis of colitis-associated cancer and sporadic neoplasia in ulcerative colitis patients. Dig Liver Dis 2019; 51:1257-1264. [PMID: 31151895 DOI: 10.1016/j.dld.2019.05.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 04/27/2019] [Accepted: 05/02/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Although various studies have been conducted on colitis-associated cancer (CAC), few have assessed the differences in the clinical and endoscopic features, treatment, and prognosis of CAC and sporadic neoplasia (SN) in the inflamed mucosa of ulcerative colitis (UC) patients. AIMS To compare the characteristics of CAC and SN within the previously or currently inflamed mucosa. METHODS Between 1997 and 2017, we retrospectively analyzed the endoscopic chart data of 348 colonic lesions from 266 UC patients. Non-dysplastic lesions and lesions located outside the inflamed mucosa were excluded. The diagnosis of CAC or SN was confirmed by conventional histopathological and immunohistochemical evaluation of p53 and Ki67. RESULTS In total, 74 patients with CAC (97 lesions) and 46 with SN (58) were enrolled. The proportions of patients with a younger age of onset of UC, with chronic persistent UC, and with severe inflamed mucosa were significantly higher in the CAC group. In the SN group, no flat lesions were found, whereas 26% of the lesions in the CAC group were flat. Sixteen patients died during a median follow-up of 6.1 years (interquartile range (IQR) 1.8-11.1)in the CAC group, whereas 1 patient died during a median follow-up 3.2 years(IQR 1.4-4.6) in the SN group. Mortality from colorectal cancer was significantly higher (P = 0.015) in the CAC group (12/68; 17.6%) than in the SN group (1/44; 2.3%). The 5-year survival rate was 100% in the SN group and 97% in the CAC group for lesions located in the mucosa or submucosa. CONCLUSION Recognizing differences in the characteristics of CAC and SN within the inflamed mucosa is critical to avoid unnecessary total colectomy in patients with SN.
Collapse
Affiliation(s)
- Makoto Mutaguchi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Makoto Naganuma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
| | - Shinya Sugimoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Tomohiro Fukuda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Kosaku Nanki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Shinta Mizuno
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Naoki Hosoe
- Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Tokyo, Japan
| | - Masayuki Shimoda
- Department of Pathology, Keio University School of Medicine, Tokyo, Japan
| | - Haruhiko Ogata
- Center for Diagnostic and Therapeutic Endoscopy, Keio University School of Medicine, Tokyo, Japan
| | - Yasushi Iwao
- Center for Preventive Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Takanori Kanai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
| |
Collapse
|
|
43
|
Del Puerto-Nevado L, Santiago-Hernandez A, Solanes-Casado S, Gonzalez N, Ricote M, Corton M, Prieto I, Mas S, Sanz AB, Aguilera O, Gomez-Guerrero C, Ayuso C, Ortiz A, Rojo F, Egido J, Garcia-Foncillas J, Minguez P, Alvarez-Llamas G. Diabetes-mediated promotion of colon mucosa carcinogenesis is associated with mitochondrial dysfunction. Mol Oncol 2019; 13:1887-1897. [PMID: 31199051 PMCID: PMC6717745 DOI: 10.1002/1878-0261.12531] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 06/03/2019] [Accepted: 06/11/2019] [Indexed: 01/28/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) has been associated with an increased risk of cancer, including colon cancer (CC). However, we recently reported no influence of T2DM on CC prognosis, suggesting that any effect might be at the early stages of tumor development. We hypothesized that T2DM may create an environment in the healthy tissue, which acts as a carcinogenesis driver in agreement with the field of cancerization concept. Here, we focused on early carcinogenesis by analyzing paired tumor and normal colonic mucosa samples from the same patients. The proteome of CC and paired mucosa was quantitatively analyzed in 28 individuals (12 diabetics and 16 nondiabetics) by mass spectrometry with isobaric labeling. Out of 3076 identified proteins, 425 were differentially expressed at the tumor in diabetics compared with nondiabetics. In the adjacent mucosa, 143 proteins were differentially expressed in diabetics and nondiabetics. An enrichment analysis of this signature pointed to mitochondria, ribosome, and translation. Only six proteins were upregulated by diabetes both in tumor and mucosa, of which five were mitochondrial proteins. Differential expression in diabetic versus nondiabetic mucosa was confirmed for MRPL53, MRPL18, and TIMM8B. Higher levels of MRPL18, TIMM8B, and EIF1A were also found in normal colon epithelial cells exposed to high‐glucose conditions. We conclude that T2DM is associated with specific molecular changes in the normal mucosa of CC patients, consistent with field of cancerization in a diabetic environment. The mitochondrial protein signature identifies a potential therapeutic target that could underlie the higher risk of CC in diabetics.
