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1
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Liu M, Liu Q, Hu K, Dong Y, Sun X, Zou Z, Ji D, Liu T, Yu Y. Colorectal cancer with BRAF V600E mutation: Trends in immune checkpoint inhibitor treatment. Crit Rev Oncol Hematol 2024; 204:104497. [PMID: 39245296 DOI: 10.1016/j.critrevonc.2024.104497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 08/29/2024] [Accepted: 08/31/2024] [Indexed: 09/10/2024] Open
Abstract
Colorectal cancer (CRC) with BRAF V600E mutation presents a formidable scientific and clinical challenge due to its aggressive nature and poor response to standard therapeutic approaches. BRAF V600E mutation-induced conspicuous activation of the MAPK pathway contributes to the relentless tumor progression. Nevertheless, the efficacy of multi-targeted MAPK pathway inhibition remains suboptimal in clinical practice. Patients with high microsatellite instability (MSI-H) have shown favorable results with immune checkpoint inhibitors (ICIs). The combination of the MAPK pathway inhibition with ICIs has recently emerged as a promising regimen to improve clinical outcomes in the microsatellite stable (MSS) subgroup of BRAF V600E-mutant metastatic CRC patients. In this review, we elucidate the unique tumor biology of BRAF V600E-mutant CRC, with a particular focus on the immune features underlying the rationale for ICI treatments in the MSI-H and MSS subpopulations, then highlight the trends in clinical trials of the ICI therapy for BRAF V600E-mutant metastatic CRC.
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Affiliation(s)
- Mengling Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Qing Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Keshu Hu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yu Dong
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xun Sun
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhiguo Zou
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Dingkun Ji
- Institute of Molecular Medicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Tianshu Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
| | - Yiyi Yu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China; Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
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2
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Ikuta S, Saito Y, Takata S, Nakatani Y, Nagatomo I, Shiba S, Takeda Y, Totoki Y, Mizutani S, Sunakawa H, Ikematsu H, Takamaru H, Kumanogoh A, Yachida S. Variability in non-tumor areas of colorectal cancer patients as revealed by endoscopic intestinal step biopsies. Mol Cancer 2024; 23:249. [PMID: 39511621 PMCID: PMC11546198 DOI: 10.1186/s12943-024-02159-9] [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: 09/08/2024] [Accepted: 10/15/2024] [Indexed: 11/15/2024] Open
Abstract
A comprehensive endoscopic small and large intestinal untargeted step biopsy procedure was conducted to compare gene expression between the normal intestinal mucosa of healthy individuals and that of patients with colorectal tumors. From 78 participants (healthy individuals [n = 17], patients with colorectal conventional adenomas [n = 6], patients with Tis-T1 colorectal cancer [n = 41], patients with T2-4 colorectal cancer [n = 14]), biopsies of normal mucosa of the terminal ileum, right-sided colon (cecum and ascending colon), and left-sided colorectum (descending colon, sigmoid colon, and rectum) were obtained using a lower gastrointestinal endoscope. RNA was extracted from all samples, and total transcriptome sequencing was performed. Transcriptome data from 388 samples was analyzed. DNA was also extracted from tumor biopsy tissues and analyzed for whole-exome sequencing. In healthy individuals, gene expression differed significantly among the terminal ileum, right-sided colon, and left-sided colorectum, presumably linked to embryological factors. There were differences in gene expression in the normal mucosa in colorectal cancer patients, compared to healthy controls. Patients with tumors, especially T2-4 colorectal cancer, showed considerable variation in gene expression in non-tumor tissues, even in the terminal ileum distant from the tumor site. Based on endoscopic biopsies, the results imply cancer-predisposing conditions in seemingly normal tissues. The present study points to the importance of small intestine and cancer-predisposing conditions in the colon of colorectal cancer patients, with possible implications for developing novel immunotherapy and other therapeutic modalities.
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Affiliation(s)
- Shoko Ikuta
- Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, 565-0871, Osaka, Japan
| | - Yutaka Saito
- Endoscopy Division, National Cancer Center Hospital, Chuo-ku, Tokyo, 104-0045, Japan
| | - So Takata
- Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, 565-0871, Osaka, Japan
| | - Yoichiro Nakatani
- Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan
| | - Izumi Nagatomo
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, 565-0871, Osaka, Japan
- Health and Counseling Center, Osaka University, Suita, 565-0871, Osaka, Japan
| | - Satoshi Shiba
- Division of Cancer Genomics, National Cancer Center Research Institute, Chuo-ku, Tokyo, 104-0045, Japan
| | - Yoshito Takeda
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, 565-0871, Osaka, Japan
| | - Yasushi Totoki
- Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan
| | - Sayaka Mizutani
- School of Life Science and Technology, Tokyo Institute of Technology, Meguro-ku, Tokyo, 152-8550, Japan
| | - Hironori Sunakawa
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Kashiwa, 277-8577, Chiba, Japan
| | - Hiroaki Ikematsu
- Department of Gastroenterology and Endoscopy, National Cancer Center Hospital East, Kashiwa, 277-8577, Chiba, Japan
| | - Hiroyuki Takamaru
- Endoscopy Division, National Cancer Center Hospital, Chuo-ku, Tokyo, 104-0045, Japan
| | - Atsushi Kumanogoh
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, 565-0871, Osaka, Japan
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, 565-0871, Osaka, Japan
- Department of Immunopathology, Immunology Frontier Research Center (IFReC), World Premier International Research Center Initiative (WPI), Osaka University, Suita, 565- 0871, Osaka, Japan
- Center for Infectious Diseases for Education and Research (CiDER), Osaka University, Suita, 565-0871, Osaka, Japan
- Japan Agency for Medical Research and Development - Core Research for Evolutional Science and Technology (AMED-CREST), Chiyoda-ku, 100-0004, Tokyo, Japan
- Center for Advanced Modalities and DDS (CAMaD), Osaka University, Suita, 565- 0871, Osaka, Japan
| | - Shinichi Yachida
- Department of Cancer Genome Informatics, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan.
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, 565-0871, Osaka, Japan.
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3
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Rzasa P, Whelan S, Farahmand P, Cai H, Guterman I, Palacios-Gallego R, Undru SS, Sandford L, Green C, Andreadi C, Mintseva M, Parrott E, Jin H, Hey F, Giblett S, Sylvius NB, Allcock NS, Straatman-Iwanowska A, Feuda R, Tufarelli C, Brown K, Pritchard C, Rufini A. BRAF V600E-mutated serrated colorectal neoplasia drives transcriptional activation of cholesterol metabolism. Commun Biol 2023; 6:962. [PMID: 37735514 PMCID: PMC10514332 DOI: 10.1038/s42003-023-05331-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 09/07/2023] [Indexed: 09/23/2023] Open
Abstract
BRAF mutations occur early in serrated colorectal cancers, but their long-term influence on tissue homeostasis is poorly characterized. We investigated the impact of short-term (3 days) and long-term (6 months) expression of BrafV600E in the intestinal tissue of an inducible mouse model. We show that BrafV600E perturbs the homeostasis of intestinal epithelial cells, with impaired differentiation of enterocytes emerging after prolonged expression of the oncogene. Moreover, BrafV600E leads to a persistent transcriptional reprogramming with enrichment of numerous gene signatures indicative of proliferation and tumorigenesis, and signatures suggestive of metabolic rewiring. We focused on the top-ranking cholesterol biosynthesis signature and confirmed its increased expression in human serrated lesions. Functionally, the cholesterol lowering drug atorvastatin prevents the establishment of intestinal crypt hyperplasia in BrafV600E-mutant mice. Overall, our work unveils the long-term impact of BrafV600E expression in intestinal tissue and suggests that colorectal cancers with mutations in BRAF might be prevented by statins.
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Affiliation(s)
- Paulina Rzasa
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Sarah Whelan
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Pooyeh Farahmand
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Hong Cai
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Inna Guterman
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | | | - Shanthi S Undru
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Lauren Sandford
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
| | - Caleb Green
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Catherine Andreadi
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Maria Mintseva
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
- Area of Neuroscience, International School for Advanced Studies (SISSA), Trieste, Italy
| | - Emma Parrott
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Hong Jin
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Fiona Hey
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Susan Giblett
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Nicolas B Sylvius
- NUCLEUS Genomics, Core Biotechnology Services, University of Leicester, Leicester, UK
| | - Natalie S Allcock
- University of Leicester Core Biotechnology Services Electron Microscopy Facility, Leicester, UK
| | | | - Roberto Feuda
- Department of Genetics and Genome Biology, University of Leicester, Leicester, UK
| | - Cristina Tufarelli
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Karen Brown
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Catrin Pritchard
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Alessandro Rufini
- Leicester Cancer Research Centre, University of Leicester, Leicester, UK.
- Dipartimento di Bioscienze, University of Milan, Milan, Italy.
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4
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Murakami T, Kurosawa T, Fukushima H, Shibuya T, Yao T, Nagahara A. Sessile serrated lesions: Clinicopathological characteristics, endoscopic diagnosis, and management. Dig Endosc 2022; 34:1096-1109. [PMID: 35352394 DOI: 10.1111/den.14273] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 01/30/2022] [Accepted: 02/13/2022] [Indexed: 02/08/2023]
Abstract
The 2019 World Health Organization (WHO) Classification of Tumours of the Digestive System (5th edition) introduced the term "sessile serrated lesion" (SSL) to replace the term "sessile serrated adenoma/polyp" (SSA/P). SSLs are early precursor lesions in the serrated neoplasia pathway that result in colorectal carcinomas with BRAF mutations, methylation for DNA repair genes, a CpG island methylator phenotype, and high levels of microsatellite instability. Some of these lesions can rapidly become dysplastic or invasive carcinomas that exhibit high lymphatic invasion and lymph node metastasis potential. The 2019 WHO classification noted that dysplasia arising in an SSL most likely is an advanced polyp, regardless of the morphologic grade of the dysplasia. Detecting SSLs with or without dysplasia is critical; however, detection of SSLs is challenging, and their identification by endoscopists and pathologists is inconsistent. Furthermore, indications for their endoscopic treatment have not been established. Moreover, SSLs are considered to contribute to the development of post-colonoscopy colorectal cancers. Herein, the clinicopathological and endoscopic characteristics of SSLs, including features determined using white light and image-enhanced endoscopy, therapeutic indications, therapeutic methods, and surveillance are reviewed based on the literature. This information may lead to more intensive research to improve detection, diagnosis, and rates of complete resection of these lesions and reduce post-colonoscopy colorectal cancer rates.
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Affiliation(s)
- Takashi Murakami
- Departments of 1Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Taro Kurosawa
- Departments of 1Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
- Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hirofumi Fukushima
- Departments of 1Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tomoyoshi Shibuya
- Departments of 1Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Takashi Yao
- Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Akihito Nagahara
- Departments of 1Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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5
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Lehmann J, Narcisi R, Franceschini N, Chatzivasileiou D, Boer CG, Koevoet WJLM, Putavet D, Drabek D, van Haperen R, de Keizer PLJ, van Osch GJVM, Ten Berge D. WNT/beta-catenin signalling interrupts a senescence-induction cascade in human mesenchymal stem cells that restricts their expansion. Cell Mol Life Sci 2022; 79:82. [PMID: 35048158 PMCID: PMC8770385 DOI: 10.1007/s00018-021-04035-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 10/18/2021] [Accepted: 11/09/2021] [Indexed: 12/23/2022]
Abstract
Senescence, the irreversible cell cycle arrest of damaged cells, is accompanied by a deleterious pro-inflammatory senescence-associated secretory phenotype (SASP). Senescence and the SASP are major factors in aging, cancer, and degenerative diseases, and interfere with the expansion of adult cells in vitro, yet little is known about how to counteract their induction and deleterious effects. Paracrine signals are increasingly recognized as important senescence triggers and understanding their regulation and mode of action may provide novel opportunities to reduce senescence-induced inflammation and improve cell-based therapies. Here, we show that the signalling protein WNT3A counteracts the induction of paracrine senescence in cultured human adult mesenchymal stem cells (MSCs). We find that entry into senescence in a small subpopulation of MSCs triggers a secretome that causes a feed-forward signalling cascade that with increasing speed induces healthy cells into senescence. WNT signals interrupt this cascade by repressing cytokines that mediate this induction of senescence. Inhibition of those mediators by interference with NF-κB or interleukin 6 signalling reduced paracrine senescence in absence of WNT3A and promoted the expansion of MSCs. Our work reveals how WNT signals can antagonize senescence and has relevance not only for expansion of adult cells but can also provide new insights into senescence-associated inflammatory and degenerative diseases.