Collapse
Affiliation(s)
- Laura Del Puerto-Nevado
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | | | - Sonia Solanes-Casado
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Nieves Gonzalez
- Renal, Vascular and Diabetes Research Laboratory, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Marta Ricote
- Renal, Vascular and Diabetes Research Laboratory, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Marta Corton
- Genetics Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain.,Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
| | - Isabel Prieto
- Radiation Oncology, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Sebastian Mas
- Renal, Vascular and Diabetes Research Laboratory, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Ana Belen Sanz
- Nephrology and Hypertension Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Oscar Aguilera
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Carmen Gomez-Guerrero
- Renal, Vascular and Diabetes Research Laboratory, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Carmen Ayuso
- Genetics Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain.,Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
| | - Alberto Ortiz
- Nephrology and Hypertension Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Federico Rojo
- Pathology Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Jesus Egido
- Renal, Vascular and Diabetes Research Laboratory, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Jesus Garcia-Foncillas
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Pablo Minguez
- Genetics Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Gloria Alvarez-Llamas
- Immunology Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain.,REDINREN, Madrid, Spain
| | | |
Collapse
|
|
44
|
Baker AM, Cross W, Curtius K, Al Bakir I, Choi CHR, Davis HL, Temko D, Biswas S, Martinez P, Williams MJ, Lindsay JO, Feakins R, Vega R, Hayes SJ, Tomlinson IPM, McDonald SAC, Moorghen M, Silver A, East JE, Wright NA, Wang LM, Rodriguez-Justo M, Jansen M, Hart AL, Leedham SJ, Graham TA. Evolutionary history of human colitis-associated colorectal cancer. Gut 2019; 68:985-995. [PMID: 29991641 PMCID: PMC6580738 DOI: 10.1136/gutjnl-2018-316191] [Citation(s) in RCA: 113] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Revised: 06/01/2018] [Accepted: 06/02/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE IBD confers an increased lifetime risk of developing colorectal cancer (CRC), and colitis-associated CRC (CA-CRC) is molecularly distinct from sporadic CRC (S-CRC). Here we have dissected the evolutionary history of CA-CRC using multiregion sequencing. DESIGN Exome sequencing was performed on fresh-frozen multiple regions of carcinoma, adjacent non-cancerous mucosa and blood from 12 patients with CA-CRC (n=55 exomes), and key variants were validated with orthogonal methods. Genome-wide copy number profiling was performed using single nucleotide polymorphism arrays and low-pass whole genome sequencing on archival non-dysplastic mucosa (n=9), low-grade dysplasia (LGD; n=30), high-grade dysplasia (HGD; n=13), mixed LGD/HGD (n=7) and CA-CRC (n=19). Phylogenetic trees were reconstructed, and evolutionary analysis used to reveal the temporal sequence of events leading to CA-CRC. RESULTS 10/12 tumours were microsatellite stable with a median mutation burden of 3.0 single nucleotide alterations (SNA) per Mb, ~20% higher than S-CRC (2.5 SNAs/Mb), and consistent with elevated ageing-associated mutational processes. Non-dysplastic mucosa had considerable mutation burden (median 47 SNAs), including mutations shared with the neighbouring CA-CRC, indicating a precancer mutational field. CA-CRCs were often near triploid (40%) or near tetraploid (20%) and phylogenetic analysis revealed that copy number alterations (CNAs) began to accrue in non-dysplastic bowel, but the LGD/HGD transition often involved a punctuated 'catastrophic' CNA increase. CONCLUSIONS Evolutionary genomic analysis revealed precancer clones bearing extensive SNAs and CNAs, with progression to cancer involving a dramatic accrual of CNAs at HGD. Detection of the cancerised field is an encouraging prospect for surveillance, but punctuated evolution may limit the window for early detection.