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Affiliation(s)
- Johannes Lehmann
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.,Department of Cell Biology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.,Center for Molecular Medicine, Section Molecular Cancer Research, Division LAB, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Roberto Narcisi
- Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Natasja Franceschini
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Danai Chatzivasileiou
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Cindy G Boer
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Wendy J L M Koevoet
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Diana Putavet
- Center for Molecular Medicine, Section Molecular Cancer Research, Division LAB, University Medical Center Utrecht, Utrecht, The Netherlands.,Department of Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Dubravka Drabek
- Department of Cell Biology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.,Harbour Biomed, Rotterdam, the Netherlands
| | - Rien van Haperen
- Department of Cell Biology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.,Harbour Biomed, Rotterdam, the Netherlands
| | - Peter L J de Keizer
- Center for Molecular Medicine, Section Molecular Cancer Research, Division LAB, University Medical Center Utrecht, Utrecht, The Netherlands.,Department of Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Gerjo J V M van Osch
- Department of Otorhinolaryngology and Head and Neck Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.,Department of Orthopaedics and Sports Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Derk Ten Berge
- Department of Cell Biology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
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6
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Murakami T, Sakamoto N, Fukushima H, Shibuya T, Yao T, Nagahara A. Usefulness of the Japan narrow-band imaging expert team classification system for the diagnosis of sessile serrated lesion with dysplasia/carcinoma. Surg Endosc 2021; 35:4528-4538. [PMID: 32909209 DOI: 10.1007/s00464-020-07967-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 08/27/2020] [Indexed: 01/03/2023]
Abstract
BACKGROUND Sessile serrated lesion (SSL) is a colorectal polyp that has malignant potential. However, the dysplastic components within an SSL can be difficult to diagnose with conventional endoscopy, because most SSLs with dysplasia/carcinoma have subtle mucosal features. Many studies have indicated that narrow-band imaging (NBI) observations of colorectal polyps are very useful, accurate predictors of histology. We aimed to verify the usefulness of the Japan NBI Expert Team (JNET) classification system for the diagnosis of SSLs with dysplasia/carcinoma. METHODS We examined 709 endoscopically or surgically resected lesions that were pathologically diagnosed as SSL, including 647 with no dysplasia, 37 with low-grade dysplasia, 15 with high-grade dysplasia, and 10 with submucosal invasive carcinoma. We retrospectively evaluated their clinicopathologic characteristics and conventional endoscopic and magnifying NBI endoscopic findings using the JNET system. RESULTS Cases in all groups were more frequently located in the proximal colon. Submucosal invasive carcinomas were significantly larger than no dysplasia and low-grade dysplasia lesions. Almost all studied lesions (96.3%) were covered with a mucus cap. Five hundred and eighty (81.8%) lesions exhibited dark spots inside the crypts, which are NBI findings' characteristic of SSL. As for the JNET classification of magnifying NBI endoscopic findings, all 709 lesions showed Type 1. Six hundred and eighteen (95.5%) SSLs with no dysplasia lesions exhibited Type 1 only, whereas 52 (83.9%) SSLs with dysplasia/carcinoma had a combination of Type 1 and Type 2A, 2B, or 3, corresponding to SSL and dysplasia/carcinoma, respectively. The JNET classification had high sensitivity (83.9%), specificity (95.5%), and overall diagnostic accuracy (94.5%) for diagnosing SSLs with dysplasia/carcinoma. CONCLUSIONS Use of magnifying NBI endoscopy with the JNET classification might be useful for diagnosing SSLs with dysplasia/carcinoma. This increased awareness may also improve the recognition of SSLs with dysplasia/carcinoma.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Hirofumi Fukushima
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Tomoyoshi Shibuya
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
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7
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Monreal-Robles R, Jáquez-Quintana JO, Benavides-Salgado DE, González-González JA. Serrated polyps of the colon and rectum: a concise review. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2021; 86:276-286. [PMID: 34116964 DOI: 10.1016/j.rgmxen.2021.06.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 02/26/2021] [Indexed: 02/07/2023]
Abstract
"Serrated polyps" is the term used for epithelial lesions of the colon and rectum that have a "sawtooth" pattern on the polyp's surface and crypt epithelium. The so-called serrated pathway describes the progression of sessile serrated adenomas and traditional serrated adenomas to colorectal cancer. Said pathway is well recognized as an alternative mechanism of carcinogenesis and accounts for 15-30% of the cases of colorectal cancer. It also explains a large number of the cases of interval colorectal cancer. Thus, due to their usually aggressive and uncertain behavior, serrated polyps are of the utmost importance in colorectal cancer screening. Our aim was to review the history, current nomenclature, pathophysiology, morphology, treatment, and surveillance of serrated polyps.
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Affiliation(s)
- R Monreal-Robles
- Servicio de Gastroenterología, Hospital Universitario Dr. José E. González, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico; Escuela de Medicina y Ciencias de la Salud, Instituto Tecnológico y de Estudios Superiores de Monterrey, Monterrey, Nuevo León, Mexico.
| | - J O Jáquez-Quintana
- Servicio de Gastroenterología, Hospital Universitario Dr. José E. González, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico
| | - D E Benavides-Salgado
- Servicio de Gastroenterología, Hospital Universitario Dr. José E. González, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico
| | - J A González-González
- Servicio de Gastroenterología, Hospital Universitario Dr. José E. González, Universidad Autónoma de Nuevo León, Monterrey, Nuevo León, Mexico
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8
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Leach JDG, Vlahov N, Tsantoulis P, Ridgway RA, Flanagan DJ, Gilroy K, Sphyris N, Vázquez EG, Vincent DF, Faller WJ, Hodder MC, Raven A, Fey S, Najumudeen AK, Strathdee D, Nixon C, Hughes M, Clark W, Shaw R, van Hooff SR, Huels DJ, Medema JP, Barry ST, Frame MC, Unciti-Broceta A, Leedham SJ, Inman GJ, Jackstadt R, Thompson BJ, Campbell AD, Tejpar S, Sansom OJ. Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis. Nat Commun 2021. [PMID: 34103493 DOI: 10.1038/s41467‐021‐23717‐5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.
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Affiliation(s)
- Joshua D G Leach
- Cancer Research UK Beatson Institute, Glasgow, UK.,Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | - Petros Tsantoulis
- Department of Medical Specialties, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland
| | | | | | | | | | - Ester G Vázquez
- Gastrointestinal Stem Cell Biology Lab, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | | | - William J Faller
- Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Michael C Hodder
- Cancer Research UK Beatson Institute, Glasgow, UK.,Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | - Sigrid Fey
- Cancer Research UK Beatson Institute, Glasgow, UK.,Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | | | - Colin Nixon
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Mark Hughes
- Cancer Research UK Beatson Institute, Glasgow, UK
| | | | - Robin Shaw
- Cancer Research UK Beatson Institute, Glasgow, UK
| | | | - Sander R van Hooff
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.,Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands
| | - David J Huels
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.,Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands.,Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands
| | - Simon T Barry
- Bioscience, Early Oncology, AstraZeneca, Cambridge, UK
| | - Margaret C Frame
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Asier Unciti-Broceta
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Simon J Leedham
- Gastrointestinal Stem Cell Biology Lab, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Gareth J Inman
- Cancer Research UK Beatson Institute, Glasgow, UK.,Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | - Barry J Thompson
- EMBL Australia, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | | | - Sabine Tejpar
- Molecular Digestive Oncology, Department of Oncology, University of Leuven, Leuven, Belgium
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, UK. .,Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
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9
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Leach JDG, Vlahov N, Tsantoulis P, Ridgway RA, Flanagan DJ, Gilroy K, Sphyris N, Vázquez EG, Vincent DF, Faller WJ, Hodder MC, Raven A, Fey S, Najumudeen AK, Strathdee D, Nixon C, Hughes M, Clark W, Shaw R, van Hooff SR, Huels DJ, Medema JP, Barry ST, Frame MC, Unciti-Broceta A, Leedham SJ, Inman GJ, Jackstadt R, Thompson BJ, Campbell AD, Tejpar S, Sansom OJ. Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis. Nat Commun 2021; 12:3464. [PMID: 34103493 PMCID: PMC8187652 DOI: 10.1038/s41467-021-23717-5] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Accepted: 05/11/2021] [Indexed: 02/08/2023] Open
Abstract
Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFβ signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFβ-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFβ-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.
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Affiliation(s)
- Joshua D G Leach
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | - Petros Tsantoulis
- Department of Medical Specialties, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland
| | | | | | | | | | - Ester G Vázquez
- Gastrointestinal Stem Cell Biology Lab, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | | | - William J Faller
- Division of Oncogenomics, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Michael C Hodder
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | - Sigrid Fey
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | | | - Colin Nixon
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Mark Hughes
- Cancer Research UK Beatson Institute, Glasgow, UK
| | | | - Robin Shaw
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Sander R van Hooff
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
- Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands
| | - David J Huels
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
- Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM) and Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
- Oncode Institute, Academic Medical Center, Amsterdam, The Netherlands
| | - Simon T Barry
- Bioscience, Early Oncology, AstraZeneca, Cambridge, UK
| | - Margaret C Frame
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Asier Unciti-Broceta
- Cancer Research UK Edinburgh Centre, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - Simon J Leedham
- Gastrointestinal Stem Cell Biology Lab, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Gareth J Inman
- Cancer Research UK Beatson Institute, Glasgow, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | - Barry J Thompson
- EMBL Australia, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia
| | | | - Sabine Tejpar
- Molecular Digestive Oncology, Department of Oncology, University of Leuven, Leuven, Belgium
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, UK.
- Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
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10
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Nishimura H, Fukui H, Wang X, Ebisutani N, Nakanishi T, Tomita T, Oshima T, Hirota S, Miwa H. Role of the β-Catenin/REG Iα Axis in the Proliferation of Sessile Serrated Adenoma/Polyps Associated with Fusobacterium nucleatum. Pathogens 2021; 10:pathogens10040434. [PMID: 33917384 PMCID: PMC8067346 DOI: 10.3390/pathogens10040434] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 03/30/2021] [Accepted: 04/02/2021] [Indexed: 12/24/2022] Open
Abstract
Although sessile serrated adenoma/polyps (SSA/Ps) may arise through a pathway different from the traditional adenoma–carcinoma sequence, details of SSA/P tumorigenesis still remain unclear. Fusobacterium nucleatum (Fn) is frequently detected in colorectal cancer (CRC) tissues and may play a pivotal role in colorectal carcinogenesis. Here, we investigated the relationship between Fn and the β-catenin/REG Iα axis in SSA/Ps and their involvement in the proliferation of these lesions. Fn was detected in SSA/Ps by fluorescence in situ hybridization using a Fn-targeted probe, and expression of β-catenin, REG Iα and Ki67 was examined using immunohistochemistry. Sixteen of 30 SSA/P lesions (53.3%) were positive for Fn. Eighteen SSA/P lesions (60%) showed β-catenin immunoreactivity in the tumor cell nuclei. A significant majority of Fn-positive lesions showed nuclear expression of β-catenin (87.5%) and higher REG Iα scores and Ki67 labeling indices relative to Fn-negative lesions. The SSA/P lesions expressing β-catenin in nuclei had significantly higher REG Iα scores and Ki67 labeling indices than those expressing β-catenin on cytomembranes. The REG Iα score was positively correlated with the Ki67 labeling index in SSA/P lesions. The treatment with Wnt agonist SKL2001 promoted nuclear β-catenin translocation and enhanced REG Ia expression in Caco2 cells. Fn may play a role in the proliferation of SSA/P lesions through promotion of β-catenin nuclear translocation and REG Iα expression.
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Affiliation(s)
- Heihachiro Nishimura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan; (H.N.); (X.W.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
| | - Hirokazu Fukui
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan; (H.N.); (X.W.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
- Correspondence: ; Tel.: +81-798-456-662
| | - Xuan Wang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan; (H.N.); (X.W.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
| | - Nobuhiko Ebisutani
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan; (H.N.); (X.W.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
| | - Takashi Nakanishi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan; (H.N.); (X.W.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
| | - Toshihiko Tomita
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan; (H.N.); (X.W.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
| | - Tadayuki Oshima
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan; (H.N.); (X.W.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
| | - Seiichi Hirota
- Department of Surgical Pathology, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan;
| | - Hiroto Miwa
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Hyogo College of Medicine 1-1, Mukogawa, Nishinomiya 663-8501, Japan; (H.N.); (X.W.); (N.E.); (T.N.); (T.T.); (T.O.); (H.M.)