Collapse
Affiliation(s)
- Ann-Marie Baker
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - William Cross
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Kit Curtius
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Ibrahim Al Bakir
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Inflammatory Bowel Disease Unit, St Mark’s Hospital, London, UK
| | - Chang-Ho Ryan Choi
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Inflammatory Bowel Disease Unit, St Mark’s Hospital, London, UK
| | | | - Daniel Temko
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Department of Computer Science, University College London, London, UK
- Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, London, UK
| | - Sujata Biswas
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Pierre Martinez
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Marc J Williams
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, London, UK
- Department of Cell and Developmental Biology, University College London, London, UK
| | - James O Lindsay
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Roger Feakins
- Department of Histopathology, The Royal London Hospital, London, UK
| | - Roser Vega
- Department of Gastroenterology, University College London Hospital, London, UK
| | - Stephen J Hayes
- Department of Histopathology, Salford Royal NHS Foundation Trust, University of Manchester, Manchester, UK
| | - Ian P M Tomlinson
- Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Stuart A C McDonald
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Morgan Moorghen
- Inflammatory Bowel Disease Unit, St Mark’s Hospital, London, UK
| | - Andrew Silver
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - James E East
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Nicholas A Wright
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Lai Mun Wang
- Cellular Pathology, John Radcliffe Hospital, Oxford, UK
| | | | - Marnix Jansen
- Department of Histopathology, University College London Hospital, London, UK
| | - Ailsa L Hart
- Inflammatory Bowel Disease Unit, St Mark’s Hospital, London, UK
| | - Simon J Leedham
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
- Translational Gastroenterology Unit, Nuffield Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
| | - Trevor A Graham
- Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| |
Collapse
|
|
45
|
van der Heijden M, Vermeulen L. Stem cells in homeostasis and cancer of the gut. Mol Cancer 2019; 18:66. [PMID: 30927915 PMCID: PMC6441158 DOI: 10.1186/s12943-019-0962-x] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 02/20/2019] [Indexed: 12/14/2022] Open
Abstract
The intestinal epithelial lining is one of the most rapidly renewing cell populations in the body. As a result, the gut has been an attractive model to resolve key mechanisms in epithelial homeostasis. In particular the role of intestinal stem cells (ISCs) in the renewal process has been intensely studied. Interestingly, as opposed to the traditional stem cell theory, the ISC is not a static population but displays significant plasticity and in situations of tissue regeneration more differentiated cells can revert back to a stem cell state upon exposure to extracellular signals. Importantly, normal intestinal homeostasis provides important insight into mechanisms that drive colorectal cancer (CRC) development and growth. Specifically, the dynamics of cancer stem cells bear important resemblance to ISC functionality. In this review we present an overview of the current knowledge on ISCs in homeostasis and their role in malignant transformation. Also, we discuss the existence of stem cells in intestinal adenomas and CRC and how these cells contribute to (pre-)malignant growth. Furthermore, we will focus on new paradigms in the field of dynamical cellular hierarchies in CRC and the intimate relationship between tumor cells and their niche.
Collapse
Affiliation(s)
- Maartje van der Heijden
- Amsterdam UMC, University of Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Meibergdreef 9, 1105, Amsterdam, AZ, Netherlands
| | - Louis Vermeulen
- Amsterdam UMC, University of Amsterdam, Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Meibergdreef 9, 1105, Amsterdam, AZ, Netherlands.
| |
Collapse
|
|
46
|
Del Puerto-Nevado L, Minguez P, Corton M, Solanes-Casado S, Prieto I, Mas S, Sanz AB, Gonzalez-Alonso P, Villaverde C, Portal-Nuñez S, Aguilera O, Gomez-Guerrero C, Esbrit P, Vivanco F, Gonzalez N, Ayuso C, Ortiz A, Rojo F, Egido J, Alvarez-Llamas G, Garcia-Foncillas J. Molecular evidence of field cancerization initiated by diabetes in colon cancer patients. Mol Oncol 2019; 13:857-872. [PMID: 30628165 PMCID: PMC6441931 DOI: 10.1002/1878-0261.12438] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2018] [Revised: 12/01/2018] [Accepted: 12/27/2018] [Indexed: 12/20/2022] Open
Abstract
The potential involvement of type 2 diabetes mellitus (T2DM) as a risk factor for colon cancer (CC) has been previously reported. While several clinical studies show a higher incidence of CC and a lower survival rate in diabetics, others report no association. Our own experience indicates that diabetes does not seem to worsen the prognosis once the tumor is present. Despite this controversy, there are no wide‐spectrum molecular studies that delve into the impact of T2DM‐related mechanisms in colon carcinogenesis. Here, we present a transcriptomic and proteomic profiling of paired tumor and normal colon mucosa samples in a cohort of 42 CC patients, 23 of which have T2DM. We used gene set enrichment and network approaches to extract relevant pathways in diabetics, referenced them to current knowledge, and tested them using in vitro techniques. Through our transcriptomics approach, we identified an unexpected overlap of pathways overrepresented in diabetics compared to nondiabetics, in both tumor and normal mucosa, including diabetes‐related metabolic and signaling processes. Proteomic approaches highlighted several cancer‐related signaling routes in diabetics found only in normal mucosa, not in tumors. An integration of the transcriptome and proteome analyses suggested the deregulation of key pathways related to colon carcinogenesis which converged on tumor initiation axis TEAD/YAP‐TAZ as a potential initiator of the process. In vitro studies confirmed upregulation of this pathway in nontumor colon cells under high‐glucose conditions. In conclusion, T2DM associates with deregulation of cancer‐related processes in normal colon mucosa adjacent to tissue which has undergone a malignant transformation. These data support that in diabetic patients, the local microenvironment in normal colon mucosa may be a factor driving field cancerization promoting carcinogenesis. Our results set a new framework to study links between diabetes and colon cancer, including a new role of the TEAD/YAP‐TAZ complex as a potential driver.
Collapse
Affiliation(s)
- Laura Del Puerto-Nevado
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Pablo Minguez
- Genetics Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Marta Corton
- Genetics Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain.,Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
| | - Sonia Solanes-Casado
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Isabel Prieto
- Radiation Oncology, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Sebastian Mas
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Ana Belen Sanz
- Nephrology and Hypertension Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain.,REDINREN, Madrid, Spain
| | | | - Cristina Villaverde
- Genetics Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain.,Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
| | - Sergio Portal-Nuñez
- Bone and Mineral Metabolism Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain.,Applied Molecular Medicine Institute, School of Medicine, Universidad San Pablo CEU, CEU Universities, Madrid, Spain
| | - Oscar Aguilera
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Carmen Gomez-Guerrero
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Pedro Esbrit
- Bone and Mineral Metabolism Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Fernando Vivanco
- Immunoallergy and Proteomics Laboratory, Immunology Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Nieves Gonzalez
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Carmen Ayuso
- Genetics Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain.,Center for Biomedical Network Research on Rare Diseases (CIBERER), ISCIII, Madrid, Spain
| | - Alberto Ortiz
- Nephrology and Hypertension Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain.,REDINREN, Madrid, Spain
| | - Federico Rojo
- Pathology Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Jesus Egido
- Renal, Vascular and Diabetes Research Laboratory, IIS-Fundacion Jimenez Diaz-UAM, Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain
| | - Gloria Alvarez-Llamas
- REDINREN, Madrid, Spain.,Immunoallergy and Proteomics Laboratory, Immunology Department, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | - Jesus Garcia-Foncillas
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| | -
- Translational Oncology Division, Oncohealth Institute, IIS-Fundacion Jimenez Diaz-UAM, Madrid, Spain
| |
Collapse
|
|
47
|
Haberman Y, Karns R, Dexheimer PJ, Schirmer M, Somekh J, Jurickova I, Braun T, Novak E, Bauman L, Collins MH, Mo A, Rosen MJ, Bonkowski E, Gotman N, Marquis A, Nistel M, Rufo PA, Baker SS, Sauer CG, Markowitz J, Pfefferkorn MD, Rosh JR, Boyle BM, Mack DR, Baldassano RN, Shah S, Leleiko NS, Heyman MB, Grifiths AM, Patel AS, Noe JD, Aronow BJ, Kugathasan S, Walters TD, Gibson G, Thomas SD, Mollen K, Shen-Orr S, Huttenhower C, Xavier RJ, Hyams JS, Denson LA. Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response. Nat Commun 2019; 10:38. [PMID: 30604764 PMCID: PMC6318335 DOI: 10.1038/s41467-018-07841-3] [Citation(s) in RCA: 216] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Accepted: 11/28/2018] [Indexed: 02/07/2023] Open
Abstract
Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α4β7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.