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11
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Mosnier JF, Airaud F, Métairie S, Volteau C, Bezieau S, Denis M. Mapping of colorectal carcinoma diseases with activation of Wnt/beta-catenin signalling pathway using hierarchical clustering approach. J Clin Pathol 2021; 75:168-175. [PMID: 33441391 DOI: 10.1136/jclinpath-2020-207144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 12/11/2020] [Accepted: 12/12/2020] [Indexed: 11/04/2022]
Abstract
AIMS To map the colorectal carcinoma (CRC) diseases with significant Wnt signalling pathway activation for delineating their clinicopathological and molecular profiles. METHODS Mapping is based on hierarchical clustering analyses of a series of 283 CRCs. Data tabulated were histopathological patterns, immunophenotypic differentiation, RAS, RAF, CTNNB1 mutations and microsatellite instability status, tumour-infiltrating lymphocytes (TILs) and genetic setting. Beta-catenin expression in more than 10% of cell nuclei in the centre of tumour serves as a surrogate marker of significant activation of Wnt signalling pathway. RESULTS Nuclei beta-catenin expression was present in 95% of CRCs; 56% of them met the criteria of high level of nuclei beta-catenin expression (≥10%). Proportion of beta-catenin positive nuclei was significantly higher in younger patients, rectal and left-sided colonic carcinomas. CRCs with high level of nuclei beta-catenin expression were regrouped into three clusters: (1) microsatellite stability (MSS) CRCs with no constitutive MAPK pathway activation including 90% of low-grade adenocarcinoma, NOS, with intestinal differentiation without TILs; (2) RAS-mutated MSS CRCs including low-grade adenocarcinoma, NOS, with intestinal differentiation and mucinous adenocarcinoma without TILs; (3) MSI-H CRCs including both BRAF-mutated CRCs evolving from serrated pathway and CTNNB1-mutated CRCs associated with Lynch syndrome. CONCLUSIONS MSS low-grade adenocarcinoma, NOS, with intestinal differentiation without TILs ('crypt-like adenocarcinoma') might be the morphological pending of canonical molecular subtype of CRC defined as displayed molecular epithelial differentiation and upregulation of WNT in consensus molecular classification of CRC.
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Affiliation(s)
| | - Fabrice Airaud
- Department of Genetics, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Sylvie Métairie
- Department of Digestive and Endocrinology Surgeries, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Christelle Volteau
- Biostatistics Department, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Stéphane Bezieau
- Department of Genetics, Centre Hospitalier Universitaire de Nantes, Nantes, France
| | - Marc Denis
- Department of Biochemistry and Oncogenomics, Centre Hospitalier Universitaire, Nantes, France
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12
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Kim JH, Kang GH. Evolving pathologic concepts of serrated lesions of the colorectum. J Pathol Transl Med 2020; 54:276-289. [PMID: 32580537 PMCID: PMC7385269 DOI: 10.4132/jptm.2020.04.15] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/13/2020] [Accepted: 04/15/2020] [Indexed: 12/12/2022] Open
Abstract
Here, we provide an up-to-date review of the histopathology and molecular pathology of serrated colorectal lesions. First, we introduce the updated contents of the 2019 World Health Organization classification for serrated lesions. The sessile serrated lesion (SSL) is a new diagnostic terminology that replaces sessile serrated adenoma and sessile serrated polyp. The diagnostic criteria for SSL were revised to require only one unequivocal distorted serrated crypt, which is sufficient for diagnosis. Unclassified serrated adenomas have been included as a new category of serrated lesions. Second, we review ongoing issues concerning the morphology of serrated lesions. Minor morphologic variants with distinct molecular features were recently defined, including serrated tubulovillous adenoma, mucin-rich variant of traditional serrated adenoma (TSA), and superficially serrated adenoma. In addition to intestinal dysplasia and serrated dysplasia, minimal deviation dysplasia and not otherwise specified dysplasia were newly suggested as dysplasia subtypes of SSLs. Third, we summarize the molecular features of serrated lesions. The critical determinant of CpG island methylation development in SSLs is patient age. Interestingly, there may be ethnic differences in BRAF/KRAS mutation frequencies in SSLs. The molecular pathogenesis of TSAs is divided into KRAS and BRAF mutation pathways. SSLs with MLH1 methylation can progress into favorable prognostic microsatellite instability-positive (MSI+)/CpG island methylator phenotype-positive (CIMP+) carcinomas, whereas MLH1-unmethylated SSLs and BRAF-mutated TSAs can be precursors of poor-prognostic MSI-/CIMP+ carcinomas. Finally, based on our recent data, we propose an algorithm for stratifying risk subgroups of non-dysplastic SSLs.
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Affiliation(s)
- Jung Ho Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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13
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Nakanishi H, Sawada T, Kaizaki Y, Ota R, Suzuki H, Yamamoto E, Aoki H, Eizuka M, Hasatani K, Takahashi N, Inagaki S, Ebi M, Kato H, Kubota E, Kataoka H, Takahashi S, Tokino T, Minamoto T, Sugai T, Sasaki Y. Significance of gene mutations in the Wnt signaling pathway in traditional serrated adenomas of the colon and rectum. PLoS One 2020; 15:e0229262. [PMID: 32092099 PMCID: PMC7039454 DOI: 10.1371/journal.pone.0229262] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Accepted: 02/02/2020] [Indexed: 12/16/2022] Open
Abstract
Recent studies have shown that colorectal serrated lesions, which include sessile serrated adenomas (SSAs) and traditional serrated adenomas (TSAs), are precursors of colorectal cancer. However, the molecular mechanisms underlying the carcinogenesis, particularly in TSAs, remain largely uncharacterized. To clarify their molecular and clinicopathological characteristics, we performed mutation and methylation analyses of cancer-associated genes in 78 serrated lesions, including TSAs, SSAs and microvesicular hyperplastic polyps. Target exon sequence analysis was performed with 39 genes, including genes known to be frequently mutated in colorectal cancers and/or serrated lesions. We also used bisulfite pyrosequencing to assess the methylation status of various cancer-associated genes and marker genes of the CpG island methylator phenotype (CIMP). The prevalence of mutations in genes associated with Wnt signaling was significantly higher in TSAs than SSAs (65% vs. 28%, p < 0.01). Among those, RNF43 mutations were observed in 38% of TSAs and 17% of SSAs. In immunohistochemical studies of 39 serrated lesions, the prevalence of abnormal nuclear β-catenin accumulation was significantly higher in TSAs (57%) than SSAs (8%) (P = 0.01). SMOC1 methylation was detected in 54% of TSAs but in no SSAs (p < 0.01). Additionally, SMOC1 methylation was more prevalent among TSAs with KRAS mutation (82%) than with BRAF mutation (38%, p = 0.03). Lesions with CIMP-high or RNF43 mutations were detected only in TSAs with BRAF mutation, suggesting two distinct carcinogenic pathways in TSAs. Mutations in genes associated with Wnt signaling play a greater role in the carcinogenesis of TSAs than SSAs.
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Affiliation(s)
- Hiroyoshi Nakanishi
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Takeshi Sawada
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.,Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yasuharu Kaizaki
- Department of Pathology, Fukui Prefectural Hospital, Fukui, Japan
| | - Ryosuke Ota
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Eiichiro Yamamoto
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hironori Aoki
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Makoto Eizuka
- Department of Molecular Diagnostic Pathology, Iwate Medical University School of Medicine, Morioka, Japan
| | - Kenkei Hasatani
- Department of Gastroenterology, Fukui Prefectural Hospital, Fukui, Japan
| | - Naoki Takahashi
- Department of Gastroenterology, Saitama Cancer Center, Saitama, Japan
| | - Satoko Inagaki
- Department of Advanced Research in Community Medicine, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan
| | - Masahide Ebi
- Department of Gastroenterology, Aichi Medical University, Nagakute, Japan
| | - Hiroyuki Kato
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Eiji Kubota
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hiromi Kataoka
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Satoru Takahashi
- Department of Experimental Pathology and Tumor Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takashi Tokino
- Department of Medical Genome Sciences, Research Institute for Frontier Medicine, Sapporo Medical University, Sapporo, Japan
| | - Toshinari Minamoto
- Division of Translational and Clinical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, Iwate Medical University School of Medicine, Morioka, Japan
| | - Yasushi Sasaki
- Division of Biology, Department of Liberal Arts and Sciences, Center for Medical Education, Sapporo Medical University, Sapporo, Japan
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14
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Post JB, Roodhart JML, Snippert HJG. Colorectal Cancer Modeling with Organoids: Discriminating between Oncogenic RAS and BRAF Variants. Trends Cancer 2020; 6:111-129. [PMID: 32061302 DOI: 10.1016/j.trecan.2019.12.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 11/27/2019] [Accepted: 12/06/2019] [Indexed: 12/12/2022]
Abstract
RAS and BRAF proteins are frequently mutated in colorectal cancer (CRC) and have been associated with therapy resistance in metastatic CRC patients. RAS isoforms are considered to act as redundant entities in physiological and pathological settings. However, there is compelling evidence that mutant variants of RAS and BRAF have different oncogenic potentials and therapeutic outcomes. In this review we describe similarities and differences between various RAS and BRAF oncogenes in CRC development, histology, and therapy resistance. In addition, we discuss the potential of patient-derived tumor organoids for personalized therapy, as well as CRC modeling using genome editing in preclinical model systems to study similarities and discrepancies between the effects of oncogenic MAPK pathway mutations on tumor growth and drug response.
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Affiliation(s)
- Jasmin B Post
- Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, CX Utrecht, The Netherlands; Oncode Institute Netherlands, Office Jaarbeurs Innovation Mile, Utrecht, The Netherlands
| | - Jeanine M L Roodhart
- Department of Medical Oncology, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands; Oncode Institute Netherlands, Office Jaarbeurs Innovation Mile, Utrecht, The Netherlands
| | - Hugo J G Snippert
- Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, CX Utrecht, The Netherlands; Oncode Institute Netherlands, Office Jaarbeurs Innovation Mile, Utrecht, The Netherlands.
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15
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Kane AM, Fennell LJ, Liu C, Borowsky J, McKeone DM, Bond CE, Kazakoff S, Patch AM, Koufariotis LT, Pearson J, Waddell N, Leggett BA, Whitehall VLJ. Alterations in signaling pathways that accompany spontaneous transition to malignancy in a mouse model of BRAF mutant microsatellite stable colorectal cancer. Neoplasia 2020; 22:120-128. [PMID: 31935636 PMCID: PMC6961716 DOI: 10.1016/j.neo.2019.12.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 12/10/2019] [Accepted: 12/12/2019] [Indexed: 12/19/2022] Open
Abstract
The serrated neoplasia pathway gives rise to a distinct subgroup of colorectal cancers distinguished by the presence of mutant BRAFV600E and the CpG Island Methylator Phenotype (CIMP). BRAF mutant CRC are commonly associated with microsatellite instability, which have an excellent clinical outcome. However, a proportion of BRAF mutant CRC retain microsatellite stability and have a dismal prognosis. The molecular drivers responsible for the development of this cancer subgroup are unknown. To address this, we established a murine model of BRAFV600E mutant microsatellite stable CRC and comprehensively investigated the exome and transcriptome to identify molecular alterations in signaling pathways that drive malignancy. Exome sequencing of murine serrated lesions (mSL) and carcinomas identified frequent hot spot mutations within the gene encoding β-catenin (Ctnnb1). Immunohistochemical staining of β-catenin indicated that these mutations led to an increase in the presence of aberrant nuclear β-catenin that resulted in gene expression changes in targets of β-catenin transcription. Gene expression profiling identified a significant enrichment for transforming growth factor-β (TGF-β) signaling that was present in mSL and carcinomas. Early activation of TGF-β suggests that this pathway may be an early cue directing mSL to microsatellite stable carcinoma. These findings in the mouse model support the importance of alterations in WNT and TGF-β signaling during the transition of human sessile serrated lesions to malignancy.