Collapse
Affiliation(s)
- Yael Haberman
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
- Sheba Medical Center, Tel Hashomer, affiliated with the Tel Aviv University, Tel Aviv, 5265601, Israel
| | - Rebekah Karns
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
| | - Phillip J Dexheimer
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
| | - Melanie Schirmer
- Broad Institute of MIT and Harvard University, Cambridge, 02142, MA, USA
| | - Judith Somekh
- Faculty of Medicine, Technion, Haifa, 3109601, Israel
- Department of Information Systems, University of Haifa, Haifa, 3498838, Israel
| | - Ingrid Jurickova
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
| | - Tzipi Braun
- Sheba Medical Center, Tel Hashomer, affiliated with the Tel Aviv University, Tel Aviv, 5265601, Israel
| | - Elizabeth Novak
- Children's Hospital of Pittsburgh, Pittsburgh, 15224, PA, USA
| | - Laura Bauman
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
- Department of Pediatrics, University of California at San Diego, La Jolla, 92162, CA, USA
| | - Margaret H Collins
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
| | - Angela Mo
- Georgia Institute of Technology, Atlanta, 30332, GA, USA
| | - Michael J Rosen
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
| | - Erin Bonkowski
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
| | - Nathan Gotman
- Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill, 27516, NC, USA
| | - Alison Marquis
- Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill, 27516, NC, USA
| | - Mason Nistel
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
| | - Paul A Rufo
- Harvard-Children's Hospital Boston, Boston, 02115, MA, USA
| | - Susan S Baker
- Women & Children's Hospital of Buffalo WCHOB, Buffalo, 14222, NY, USA
| | | | - James Markowitz
- Cohen Children's Medical Center of New York, 11040, New Hyde Park, NY, USA
| | | | - Joel R Rosh
- Goryeb Children's Hospital-Atlantic Health, Morristown, 07960, NJ, USA
| | | | - David R Mack
- Children's Hospital of East Ontario, Ottawa, Ontario, K1P 1J1, Canada
| | | | - Sapana Shah
- Children's Hospital of Pittsburgh of UPMC, Pittsburgh, 15224, PA, USA
| | | | - Melvin B Heyman
- University of California at San Francisco, San Francisco, 94143, CA, USA
| | | | | | - Joshua D Noe
- Medical College of Wisconsin, Milwaukee, 53226, WI, USA
| | - Bruce J Aronow
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA
| | | | | | - Greg Gibson
- Georgia Institute of Technology, Atlanta, 30332, GA, USA
| | - Sonia Davis Thomas
- Collaborative Studies Coordinating Center, University of North Carolina, Chapel Hill, 27516, NC, USA
- RTI International, Research Triangle Park, 27709, NC, USA
| | - Kevin Mollen
- Children's Hospital of Pittsburgh, Pittsburgh, 15224, PA, USA
| | - Shai Shen-Orr
- Faculty of Medicine, Technion, Haifa, 3109601, Israel
| | - Curtis Huttenhower
- Broad Institute of MIT and Harvard University, Cambridge, 02142, MA, USA
- Harvard School of Public Health, Boston, 02115, MA, USA
| | - Ramnik J Xavier
- Broad Institute of MIT and Harvard University, Cambridge, 02142, MA, USA
- Massachusetts General Hospital, Harvard Medical School, Boston, 02114, MA, USA
| | - Jeffrey S Hyams
- Connecticut Children's Medical Center, Hartford, 06106, CT, USA
| | - Lee A Denson
- Cincinnati Children's Hospital Medical Center, and the University of Cincinnati College of Medicine, 45229, Cincinnati, OH, USA.
| |
Collapse
|
|
48
|
Beggs AD, Mehta S, Deeks JJ, James JD, Caldwell GM, Dilworth MP, Stockton JD, Blakeway D, Pestinger V, Vince A, Taniere P, Iqbal T, Magill L, Matthews G, Morton DG. Validation of epigenetic markers to identify colitis associated cancer: Results of module 1 of the ENDCAP-C study. EBioMedicine 2019; 39:265-271. [PMID: 30473377 PMCID: PMC6355942 DOI: 10.1016/j.ebiom.2018.11.034] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 10/04/2018] [Accepted: 11/16/2018] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Chronic inflammation caused by ulcerative colitis (UC) causes a pro-neoplastic drive in the inflamed colon, leading to a markedly greater risk of invasive malignancy compared to the general population. Despite surveillance protocols, 50% of cases proceed to cancer before neoplasia is detected. The Enhanced Neoplasia Detection and Cancer Prevention in Chronic Colitis (ENDCaP-C) trial is an observational multi-centre test accuracy study to ascertain the role of molecular markers in improving the detection of dysplasia. We aimed to validate previously identified biomarkers of neoplasia in a retrospective cohort and create predictive models for later validation in a prospective cohort. METHODS A retrospective analysis using bisulphite pyrosequencing of an 11 marker panel (SFRP1, SFRP2, SRP4, SRP5, WIF1, TUBB6, SOX7, APC1A, APC2, MINT1, RUNX3) in samples from 35 patients with cancer, 78 with dysplasia and 343 without neoplasia undergoing surveillance for UC associated neoplasia across 6 medical centres. Predictive models for UC associated cancer/dysplasia were created in the setting of neoplastic and non-neoplastic mucosa. FINDINGS For neoplastic mucosa a five marker panel (SFRP2, SFRP4, WIF1, APC1A, APC2) was accurate in detecting pre-cancerous and invasive neoplasia (AUC = 0.83; 95% CI: 0.79, 0.88), and dysplasia (AUC = 0.88; (0.84, 0.91). For non-neoplastic mucosa a four marker panel (APC1A, SFRP4, SFRP5, SOX7) had modest accuracy (AUC = 0.68; 95% CI: 0.62,0.73) in predicting associated bowel neoplasia through the methylation signature of distant non-neoplastic colonic mucosa. INTERPRETATION This multiplex methylation marker panel is accurate in the detection of ulcerative colitis associated dysplasia and neoplasia and is currently being validated in a prospective clinical trial. FUNDING The ENDCAP-C study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) Programme (11/100/29).
Collapse
Affiliation(s)
- Andrew D Beggs
- Institute of Cancer & Genomic Science, University of Birmingham, UK.
| | - Samir Mehta
- Birmingham Clinical Trials Unit, University of Birmingham, UK
| | - Jonathan J Deeks
- Birmingham Clinical Trials Unit, University of Birmingham, UK; National Institute for Health Research (NIHR), Birmingham Inflammation Biomedical Research Centre, UK
| | - Jonathan D James
- Institute of Cancer & Genomic Science, University of Birmingham, UK
| | | | - Mark P Dilworth
- Institute of Cancer & Genomic Science, University of Birmingham, UK
| | | | - Daniel Blakeway
- Institute of Cancer & Genomic Science, University of Birmingham, UK
| | | | - Alexandra Vince
- Birmingham Clinical Trials Unit, University of Birmingham, UK
| | | | - Tariq Iqbal
- Institute of Cancer & Genomic Science, University of Birmingham, UK
| | - Laura Magill
- Birmingham Clinical Trials Unit, University of Birmingham, UK
| | - Glenn Matthews
- Institute of Cancer & Genomic Science, University of Birmingham, UK
| | - Dion G Morton
- Institute of Cancer & Genomic Science, University of Birmingham, UK
| |
Collapse
|
|
49
|
Badr EAE, Ali Assar MF, Gohar SF, Badr MH, Hathout RM, El-Kousy SM. The clinical impact of miRNA34a and P53 gene expression in colon cancer. Biochem Biophys Rep 2018; 16:88-95. [PMID: 30377673 PMCID: PMC6202666 DOI: 10.1016/j.bbrep.2018.10.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 08/22/2018] [Accepted: 10/05/2018] [Indexed: 12/12/2022] Open
Abstract
Objective To study the potential role of miRNA34a gene expression and its relationship with P53 gene expression, fate, stage, metastasis and overall survival of colorectal cancer. Patients and methods This study was carried out 30 patients with colon adenocarcinoma, 30 patients with benign colon polyp and 30 apparently healthy persons served as controls. All participants were subjected to full history taking, general clinical examination. Complete blood count, liver and kidney function, determination of serum tumor markers were done. Estimation of microRNA 34a and P53 Gene expression by real-time PCR were done. Results There was a significant negative relationship between serum tumor markers and micro RNA 34a gene expression in cancer patients. Also, there was a statistically significant positive relationship between miRNA34a gene expression and P53 gene expression in both patients groups. The diagnostic accuracy of miRNA34a gene expression was both sensitive and specific for colon cancer. MiRNA34a and P53 gene expression had statistically significant relation with tumor stage and presence of metastases. Conclusion It can be concluded that the level of miRNA34a can be used to differentiate between colon cancers and begin adenomas. MiRNA34a can be used as a prognostic marker in colon cancer.