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Affiliation(s)
- Alexandra M Kane
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; The University of Queensland, Brisbane, Queensland, Australia; Conjoint Internal Medicine Laboratory, Pathology Queensland, Queensland Health, Brisbane, Queensland, Australia.
| | - Lochlan J Fennell
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; The University of Queensland, Brisbane, Queensland, Australia
| | - Cheng Liu
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; The University of Queensland, Brisbane, Queensland, Australia; Envoi Specialist Pathologists, Brisbane, Queensland, Australia
| | - Jennifer Borowsky
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; The University of Queensland, Brisbane, Queensland, Australia
| | - Diane M McKeone
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Catherine E Bond
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Stephen Kazakoff
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Ann-Marie Patch
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | | | - John Pearson
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Nicola Waddell
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Barbara A Leggett
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; The University of Queensland, Brisbane, Queensland, Australia; The Royal Brisbane and Women's Hospital, Queensland Health, Brisbane, Queensland, Australia
| | - Vicki L J Whitehall
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; The University of Queensland, Brisbane, Queensland, Australia; Conjoint Internal Medicine Laboratory, Pathology Queensland, Queensland Health, Brisbane, Queensland, Australia
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16
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Acquisition of WNT Pathway Gene Alterations Coincides With the Transition From Precursor Polyps to Traditional Serrated Adenomas. Am J Surg Pathol 2019; 43:132-139. [PMID: 30179900 DOI: 10.1097/pas.0000000000001149] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colorectal traditional serrated adenomas (TSAs) are often associated with precursor polyps, including hyperplastic polyps and sessile serrated adenoma/polyps. To elucidate the molecular mechanisms involved in the progression from precursor polyps to TSAs, the present study analyzed 15 precursor polyp-associated TSAs harboring WNT pathway gene mutations. Laser microdissection-based sequencing analysis showed that BRAF or KRAS mutations were shared between TSA and precursor polyps in all lesions. In contrast, the statuses of WNT pathway gene mutations were different between the 2 components. In 8 lesions, RNF43, APC, or CTNNB1 mutations, were exclusively present in TSA. RNF43 mutations were shared between the TSA and precursor components in 3 lesions; however, they were heterozygous in the precursor polyps whereas homozygous in the TSA. In 4 lesions with PTPRK-RSPO3 fusions, RNA in situ hybridization demonstrated that overexpression of RSPO3, reflecting PTPRK-RSPO3 fusion transcripts, was restricted to TSA components. Consistent with the results of the genetic and in situ hybridization analyses, nuclear β-catenin accumulation and MYC overexpression were restricted to the TSA component in 13 and 12 lesions, respectively. These findings indicate that the WNT pathway gene alterations are acquired during the progression from the precursor polyps to TSAs and that the activation of the WNT pathway plays a critical role in the development of TSA rather than their progression to high-grade lesions.
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17
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Murakami T, Sakamoto N, Nagahara A. Clinicopathological features, diagnosis, and treatment of sessile serrated adenoma/polyp with dysplasia/carcinoma. J Gastroenterol Hepatol 2019; 34:1685-1695. [PMID: 31158302 DOI: 10.1111/jgh.14752] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 05/22/2019] [Accepted: 05/28/2019] [Indexed: 12/17/2022]
Abstract
Sessile serrated adenoma/polyps (SSA/Ps) are early precursor lesions in the serrated neoplasia pathway, which results in BRAF-mutated colorectal carcinomas with not only high levels of microsatellite instability but also microsatellite stable. SSA/Ps with advanced histology, including cytological dysplasia or minimally invasive carcinomas, are important lesions because SSA/Ps are considered major contributors to "interval cancers" and these lesions can rapidly become dysplastic or invasive carcinomas. Clinicopathologically, SSA/Ps with dysplasia or invasive carcinoma were associated with advanced age, female sex, and proximal colon. Although SSA/Ps with submucosal invasive carcinoma were smaller and invaded less deeply into the submucosal layer than conventional tubular adenomas with submucosal invasive carcinoma, SSA/Ps with submucosal invasive carcinoma frequently had a mucinous component and exhibited a higher potential for lymphatic invasion and lymph node metastasis. In an SSA/P series, endoscopic characteristics, including (semi)pedunculated morphology, double elevation, central depression, and reddishness, may help accurately diagnose SSA/Ps with advanced histology. Removal of SSA/Ps with dysplasia or invasive carcinoma was recommended. Endoscopic treatment such as endoscopic mucosal resection or endoscopic submucosal dissection is useful for those lesions. However, surgical resection with lymph node dissection might be indicated when SSA/Ps with invasive carcinoma are endoscopically suspected, because these have the high risk of lymph node metastasis. Greater awareness may promote further research into improving the detection, recognition, and complete resection rates of SSA/Ps with dysplasia or invasive carcinoma and reduce the interval cancer rates.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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Xie X, Yin J, Zhou Z, Dang C, Zhang H, Zhang Y. Young age increases the risk for lymph node metastasis in patients with early Colon Cancer. BMC Cancer 2019; 19:803. [PMID: 31412872 PMCID: PMC6693219 DOI: 10.1186/s12885-019-5995-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Accepted: 07/30/2019] [Indexed: 02/08/2023] Open
Abstract
Background The risk of lymph node positivity in early-stage colon cancer is a parameter that impacts therapeutic recommendations. However, little is known about the effect of age on lymph node positivity in colon cancer with mucosal invasion. In this study, we aimed to quantify the effect of younger age on lymph node positivity in colon cancer with mucosal invasion. Methods All patients were identified between 2004 and 2014 in the Surveillance, Epidemiology, and End Results database. Patients were stage T1-T2, did not undergo preoperative radiotherapy, had at least one lymph node examined, and underwent a standard colon cancer operation. Demographics and pathological data were compared between different age ranges. A nomogram model was built to estimate the probability of nodal involvement according to different characteristics. Decision curve analysis was performed by calculating the net benefits for a range of threshold probabilities. Results This study identified 41,490 patients who met the eligibility criteria for our study. 1.4% (n = 620) of patients were under 40 years old; 5.9% (n = 2571) were between 40 and 49 years old. Within each T stage, positive lymph node rates decreased with increasing age. In univariate analyses, the positive lymph node rates for patients 20 to 39 years of age were significantly higher than in patients in the reference group for stages T1 and T2. After dividing the colon into the left and right parts, these trends remained. The lymph node metastatic rate was higher in the right colon than in the left colon in terms of different age ranges. The nomogram prediction system represents a novel model with which to estimate lymph node metastasis in early T stage colon adenocarcinomas based on four risk factors with a C-index of 0.657 (95% CI: 0.658–0666). Conclusions Our study demonstrates that the risk of lymph node metastasis was higher in young (< 40 years) patients with early-stage colon adenocarcinomas. Therefore, more aggressive screening and therapeutic strategies should be considered for young patients with colon adenocarcinoma.
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Affiliation(s)
- Xin Xie
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Jianhao Yin
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Zhangjian Zhou
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Chengxue Dang
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Hao Zhang
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
| | - Yong Zhang
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
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Cell type-dependent differential activation of ERK by oncogenic KRAS in colon cancer and intestinal epithelium. Nat Commun 2019; 10:2919. [PMID: 31266962 PMCID: PMC6606648 DOI: 10.1038/s41467-019-10954-y] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 06/12/2019] [Indexed: 12/26/2022] Open
Abstract
Oncogenic mutations in KRAS or BRAF are frequent in colorectal cancer and activate the ERK kinase. Here, we find graded ERK phosphorylation correlating with cell differentiation in patient-derived colorectal cancer organoids with and without KRAS mutations. Using reporters, single cell transcriptomics and mass cytometry, we observe cell type-specific phosphorylation of ERK in response to transgenic KRASG12V in mouse intestinal organoids, while transgenic BRAFV600E activates ERK in all cells. Quantitative network modelling from perturbation data reveals that activation of ERK is shaped by cell type-specific MEK to ERK feed forward and negative feedback signalling. We identify dual-specificity phosphatases as candidate modulators of ERK in the intestine. Furthermore, we find that oncogenic KRAS, together with β-Catenin, favours expansion of crypt cells with high ERK activity. Our experiments highlight key differences between oncogenic BRAF and KRAS in colorectal cancer and find unexpected heterogeneity in a signalling pathway with fundamental relevance for cancer therapy. KRASG12V and BRAFV600E are oncogenic mutations that activate ERK signalling. Here, the authors use single cell analysis in intestinal organoids and show that BRAFV600E activates ERK in all intestinal cell types, while KRASG12V induces ERK activation in only a subset of cells, depending on cell differentiation state.
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Nourbakhsh M, Mansoor A, Koro K, Zhang Q, Minoo P. Expression Profiling Reveals Involvement of WNT Pathway in the Malignant Progression of Sessile Serrated Adenomas. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:1732-1743. [PMID: 31199922 DOI: 10.1016/j.ajpath.2019.05.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 05/03/2019] [Accepted: 05/07/2019] [Indexed: 02/07/2023]
Abstract
Approximately 15% to 20% of colorectal cancers are developed through the serrated pathway of tumorigenesis, which is associated with BRAF mutation, CpG island methylation phenotype, and MLH1 methylation. However, the detailed process of progression from sessile serrated adenoma (SSA) to dysplasia and carcinoma has not been elucidated. To further characterize mechanisms involved in the dysplastic progression of SSA, we investigated differential expressions of mRNAs between areas with and without dysplasia within the same SSA polyps. Significantly dysregulated genes in paired samples were applied for functional annotation and biological significance. The same lysates from a subset of matched samples were subjected for miRNA expression profiling. Differentially expressed miRNAs were determined, and their targeted mRNAs were compared in parallel to the list of differentially expressed mRNAs from an RNA sequencing study. Fourteen common mRNA targets were identified, which include AXIN2, a known indicator of WNT/β-catenin pathway activation. Together, in this study, different genes, pathways, and biological processes involved in the initiation and progression of dysplasia in the serrated pathway are documented. One of the most significant findings is the involvement of the WNT/β-catenin pathway in the dysplastic progression of SSAs with different genes being targeted in early versus advanced dysplasia.
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Affiliation(s)
- Mahra Nourbakhsh
- Department of Pathology, Cumming School of Medicine and Alberta Public Laboratories, University of Calgary, Calgary, Alberta, Canada; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Adnan Mansoor
- Department of Pathology, Cumming School of Medicine and Alberta Public Laboratories, University of Calgary, Calgary, Alberta, Canada; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Konstantin Koro
- Department of Pathology, Cumming School of Medicine and Alberta Public Laboratories, University of Calgary, Calgary, Alberta, Canada; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Qingrun Zhang
- Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada
| | - Parham Minoo
- Department of Pathology, Cumming School of Medicine and Alberta Public Laboratories, University of Calgary, Calgary, Alberta, Canada; Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
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Tao Y, Kang B, Petkovich DA, Bhandari YR, In J, Stein-O'Brien G, Kong X, Xie W, Zachos N, Maegawa S, Vaidya H, Brown S, Chiu Yen RW, Shao X, Thakor J, Lu Z, Cai Y, Zhang Y, Mallona I, Peinado MA, Zahnow CA, Ahuja N, Fertig E, Issa JP, Baylin SB, Easwaran H. Aging-like Spontaneous Epigenetic Silencing Facilitates Wnt Activation, Stemness, and Braf V600E-Induced Tumorigenesis. Cancer Cell 2019; 35:315-328.e6. [PMID: 30753828 PMCID: PMC6636642 DOI: 10.1016/j.ccell.2019.01.005] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2018] [Revised: 09/25/2018] [Accepted: 01/07/2019] [Indexed: 11/22/2022]
Abstract
We addressed the precursor role of aging-like spontaneous promoter DNA hypermethylation in initiating tumorigenesis. Using mouse colon-derived organoids, we show that promoter hypermethylation spontaneously arises in cells mimicking the human aging-like phenotype. The silenced genes activate the Wnt pathway, causing a stem-like state and differentiation defects. These changes render aged organoids profoundly more sensitive than young ones to transformation by BrafV600E, producing the typical human proximal BRAFV600E-driven colon adenocarcinomas characterized by extensive, abnormal gene-promoter CpG-island methylation, or the methylator phenotype (CIMP). Conversely, CRISPR-mediated simultaneous inactivation of a panel of the silenced genes markedly sensitizes to BrafV600E-induced transformation. Our studies tightly link aging-like epigenetic abnormalities to intestinal cell fate changes and predisposition to oncogene-driven colon tumorigenesis.