MiRNA34a has an important role in colon cancer. Presence of correlation between P53 and miRNA34a gene expression. MiRNA34a can be used as a prognostic marker in colon cancer. MiRNA34a can be used to differentiate between colon cancer and benign adenoma.
Collapse
Affiliation(s)
- Eman A E Badr
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine - Menoufia University, Egypt
| | - Mohamed Farag Ali Assar
- Department of Chemistry, Biochemistry Division, Faculty of science - Menoufia University, Egypt
| | - Suzy F Gohar
- Department of Clinical Oncology, Faculty of Medicine - Menoufia University, Egypt
| | - Mohamed Hamdy Badr
- Department of Internal Medicine, Faculty of Medicine - Menoufia University, Egypt
| | | | | |
Collapse
|
|
50
|
Granofszky N, Lang M, Khare V, Schmid G, Scharl T, Ferk F, Jimenez K, Knasmüller S, Campregher C, Gasche C. Identification of PMN-released mutagenic factors in a co-culture model for colitis-associated cancer. Carcinogenesis 2018; 39:146-157. [PMID: 29106440 PMCID: PMC5826597 DOI: 10.1093/carcin/bgx118] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2016] [Accepted: 10/30/2017] [Indexed: 02/07/2023] Open
Abstract
Microsatellite instability (MSI) is present in ulcerative colitis (UC) and colitis-associated colorectal cancers (CAC). Certain factors released by polymorphonuclear cells (PMNs) may drive mucosal frameshift mutations resulting in MSI and cancer. Here, we applied a co-culture system with PMNs and colon epithelial cells to identify such culprit factors. Subjecting HCT116 + chr3 and human colonic epithelial cells (HCEC)-1CT MSI-reporter cell lines harboring mono-, di- or tetranucleotide DNA repeats linked to enhanced green fluorescent protein (EGFP) to activated PMNs induced frameshift mutations within all repeats, as quantified by flow cytometry. Activated PMNs released superoxide and hydrogen peroxide (H2O2), as measured by lucigenin-amplified chemiluminescence and fluorometry, respectively. Catalase, which scavenges H2O2, reduced such PMN-induced MSI. The NADPH-oxidase inhibitor apocynin, which blocks the oxidative burst in PMNs, similarly inhibited PMN-induced MSI. A bead-based multiplex assay revealed that PMNs release a wide range of cytokines such as interleukin (IL)-8, IL-6 and tumor necrosis factor-α (TNF-α). In vitro, these cytokines increased MSI in colon epithelial cells, and the Janus kinase (JAK) inhibitor tofacitinib abolished IL-6-induced or PMN-induced MSI. Intracellular reactive oxygen species (ROS) formation, as measured by 2’,7’–dichlorofluorescein diacetate (DCFDA) assay, was induced upon cytokine treatment. DNA oxidation upon IL-6 was present, as detected by formamidopyrimidine glycosylase (FPG)-modified comet assay. In conclusion, activated PMNs induce frameshift mutations in colon epithelial cells resulting in MSI. Both oxidative burst with release of ROS and PMN-secreted cytokines, such as IL-8, IL-6 or TNF-α, contribute to MSI. ROS scavengers and/or specific inhibitors of cytokine signaling may delay or prevent cancer development in the setting of colitis.
Collapse
Affiliation(s)
- Nicolas Granofszky
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.,Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Michaela Lang
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.,Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Vineeta Khare
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.,Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Gerald Schmid
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.,Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Theresa Scharl
- ACIB GmbH, c/o Institute of Applied Statistics and Computing, University of Natural Resources and Life Sciences, Vienna, Austria
| | - Franziska Ferk
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Kristine Jimenez
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.,Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Siegfried Knasmüller
- Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria
| | - Christoph Campregher
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.,Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| | - Christoph Gasche
- Christian Doppler Laboratory for Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria.,Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria.,Department of Medicine 3, Medical University of Vienna, Vienna, Austria
| |
Collapse
|