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Affiliation(s)
- Yong Tao
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA
| | - Byunghak Kang
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA
| | - Daniel A Petkovich
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA
| | - Yuba R Bhandari
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA
| | - Julie In
- Hopkins Conte Digestive Disease, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Genevieve Stein-O'Brien
- Division of Biostatistics & Bioinformatics, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Xiangqian Kong
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA
| | - Wenbing Xie
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA
| | - Nicholas Zachos
- Hopkins Conte Digestive Disease, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Shinji Maegawa
- Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Unit 853, 1515 Holcombe Boulevard, Houston, TX 77030, USA
| | - Himani Vaidya
- Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19122, USA
| | - Stephen Brown
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA
| | - Ray-Whay Chiu Yen
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA
| | - Xiaojian Shao
- Department of Human Genetics, Canadian Centre for Computational Genomics, McGill University, Montreal, QC, Canada
| | - Jai Thakor
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA
| | - Zhihao Lu
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yi Cai
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA
| | - Yuezheng Zhang
- Department of Pathology, University of Washington, Seattle, WA 98195, USA
| | - Izaskun Mallona
- Germans Trias i Pujol Health Science Research Institute (IGTP), Program for Personalized Medicine of Cancer, Badalona, 08916 Catalonia, Spain
| | - Miguel Angel Peinado
- Germans Trias i Pujol Health Science Research Institute (IGTP), Program for Personalized Medicine of Cancer, Badalona, 08916 Catalonia, Spain
| | - Cynthia A Zahnow
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA
| | - Nita Ahuja
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA
| | - Elana Fertig
- Division of Biostatistics & Bioinformatics, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Jean-Pierre Issa
- Fels Institute for Cancer Research and Molecular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19122, USA
| | - Stephen B Baylin
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA.
| | - Hariharan Easwaran
- CRB1, Department of Oncology and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Room 530, Baltimore, MD 21287, USA.
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Murakami T, Akazawa Y, Yatagai N, Hiromoto T, Sasahara N, Saito T, Sakamoto N, Nagahara A, Yao T. Molecular characterization of sessile serrated adenoma/polyps with dysplasia/carcinoma based on immunohistochemistry, next-generation sequencing, and microsatellite instability testing: a case series study. Diagn Pathol 2018; 13:88. [PMID: 30458818 PMCID: PMC6247685 DOI: 10.1186/s13000-018-0771-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 11/08/2018] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Colorectal sessile serrated adenoma/polyps (SSA/Ps) are considered early precursor lesions in the serrated neoplasia pathway. Recent studies have shown associations of SSA/Ps with lost MLH1 expression, a CpG island methylator phenotype, and BRAF mutations. However, the molecular biological features of SSA/Ps with early neoplastic progression have not yet been fully elucidated, owing to the rarity of cases of SSA/P with advanced histology such as cytologic dysplasia or invasive carcinoma. In this study, we aimed to elucidate the molecular biological features of SSA/Ps with dysplasia/carcinoma, representing relatively early stages of the serrated neoplasia pathway. METHODS We performed immunostaining for β-catenin, MLH1, and mucins (e.g., MUC2, MUC5AC, MUC6, and CD10); targeted next-generation sequencing; and microsatellite instability (MSI) testing in 8 SSA/P lesions comprised of 4 SSA/Ps with high-grade dysplasia and 4 SSA/Ps with submucosal carcinoma. RESULTS Lost MLH1 expression was found in 5 cases. All lesions studied were positive for nuclear β-catenin expression. Regarding phenotypic mucin expression, all lesions were positive for MUC2, but negative for CD10. MUC5AC and MUC6 positivity was observed in 7 cases. Genetically, the most frequently mutated gene was BRAF (7 cases), and other mutations were detected in FBXW7 (3 cases); TP53 (2 cases), and KIT, PTEN, SMAD4, and SMARCB1 (1 case each). Furthermore, 4 of 8 lesions were MSI-high and the remaining 4 lesions were microsatellite-stable (MSS). Interestingly, all 4 MSI-high lesions displayed MLH1 loss, 3 of which harbored a FBXW7 mutation, but not a TP53 mutation. However, 2 MSS lesions harbored a TP53 mutation, although none harbored a FBXW7 mutation. CONCLUSIONS SSA/Ps with dysplasia/carcinoma frequently harbored BRAF mutations. Activation of the WNT/β-catenin signaling pathway may facilitate the development of dysplasia in SSA/Ps and progression to carcinoma. Furthermore, our results suggested that these lesions might be associated with both MSI-high and MSS colorectal cancer, which might be distinguished by distinct molecular biological features such as lost MLH1 expression, FBXW7 mutations, and TP53 mutations.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Yoichi Akazawa
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Noboru Yatagai
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Takafumi Hiromoto
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Noriko Sasahara
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tsuyoshi Saito
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421 Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
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García-Morales N, Satorres C, Bustamante-Balén M. Calcium and vitamin D in the serrated neoplastic pathway: Friends or foes? World J Gastrointest Pathophysiol 2018; 9:59-62. [PMID: 30386666 PMCID: PMC6209580 DOI: 10.4291/wjgp.v9.i3.59] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 09/11/2018] [Accepted: 10/09/2018] [Indexed: 02/06/2023] Open
Abstract
Sessile serrated adenoma/polyps (known as SSA/Ps) may play an important role in the development of interval colorectal cancer (CRC). These lesions are more difficult to detect with conventional endoscopy and they may quickly turn into CRC, especially when dysplasia has developed. Therefore, primary or secondary chemoprevention may be an appealing strategy at a population level. Calcium and vitamin D have been shown in epidemiological studies to reduce the risk of CRC and conventional adenomas, but the evidence regarding their effect on SSA/Ps is controversial. In this editorial we comment on the results of a recent randomized controlled trial investigating the effect of calcium and vitamin D on the development of serrated lesions, summarizing the possible antineoplastic mechanisms of calcium and vitamin D, and discussing the differences found with previous observational reports.
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Affiliation(s)
- Natalia García-Morales
- Gastrointestinal Endoscopy Unit, Digestive Diseases Department, La Fe Polytechnic University Hospital, Valencia 46026, Spain
| | - Carla Satorres
- Gastrointestinal Endoscopy Unit, Digestive Diseases Department, La Fe Polytechnic University Hospital, Valencia 46026, Spain
- Gastrointestinal Endoscopy Research Group, IIS Hospital La Fe, Valencia 46026, Spain
| | - Marco Bustamante-Balén
- Gastrointestinal Endoscopy Unit, Digestive Diseases Department, La Fe Polytechnic University Hospital, Valencia 46026, Spain
- Gastrointestinal Endoscopy Research Group, IIS Hospital La Fe, Valencia 46026, Spain
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Murakami T, Sakamoto N, Nagahara A. Endoscopic diagnosis of sessile serrated adenoma/polyp with and without dysplasia/carcinoma. World J Gastroenterol 2018; 24:3250-3259. [PMID: 30090005 PMCID: PMC6079289 DOI: 10.3748/wjg.v24.i29.3250] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 06/27/2018] [Accepted: 06/28/2018] [Indexed: 02/06/2023] Open
Abstract
Sessile serrated adenoma/polyps (SSA/Ps) are early precursor lesions in the serrated neoplasia pathway, which results in colorectal carcinomas with BRAF mutations, methylation for DNA repair genes, a CpG island methylator phenotype, and high levels of microsatellite instability. Some of these lesions can rapidly become dysplastic or invasive carcinomas that exhibit high lymphatic invasion and lymph node metastasis potentials. Detecting serrated lesions, including SSA/Ps with and without dysplasia/carcinoma, is critical, but SSA/Ps can be difficult to detect, are inconsistently identified by endoscopists and pathologists, and are often incompletely resected. Therefore, SSA/Ps are considered to be major contributors to "interval cancers". If colonoscopists can identify the specific endoscopic characteristics of SSA/Ps, their detection and the effectiveness of colonoscopy may improve. Here, the endoscopic features of SSA/Ps with and without dysplasia/carcinoma, including the characteristics determined using magnifying endoscopy, are reviewed in the context of previous reports. Endoscopically, these subtle polyps are like hyperplastic polyps, because they are slightly elevated and pale. Unlike hyperplastic polyps, SSA/Ps are usually larger than 5 mm, frequently covered by a thin layer called the ''mucus cap'', and are more commonly located in the proximal colon. Magnifying narrow-band imaging findings, which include dark spots inside the crypts and varicose microvascular vessels, in addition to the type II-open pit patterns detected using magnifying chromoendoscopy, effectively differentiate SSA/Ps from hyperplastic polyps. The lesions' endoscopic characteristics, which include their (semi)pedunculated morphologies, double elevations, central depressions, and reddishness, and the use of magnifying endoscopy, might help to detect dysplasia/carcinoma within SSA/Ps. Greater awareness may promote further research into improving the detection, identification, and complete resection rates of SSA/Ps with and without dysplasia/carcinoma and reduce the interval cancer rates.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
| | - Akihito Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
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He X, Wu K, Ogino S, Giovannucci EL, Chan AT, Song M. Association Between Risk Factors for Colorectal Cancer and Risk of Serrated Polyps and Conventional Adenomas. Gastroenterology 2018; 155:355-373.e18. [PMID: 29702117 PMCID: PMC6067965 DOI: 10.1053/j.gastro.2018.04.019] [Citation(s) in RCA: 157] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 03/29/2018] [Accepted: 04/13/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Serrated polyps (SPs) and conventional adenomas are precursor lesions for colorectal cancer (CRC), but they are believed to arise via distinct pathways. We characterized risk factor profiles for SPs and conventional adenomas in a post hoc analysis of data from 3 large prospective studies. METHODS We collected data from the Nurses' Health Study, the Nurses' Health Study 2, and the Health Professionals Follow-up Study on subjects who developed SPs or conventional adenomas. Our analysis comprised 141,143 participants who had undergone lower gastrointestinal endoscopy, provided updated diet and lifestyle data every 2-4 years, and were followed until diagnosis of a first polyp. We assessed 13 risk factors for CRC in patients with SPs or conventional adenomas and examined the associations according to histopathology features. RESULTS We documented 7945 SPs, 9212 conventional adenomas, and 2382 synchronous SPs and conventional adenomas during 18-20 years of follow-up. Smoking, body mass index, alcohol intake, family history of CRC, and height were associated with higher risk of SPs and conventional adenomas, whereas higher intake of vitamin D and marine omega-3 fatty acid were associated with lower risk. The associations tended to be stronger for synchronous SPs and conventional adenomas. Smoking, body mass index, and alcohol intake were more strongly associated with SPs than conventional adenomas (P for heterogeneity <.05), whereas physical activity and intake of total folate and calcium were inversely associated with conventional adenomas but not SPs. For SPs and conventional adenomas, the associations tended to be stronger for polyps in the distal colon and rectum, of 10 mm or larger or with advanced histology. CONCLUSIONS In an analysis of data from 3 large prospective studies, we found that although SPs and conventional adenomas share many risk factors, some factors are more strongly associated with one type of lesion than the other. These findings provide support for the etiologic heterogeneity of colorectal neoplasia.
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Affiliation(s)
- Xiaosheng He
- Department of Colorectal Surgery, The Six Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Kana Wu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts; Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Edward L Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Mingyang Song
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
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Zhang Y, Li A, Shi J, Fang Y, Gu C, Cai J, Lin C, Zhao L, Liu S. Imbalanced LIMK1 and LIMK2 expression leads to human colorectal cancer progression and metastasis via promoting β-catenin nuclear translocation. Cell Death Dis 2018; 9:749. [PMID: 29970879 PMCID: PMC6030168 DOI: 10.1038/s41419-018-0766-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 05/05/2018] [Accepted: 05/30/2018] [Indexed: 12/18/2022]
Abstract
Epithelial–mesenchymal transition (EMT)-induced metastasis contributes to human colorectal cancer (CRC) progression, especially in advanced CRC. However, the underlying mechanism of β-catenin in this process is elusive. We identified that LIM domain kinase (LIMK)2 was progressively downregulated with tumor progression from precancerous lesions to advanced cancer. Gain- and loss-of-function assays revealed that LIMK2 inhibits cell proliferation via cell cycle arrest at the G1–S transition and suppresses the ability of cell metastasis by restricting the EMT process. Reduced LIMK2 expression enhanced the nuclear accumulation of β-catenin and activated the Wnt signaling pathway, thus contributing to tumor progression. A homolog of the LIMK family, LIMK1, which was overexpressed throughout tumor progression, served as a competitive inhibitor of LIMK2 via β-catenin nuclear translocation. The imbalanced expression of LIMK1 and LIMK2 is important in CRC progression, and the combined effects provide a new insight into the mechanism of CRC progression. These findings provide a new understanding for LIMK-based anticancer therapy.
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Affiliation(s)
- Yue Zhang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Aimin Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jiaolong Shi
- Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangdong Provincial Engineering Technology Research Center of Minimally Invasive Surgery, Guangzhou, Guandong, China
| | - Yuxin Fang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chuncai Gu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jianqun Cai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chuang Lin
- Department of pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guandong, China
| | - Liang Zhao
- Department of pathology, Nanfang Hospital, Southern Medical University, Guangzhou, Guandong, China.
| | - Side Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China.
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28
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Early onset sporadic colorectal cancer: Worrisome trends and oncogenic features. Dig Liver Dis 2018; 50:521-532. [PMID: 29615301 DOI: 10.1016/j.dld.2018.02.009] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 02/09/2018] [Accepted: 02/12/2018] [Indexed: 02/07/2023]
Abstract
Early onset colorectal cancers, defined as arising before 50 years of age, are a growing health hazard in western and eastern countries alike. The incidence of colon and rectal cancers in young individuals is projected to increase by as much as 90% and 140%, respectively, by 2030. Although several known cancer risk factors (e.g. smoking, alcohol, dietary habits) have been investigated, there is no single compelling explanation for this epidemiological trend. While some early onset colorectal cancers have been associated with germline mutations in cancer predisposition genes, genetic syndromes are implicated in only a fraction of these cancers (20%) and do not explain the rising incidence. Colorectal neoplasms develop through microsatellite instability or chromosomal instability pathways, with most of the early onset colorectal cancers exhibiting microsatellite stable phenotypes. Genome-wide hypomethylation is a feature of a subgroup of early onset cancers, which appears to be correlated with chromosomal instability and poor prognosis.
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Borowsky J, Dumenil T, Bettington M, Pearson SA, Bond C, Fennell L, Liu C, McKeone D, Rosty C, Brown I, Walker N, Leggett B, Whitehall V. The role of APC in WNT pathway activation in serrated neoplasia. Mod Pathol 2018; 31:495-504. [PMID: 29148535 DOI: 10.1038/modpathol.2017.150] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 09/14/2017] [Accepted: 09/15/2017] [Indexed: 02/07/2023]
Abstract
Conventional adenomas are initiated by APC gene mutation that activates the WNT signal. Serrated neoplasia is commonly initiated by BRAF or KRAS mutation. WNT pathway activation may also occur, however, to what extent this is owing to APC mutation is unknown. We examined aberrant nuclear β-catenin immunolocalization as a surrogate for WNT pathway activation and analyzed the entire APC gene coding sequence in serrated and conventional pathway polyps and cancers. WNT pathway activation was a common event in conventional pathway lesions with aberrant nuclear immunolocalization of β-catenin and truncating APC mutations in 90% and 89% of conventional adenomas and 82% and 70% of BRAF wild-type cancers, respectively. WNT pathway activation was seen to a lesser extent in serrated pathway lesions. It occurred at the transition to dysplasia in serrated polyps with a significant increase in nuclear β-catenin labeling from sessile serrated adenomas (10%) to sessile serrated adenomas with dysplasia (55%) and traditional serrated adenomas (9%) to traditional serrated adenomas with dysplasia (39%) (P=0.0001). However, unlike the conventional pathway, truncating APC mutations were rare in the serrated pathway lesions especially sessile serrated adenomas even when dysplastic (15%) and in the BRAF mutant cancers with microsatellite instability that arise from them (8%). In contrast, APC missense mutations that were rare in conventional pathway adenomas and cancers (3% in BRAF wild-type cancers) were more frequent in BRAF mutant cancers with microsatellite instability (32%). We conclude that increased WNT signaling is important in the transition to malignancy in the serrated pathway but that APC mutation is less common and the spectrum of mutations is different than in conventional colorectal carcinogenesis. Moderate impact APC mutations and non-APC-related causes of increased WNT signaling may have a more important role in serrated neoplasia than the truncating APC mutations common in conventional adenomas.
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Affiliation(s)
- Jennifer Borowsky
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.,School of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Envoi Specialist Pathologists, Kelvin Grove, Brisbane, QLD, Australia
| | - Troy Dumenil
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia
| | - Mark Bettington
- Envoi Specialist Pathologists, Kelvin Grove, Brisbane, QLD, Australia
| | - Sally-Ann Pearson
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia
| | - Catherine Bond
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia
| | - Lochlan Fennell
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia
| | - Cheng Liu
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.,School of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Diane McKeone
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia
| | - Christophe Rosty
- Envoi Specialist Pathologists, Kelvin Grove, Brisbane, QLD, Australia
| | - Ian Brown
- Envoi Specialist Pathologists, Kelvin Grove, Brisbane, QLD, Australia.,Pathology Queensland, Queensland Health, Brisbane, QLD, Australia
| | - Neal Walker
- Envoi Specialist Pathologists, Kelvin Grove, Brisbane, QLD, Australia
| | - Barbara Leggett
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.,School of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Department of Gastroenterology and Hepatology, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
| | - Vicki Whitehall
- Conjoint Gastroenterology Laboratory, Queensland Institute of Medical Research Berghofer, Brisbane, QLD, Australia.,School of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Pathology Queensland, Queensland Health, Brisbane, QLD, Australia
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30
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Murakami T, Mitomi H, Yao T, Saito T, Shibuya T, Sakamoto N, Osada T, Watanabe S. Distinct histopathological characteristics in colorectal submucosal invasive carcinoma arising in sessile serrated adenoma/polyp and conventional tubular adenoma. Virchows Arch 2018; 472:383-393. [PMID: 28929387 DOI: 10.1007/s00428-017-2234-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Revised: 08/27/2017] [Accepted: 09/13/2017] [Indexed: 12/31/2022]
Abstract
The histopathological characteristics of colorectal submucosal invasive carcinoma arising in sessile serrated adenoma/polyp (SSA/P), a rare malignant tumour, have not yet been fully elucidated. To investigate the features of such, we retrospectively analysed 40 submucosal invasive carcinomas with SSA/P (CA-SSA/P) and compared them to 129 cases of submucosal invasive carcinoma with conventional tubular adenoma (CA-AD). We additionally performed hMLH1 immunostaining. CA-SSA/Ps were significantly smaller than CA-ADs (P < 0.001). Histologically, well to moderately differentiated adenocarcinoma was predominant in both CA-SSA/Ps and CA-ADs. No significant differences in depth of invasion were found between the two groups. However, lymphatic invasion was more often found in CA-SSA/Ps (30%) than in CA-ADs (13%; P = 0.028), as was lymph node metastasis (CA-SSA/Ps, 28%; CA-ADs, 7%; P = 0.011). Furthermore, mucinous component and serrated architecture were significantly more frequent in CA-SSA/Ps (30 and 63%) than in CA-ADs (5 and 18%; P < 0.001, respectively). Tumour-infiltrating lymphocytes and Crohn-like inflammatory reaction were also more frequently found in CA-SSA/Ps (70 and 30%) than in CA-ADs (31 and 9%; P ≤ 0.001, respectively), whereas the opposite was true of desmoplastic reaction (CA-SSA/Ps, 35%; CA-ADs, 67%; P < 0.001). Loss of hMLH1 expression was more frequent in CA-SSA/P cases (93%) than in CA-AD cases (5%; P < 0.001). In conclusion, CA-SSA/P lesions exhibit a higher potential for lymphatic invasion and lymph node metastasis and have distinct histopathological features, including mucinous component, serrated architecture, tumour-infiltrating lymphocytes, Crohn-like inflammatory reaction, and absence of desmoplastic reaction, compared to their conventional counterparts.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
- Department of Human Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
| | - Hiroyuki Mitomi
- Department of Diagnostic Pathology and Laboratory Medicine, Odawara Municipal Hospital, Odawara, Kanagawa, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Tsuyoshi Saito
- Department of Human Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Tomoyoshi Shibuya
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Taro Osada
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
| | - Sumio Watanabe
- Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan
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Hashimoto T, Yamashita S, Yoshida H, Taniguchi H, Ushijima T, Yamada T, Saito Y, Ochiai A, Sekine S, Hiraoka N. WNT Pathway Gene Mutations Are Associated With the Presence of Dysplasia in Colorectal Sessile Serrated Adenoma/Polyps. Am J Surg Pathol 2017; 41:1188-1197. [PMID: 28614199 DOI: 10.1097/pas.0000000000000877] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Sessile serrated adenoma/polyps (SSA/Ps) are believed to be the major precursor of serrated pathway-derived colorectal carcinomas. To better characterize the process of progression from SSA/Ps to carcinomas, we analyzed 46 SSA/Ps with dysplasia and 45 SSA/Ps without dysplasia using targeted next-generation sequencing and immunohistochemistry. Among the WNT pathway genes analyzed, protein-truncating mutations of RNF43, APC, and ZNRF3 were identified in 23 (50%), 4 (9%), and 3 (7%) SSA/Ps with dysplasia, respectively. In contrast, SSA/Ps without dysplasia rarely had WNT pathway gene mutations, except for 3 lesions with RNF43 mutations (7%). None of the SSA/Ps had CTNNB1 mutations or RSPO fusions. Thus, WNT pathway gene mutations were more common in SSA/Ps with dysplasia than in SSA/Ps without dysplasia (P=3.0×10). Consistently, nuclear β-catenin accumulation and MYC overexpression, indicative of active WNT signaling, were present in most of the SSA/Ps with dysplasia, but were rare in those without dysplasia. BRAF (86%) or KRAS mutations (7%) were identified in the majority of SSA/Ps, regardless of the presence or absence of dysplasia. MLH1 expression was lost in 14 SSA/Ps with dysplasia (30%). The majority of MLH1-deficient SSA/Ps with dysplasia had RNF43 mutations (86%), most of which were frameshift mutations involving mononucleotide repeats. In contrast, MLH1-retained lesions had less frequent RNF43 mutations with no hot spots (34%), and 4 had APC mutations (13%). These results suggest that WNT pathway gene mutations are involved in the development of dysplasia in SSA/Ps and that MLH1-deficient and MLH1-retained SSA/Ps with dysplasia exhibit distinct mutation profiles of WNT pathway genes.
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Affiliation(s)
- Taiki Hashimoto
- *Division of Pathology and Clinical Laboratories ∥Endoscopy Division, National Cancer Center Hospital †Course of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine ‡Division of Epigenomics §Division of Chemotherapy and Clinical Research #Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo ¶Division of Pathology, Research Center for Innovative Oncology, National Cancer Center, Chiba, Japan
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32
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Murakami T, Sakamoto N, Ritsuno H, Shibuya T, Osada T, Mitomi H, Yao T, Watanabe S. Distinct endoscopic characteristics of sessile serrated adenoma/polyp with and without dysplasia/carcinoma. Gastrointest Endosc 2017; 85:590-600. [PMID: 27663716 DOI: 10.1016/j.gie.2016.09.018] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Accepted: 09/13/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Sessile serrated adenoma/polyp (SSA/P) is a colorectal polyp that has malignant potential. However, the dysplastic components within an SSA/P can be difficult to detect. This study aimed to clarify the endoscopic characteristics of SSA/P with advanced histology. METHODS We examined 462 endoscopically or surgically resected lesions that were pathologically diagnosed as SSA/P, including 414 without and 41 with cytologic dysplasia, and 7 with invasive carcinoma. We retrospectively studied the clinicopathologic and endoscopic characteristics and performed pit pattern analysis. RESULTS A stepwise increase in the size of the SSA/P series was identified along with their dysplastic progression, although 19 of 48 (39.6%) SSA/Ps with dysplasia/carcinoma were ≤10 mm in size. Most lesions were covered with a mucus cap. Macroscopically, (semi)pedunculated morphology, double elevation, central depression, and reddishness were found more frequently in SSA/P with cytologic dysplasia and invasive carcinoma ([semi]pedunculated morphology, 17.1%/28.6%; double elevation, 63.4%/57.1%; central depression, 9.8%/28.6%; reddishness, 39.0%/85.7%) than in those without dysplasia (4.6%, 4.6%, 3.9%, and 3.4%, respectively). Furthermore, the presence of at least 1 of these 4 markers had high sensitivity (91.7%) for identifying the dysplasia/carcinoma within a SSA/P, with a specificity of 85.3%. In the pit pattern analysis, all SSA/Ps without dysplasia exhibited type II pit pattern only, whereas 94.4% of SSA/Ps with dysplasia/carcinoma showed type II in addition to type IIIL, IV, VI, or VN pit patterns. CONCLUSIONS In an SSA/P series, endoscopic characteristics, including (semi)pedunculated morphology, double elevation, central depression, and reddishness, in addition to the use of magnifying endoscopy, may be useful to accurately diagnose advanced histology within an SSA/P.
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Affiliation(s)
- Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan; Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hideaki Ritsuno
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tomoyoshi Shibuya
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Taro Osada
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hiroyuki Mitomi
- Department of Pathology, Japan Labor Health and Welfare Organization, Kanto Rosai Hospital, Kanagawa, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Sumio Watanabe
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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33
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Sharma SH, Thulasingam S, Chellappan DR, Chinnaswamy P, Nagarajan S. Morin and Esculetin supplementation modulates c-myc induced energy metabolism and attenuates neoplastic changes in rats challenged with the procarcinogen 1,2 - dimethylhydrazine. Eur J Pharmacol 2017; 796:20-31. [DOI: 10.1016/j.ejphar.2016.12.019] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 12/13/2016] [Accepted: 12/14/2016] [Indexed: 02/07/2023]
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Bettington M, Walker N, Rosty C, Brown I, Clouston A, McKeone D, Pearson SA, Leggett B, Whitehall V. Clinicopathological and molecular features of sessile serrated adenomas with dysplasia or carcinoma. Gut 2017; 66:97-106. [PMID: 26475632 DOI: 10.1136/gutjnl-2015-310456] [Citation(s) in RCA: 147] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Revised: 09/15/2015] [Accepted: 09/20/2015] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Sessile serrated adenomas (SSAs) are the precursors of at least 15% of colorectal carcinomas, but their biology is incompletely understood. We performed a clinicopathological and molecular analysis of a large number of the rarely observed SSAs with dysplasia/carcinoma to better define their features and the pathways by which they progress to carcinoma. DESIGN A cross-sectional analysis of 137 SSAs containing regions of dysplasia/carcinoma prospectively collected at a community GI pathology practice was conducted. Samples were examined for BRAF and KRAS mutations, the CpG island methylator phenotype (CIMP) and immunostained for MLH1, p53, p16, β-catenin and 0-6-methylguanine DNA methyltransferase (MGMT). RESULTS The median polyp size was 9 mm and 86.5% were proximal. Most were BRAF mutated (92.7%) and 94.0% showed CIMP. Mismatch repair deficiency, evidenced by loss of MLH1 (74.5%) is associated with older age (76.7 versus 71.0; p<0.0029), female gender (70% versus 36%; p<0.0008), proximal location (91% versus 72%; p<0.02), CIMP (98% versus 80%; p<0.02) and lack of aberrant p53 (7% versus 34%; p<0.001) when compared with the mismatch repair-proficient cases. Loss of p16 (43.1%) and gain of nuclear β-catenin (55.5%) were common in areas of dysplasia/cancer, irrespective of mismatch repair status. CONCLUSIONS SSAs containing dysplasia/carcinoma are predominantly small (<10 mm) and proximal. The mismatch repair status separates these lesions into distinct clinicopathological subgroups, although WNT activation and p16 silencing are common to both. Cases with dysplasia occur at a similar age to cases with carcinoma. This, together with the rarity of these 'caught in the act' lesions, suggests a rapid transition to malignancy following a long dwell time as an SSA without dysplasia.
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Affiliation(s)
- Mark Bettington
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Envoi Specialist Pathologists, Brisbane, Queensland, Australia.,The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Neal Walker
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Envoi Specialist Pathologists, Brisbane, Queensland, Australia
| | - Christophe Rosty
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Envoi Specialist Pathologists, Brisbane, Queensland, Australia
| | - Ian Brown
- Envoi Specialist Pathologists, Brisbane, Queensland, Australia
| | - Andrew Clouston
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Envoi Specialist Pathologists, Brisbane, Queensland, Australia
| | - Diane McKeone
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Sally-Ann Pearson
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Barbara Leggett
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,The Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
| | - Vicki Whitehall
- School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.,Department of Chemical Pathology, Pathology Queensland, Brisbane, Queensland, Australia
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35
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Fu T, Liu Y, Li K, Wan W, Pappou EP, Iacobuzio-Donahue CA, Kerner Z, Baylin SB, Wolfgang CL, Ahuja N. Tumors with unmethylated MLH1 and the CpG island methylator phenotype are associated with a poor prognosis in stage II colorectal cancer patients. Oncotarget 2016; 7:86480-86489. [PMID: 27880934 PMCID: PMC5349928 DOI: 10.18632/oncotarget.13441] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 11/09/2016] [Indexed: 01/17/2023] Open
Abstract
We previously developed a novel tumor subtype classification model for duodenal adenocarcinomas based on a combination of the CpG island methylator phenotype (CIMP) and MLH1 methylation status. Here, we tested the prognostic value of this model in stage II colorectal cancer (CRC) patients. Tumors were assigned to CIMP+/MLH1-unmethylated (MLH1-U), CIMP+/MLH1-methylated (MLH1-M), CIMP-/MLH1-U, or CIMP-/MLH1-M groups. Age, tumor location, lymphovascular invasion, and mucin production differed among the four patient subgroups, and CIMP+/MLH1-U tumors were more likely to have lymphovascular invasion and mucin production. Kaplan-Meier analyses revealed differences in both disease-free survival (DFS) and overall survival (OS) among the four groups. In a multivariate analysis, CIMP/MLH1 methylation status was predictive of both DFS and OS, and DFS and OS were shortest in CIMP+/MLH1-U stage II CRC patients. These results suggest that tumor subtype classification based on the combination of CIMP and MLH1 methylation status is informative in stage II CRC patients, and that CIMP+/MLH1-U tumors exhibit aggressive features and are associated with poor clinical outcomes.
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Affiliation(s)
- Tao Fu
- Department of Gastrointestinal Surgery II, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital, Wuhan University, Wuhan 430060, China
| | - Yanliang Liu
- Department of Gastrointestinal Surgery II, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital, Wuhan University, Wuhan 430060, China
| | - Kai Li
- Department of Gastrointestinal Surgery II, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital, Wuhan University, Wuhan 430060, China
| | - Weiwei Wan
- Department of Gastrointestinal Surgery II, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital, Wuhan University, Wuhan 430060, China
| | - Emmanouil P. Pappou
- Department of Colon and Rectal Surgery, Columbia University Medical Center, New York, NY 10032, USA
| | - Christine A. Iacobuzio-Donahue
- Department of Pathology and David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Zachary Kerner
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Stephen B. Baylin
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Christopher L. Wolfgang
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Nita Ahuja
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
- Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
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36
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Fu T, Sharmab A, Xie F, Liu Y, Li K, Wan W, Baylin SB, Wolfgang CL, Ahuja N. Methylation of MGMT Is Associated with Poor Prognosis in Patients with Stage III Duodenal Adenocarcinoma. PLoS One 2016; 11:e0162929. [PMID: 27643594 PMCID: PMC5028050 DOI: 10.1371/journal.pone.0162929] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 08/30/2016] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND O6-methylguanine-DNA methyltransferase (MGMT) methylation status has not been extensively investigated in duodenal adenocarcinoma (DA). The aim of this study was to evaluate the MGMT methylation status and examine its possible prognostic value in patients with stage III DA. METHODS Demographics, tumor characteristics and survival were available for 64 patients with stage III DA. MGMT methylation was detected by using MethyLight. A Cox proportional hazard model was built to predict survival, adjusted for clinicopathological characteristics and tumor molecular features, including the CpG island methylator phenotype (CIMP), microsatellite instability (MSI), and KRAS mutations. RESULTS MGMT methylation was detected in 17 of 64 (26.6%) patients, and was not correlated with sex, age, tumor differentiation, CIMP, MSI, or KRAS mutations. MGMT methylation was the only one factor associated with both overall survival (OS) and disease-free survival (DFS) on both univariate and multivariate analyses. In patients treated with surgery alone, MGMT-methylated group had worse OS and DFS when compared with MGMT-unmethylated group. However, in patients treated with chemotherapy/radiotherapy, outcomes became comparable between the two groups. CONCLUSIONS Our results demonstrate MGMT methylation is a reliable and independent prognostic factor in DAs. Methylation of MGMT is associated with poor prognosis in patients with stage III DAs.
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Affiliation(s)
- Tao Fu
- Department of Gastrointestinal Surgery II, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital, Wuhan University, Wuhan, China
| | - Anup Sharmab
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Fei Xie
- Department of Gastrointestinal Surgery II, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital, Wuhan University, Wuhan, China
| | - Yanliang Liu
- Department of Gastrointestinal Surgery II, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital, Wuhan University, Wuhan, China
| | - Kai Li
- Department of Gastrointestinal Surgery II, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital, Wuhan University, Wuhan, China
| | - Weiwei Wan
- Department of Gastrointestinal Surgery II, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital, Wuhan University, Wuhan, China
| | - Stephen B. Baylin
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Christopher L. Wolfgang
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Nita Ahuja
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
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Similar but different: distinct roles for KRAS and BRAF oncogenes in colorectal cancer development and therapy resistance. Oncotarget 2016; 6:20785-800. [PMID: 26299805 PMCID: PMC4673229 DOI: 10.18632/oncotarget.4750] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 07/17/2015] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is characterized by recurrent mutations deregulating key cell signaling cascades and providing the cancer cells with novel functional traits. Among the most frequent mutations in CRC are gain-of-function missense mutations in KRAS and BRAF. Oncogenic activation of KRAS and BRAF is mutually exclusive and occurs in approximately 40% and 10% of all CRCs, respectively. Here we summarize genetic alterations currently described in the literature and databases, indicating overlapping but also specific co-occurrences with either mutated BRAF or KRAS. We describe common and potentially specific biological functions of KRAS and BRAF oncoproteins in the intestinal epithelial cells and during initiation and progression of CRC. We discuss signal transduction networks, highlighting individual functions of oncogenic KRAS and BRAF in terms of feedback loops and their impact on treatment outcome. Finally, we give an update on current strategies of targeted therapeutic intervention in oncogenic RAS-RAF signaling networks for the treatment of metastatic CRC and outline future directions.
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Sekine S, Yamashita S, Tanabe T, Hashimoto T, Yoshida H, Taniguchi H, Kojima M, Shinmura K, Saito Y, Hiraoka N, Ushijima T, Ochiai A. Frequent PTPRK-RSPO3 fusions and RNF43 mutations in colorectal traditional serrated adenoma. J Pathol 2016; 239:133-8. [PMID: 26924569 DOI: 10.1002/path.4709] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 02/02/2016] [Accepted: 02/26/2016] [Indexed: 12/14/2022]
Abstract
The molecular mechanisms underlying the serrated pathway of colorectal tumourigenesis, particularly those related to traditional serrated adenomas (TSAs), are still poorly understood. In this study, we analysed genetic alterations in 188 colorectal polyps, including hyperplastic polyps, sessile serrated adenomas/polyps (SSA/Ps), TSAs, tubular adenomas, and tubulovillous adenomas by using targeted next-generation sequencing and reverse transcription-PCR. Our analyses showed that most TSAs (71%) contained genetic alterations in WNT pathway components. In particular, PTPRK-RSPO3 fusions (31%) and RNF43 mutations (24%) were frequently and almost exclusively observed in TSAs. Consistent with the WNT pathway activation, immunohistochemical analysis showed diffuse and focal nuclear accumulation of β-catenin in 53% and 30% of TSAs, respectively. APC mutations were observed in tubular and tubulovillous adenomas and in a subset of TSAs. BRAF mutations were exclusively and frequently encountered in serrated lesions. KRAS mutations were observed in all types of polyps, but were most commonly encountered in tubulovillous adenomas and TSAs. This study has demonstrated that TSAs frequently harbour genetic alterations that lead to WNT pathway activation, in addition to BRAF and KRAS mutations. In particular, PTPRK-RSPO3 fusions and RNF43 mutations were found to be characteristic genetic features of TSAs. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Shigeki Sekine
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.,Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Satoshi Yamashita
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Taro Tanabe
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Taiki Hashimoto
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Hiroshi Yoshida
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Hirokazu Taniguchi
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
| | - Motohiro Kojima
- Division of Pathology, Research Center for Innovative Oncology, National Cancer Center, Kashiwa, Chiba, Japan
| | - Kazuya Shinmura
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yutaka Saito
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Nobuyoshi Hiraoka
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.,Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Toshikazu Ushijima
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Atsushi Ochiai
- Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan.,Division of Pathology, Research Center for Innovative Oncology, National Cancer Center, Kashiwa, Chiba, Japan
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Gibson JA, Odze RD. Pathology of premalignant colorectal neoplasia. Dig Endosc 2016; 28:312-23. [PMID: 26861656 DOI: 10.1111/den.12633] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Revised: 01/29/2016] [Accepted: 02/05/2016] [Indexed: 02/08/2023]
Abstract
Colorectal cancer is a heterogeneous oncological disease that develops through several molecular pathways. Each pathway is associated with specific neoplastic precursor lesions. Classification of colorectal polyps and the molecular features of associated colorectal cancers have undergone significant changes. An understanding of colorectal carcinogenesis and the molecular features of colorectal carcinomas is now regarded as necessary for personalized treatment and management of patients with colon cancer, and even for patients undergoing screening colonoscopy for early detection and prevention of colorectal cancer. In the present review, we describe the pathological and molecular features of epithelial precursor lesions involved in the early phases of colorectal carcinogenesis.
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Affiliation(s)
- Joanna A Gibson
- Department of Pathology, Yale University School of Medicine, New Haven, USA
| | - Robert D Odze
- Department of Pathology, Brigham and Women's Hospital, Boston, USA
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40
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Fu T, Pappou EP, Guzzetta AA, de Freitas Calmon M, Sun L, Herrera A, Li F, Wolfgang CL, Baylin SB, Iacobuzio-Donahue CA, Tong W, Ahuja N. IGFBP-3 Gene Methylation in Primary Tumor Predicts Recurrence of Stage II Colorectal Cancers. Ann Surg 2016; 263:337-344. [PMID: 25822686 PMCID: PMC4648704 DOI: 10.1097/sla.0000000000001204] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES To evaluate the influence of IGFBP-3 methylation on recurrence in patients with stage II colorectal cancer (CRC) from 2 independent cohorts. BACKGROUND The relationship between IGFBP-3 methylation in primary tumors (PTs) or lymph nodes (LNs) and risk of recurrence in patients with stage II CRC treated with surgery alone is unknown. METHODS IGFBP-3 methylation of DNA from 115 PTs and 1641 LNs in patients with stage II CRC from 2 independent cohorts was analyzed. Forty patients developed recurrence, whereas 75 matched patients remained recurrence free for more than 2 years after surgery. Cox proportional hazard models were used to calculate hazard ratios (HRs) of recurrence, adjusted for patient and tumor characteristics. RESULTS Methylation of IGFBP-3 in PTs was identified to be significantly associated with risk of recurrence in the training set. The signature was tested in a validation set and classified 40.7% of patients as high risk. Five-year recurrence-free survival rates were 76.4% and 58.3% for low- and high-risk patients, respectively, with an HR of 2.21 (95% confidence interval, 1.04-4.68; P = 0.039). In multivariate analysis, the signature remained the most significant prognostic factor, with an HR of 2.40 (95% confidence interval, 1.10-5.25; P = 0.029). A combined analysis of 1641 LNs from the 2 sets identified IGFBP-3 methylation in LNs was not associated with risk of recurrence. CONCLUSIONS Detection of IGFBP-3 methylation in PTs, but not in LNs, provides a powerful tool for the identification of patients with stage II CRC at high risk of recurrence.
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Affiliation(s)
- Tao Fu
- Department of Gastrointestinal Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
- Department of Surgery
| | | | | | | | | | | | - Fan Li
- Department of Gastrointestinal Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | | | - Stephen B. Baylin
- Department of Oncology, The Sydney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Christine A. Iacobuzio-Donahue
- Department of Pathology and David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Weidong Tong
- Department of Gastrointestinal Surgery, Daping Hospital, Third Military Medical University, Chongqing, China
| | - Nita Ahuja
- Department of Surgery
- Department of Oncology, The Sydney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD
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Wnt/β-catenin signaling plays an ever-expanding role in stem cell self-renewal, tumorigenesis and cancer chemoresistance. Genes Dis 2016; 3:11-40. [PMID: 27077077 PMCID: PMC4827448 DOI: 10.1016/j.gendis.2015.12.004] [Citation(s) in RCA: 208] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Wnt signaling transduces evolutionarily conserved pathways which play important roles in initiating and regulating a diverse range of cellular activities, including cell proliferation, calcium homeostasis, and cell polarity. The role of Wnt signaling in controlling cell proliferation and stem cell self-renewal is primarily carried out through the canonical pathway, which is the best-characterized the multiple Wnt signaling branches. The past 10 years has seen a rapid expansion in our understanding of the complexity of this pathway, as many new components of Wnt signaling have been identified and linked to signaling regulation, stem cell functions, and adult tissue homeostasis. Additionally, a substantial body of evidence links Wnt signaling to tumorigenesis of cancer types and implicates it in the development of cancer drug resistance. Thus, a better understanding of the mechanisms by which dysregulation of Wnt signaling precedes the development and progression of human cancer may hasten the development of pathway inhibitors to augment current therapy. This review summarizes and synthesizes our current knowledge of the canonical Wnt pathway in development and disease. We begin with an overview of the components of the canonical Wnt signaling pathway and delve into the role this pathway has been shown to play in stemness, tumorigenesis, and cancer drug resistance. Ultimately, we hope to present an organized collection of evidence implicating Wnt signaling in tumorigenesis and chemoresistance to facilitate the pursuit of Wnt pathway modulators that may improve outcomes of cancers in which Wnt signaling contributes to aggressive disease and/or treatment resistance.
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42
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Serrated lesions of the appendix in serrated polyposis patients. Pathology 2016; 48:30-4. [DOI: 10.1016/j.pathol.2015.11.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 08/07/2015] [Accepted: 08/11/2015] [Indexed: 12/21/2022]
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Rusinek D, Swierniak M, Chmielik E, Kowal M, Kowalska M, Cyplinska R, Czarniecka A, Piglowski W, Korfanty J, Chekan M, Krajewska J, Szpak-Ulczok S, Jarzab M, Widlak W, Jarzab B. BRAFV600E-Associated Gene Expression Profile: Early Changes in the Transcriptome, Based on a Transgenic Mouse Model of Papillary Thyroid Carcinoma. PLoS One 2015; 10:e0143688. [PMID: 26625260 PMCID: PMC4666467 DOI: 10.1371/journal.pone.0143688] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Accepted: 11/09/2015] [Indexed: 01/11/2023] Open
Abstract
Background The molecular mechanisms driving the papillary thyroid carcinoma (PTC) are still poorly understood. The most frequent genetic alteration in PTC is the BRAFV600E mutation–its impact may extend even beyond PTC genomic profile and influence the tumor characteristics and even clinical behavior. Methods In order to identify BRAF-dependent signature of early carcinogenesis in PTC, a transgenic mouse model with BRAFV600E-induced PTC was developed. Mice thyroid samples were used in microarray analysis and the data were referred to a human thyroid dataset. Results Most of BRAF(+) mice developed malignant lesions. Nevertheless, 16% of BRAF(+) mice displayed only benign hyperplastic lesions or apparently asymptomatic thyroids. After comparison of non-malignant BRAF(+) thyroids to BRAF(−) ones, we selected 862 significantly deregulated genes. When the mouse BRAF-dependent signature was transposed to the human HG-U133A microarray, we identified 532 genes, potentially indicating the BRAF signature (representing early changes, not related to developed malignant tumor). Comparing BRAF(+) PTCs to healthy human thyroids, PTCs without BRAF and RET alterations and RET(+), RAS(+) PTCs, 18 of these 532 genes displayed significantly deregulated expression in all subgroups. All 18 genes, among them 7 novel and previously not reported, were validated as BRAFV600E-specific in the dataset of independent PTC samples, made available by The Cancer Genome Atlas Project. Conclusion The study identified 7 BRAF-induced genes that are specific for BRAF V600E-driven PTC and not previously reported as related to BRAF mutation or thyroid carcinoma: MMD, ITPR3, AACS, LAD1, PVRL3, ALDH3B1, and RASA1. The full signature of BRAF-related 532 genes may encompass other BRAF-related important transcripts and require further study.
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Affiliation(s)
- Dagmara Rusinek
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
- * E-mail:
| | - Michal Swierniak
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
- Genomic Medicine, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
| | - Ewa Chmielik
- Department of Tumor Pathology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Monika Kowal
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Malgorzata Kowalska
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Renata Cyplinska
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Agnieszka Czarniecka
- Department of Oncological and Reconstructive Surgery, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Wojciech Piglowski
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Joanna Korfanty
- Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Mykola Chekan
- Department of Tumor Pathology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Jolanta Krajewska
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Sylwia Szpak-Ulczok
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Michal Jarzab
- III Department of Radiotherapy and Chemotherapy, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Wieslawa Widlak
- III Department of Radiotherapy and Chemotherapy, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
- II Department of Radiotherapy and Chemotherapy, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
| | - Barbara Jarzab
- Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland
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Sporadic microsatellite instability-high colon cancers rarely display immunohistochemical evidence of Wnt signaling activation. Am J Surg Pathol 2015; 39:313-7. [PMID: 25602793 DOI: 10.1097/pas.0000000000000380] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Most sporadic colonic adenocarcinomas are microsatellite stable (MSS) and arise from conventional adenomas by dysregulation of the APC/β-catenin/Wnt signaling pathway. Sporadic adenocarcinomas with a high degree of microsatellite instability (MSI) likely arise from sessile serrated polyps through the serrated neoplastic pathway. These polyps contain BRAF mutations and are prone to epigenetic methylation that ultimately silences MLH1, leading to MSI and heralding progression of dysplasia to invasive adenocarcinoma. Most investigators believe that these 2 models of cancer progression are mutually exclusive, although recent studies describe Wnt signaling activation in serrated polyps and propose that it plays a role in the development of sporadic colonic adenocarcinomas with MSI. We sought to test this hypothesis by evaluating β-catenin immunoexpression in 44 sporadic microsatellite unstable adenocarcinomas and 44 MSS colon cancers. We defined sporadic MSI-high carcinomas as those with loss of MLH1 and PMS2 immunostaining and BRAF V600E mutations that occurred in patients 50 years of age or older without a family history of colonic adenocarcinoma or Lynch syndrome. Forty-one (93%) of these carcinomas displayed membranous β-catenin staining only, compared with 28 (64%) site-matched MSS tumors with abnormal nuclear β-catenin staining.
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Bettington ML, Walker NI, Rosty C, Brown IS, Clouston AD, McKeone DM, Pearson SA, Klein K, Leggett BA, Whitehall VLJ. A clinicopathological and molecular analysis of 200 traditional serrated adenomas. Mod Pathol 2015; 28:414-27. [PMID: 25216220 DOI: 10.1038/modpathol.2014.122] [Citation(s) in RCA: 126] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2014] [Revised: 06/13/2014] [Accepted: 06/15/2014] [Indexed: 12/12/2022]
Abstract
The traditional serrated adenoma is the least common colorectal serrated polyp. The clinicopathological features and molecular drivers of these polyps require further investigation. We have prospectively collected a cohort of 200 ordinary and advanced traditional serrated adenomas and performed BRAF and KRAS mutational profiling, CpG island methylator phenotype analysis, and immunohistochemistry for a panel of 7 antibodies (MLH1, β-catenin, p53, p16, Ki67, CK7, and CK20) on all cases. The mean age of the patients was 64 years and 50% were female. Of the polyps, 71% were distal. Advanced histology (overt dysplasia or carcinoma) was present in 19% of cases. BRAF mutation was present in 67% and KRAS mutation in 22%. BRAF mutant traditional serrated adenomas were more frequently proximal (39% versus 2%; P≤0.0001), were exclusively associated with a precursor polyp (57% versus 0%; P≤0.0001), and were more frequently CpG island methylator phenotype high (60% versus 16%; P≤0.0001) than KRAS mutant traditional serrated adenomas. Advanced traditional serrated adenomas retained MLH1 expression in 97%, showed strong p53 staining in 55%, and nuclear β-catenin staining in 40%. P16 staining was lost in the advanced areas of 55% of BRAF mutant traditional serrated adenomas compared with 10% of the advanced areas of KRAS mutant or BRAF/KRAS wild-type traditional serrated adenomas. BRAF and KRAS mutant traditional serrated adenomas are morphologically related but biologically disparate polyps with distinctive clinicopathological and molecular features. The overwhelming majority of traditional serrated adenomas retain mismatch repair enzyme function indicating a microsatellite-stable phenotype. Malignant progression occurs via TP53 mutation and Wnt pathway activation regardless of mutation status. However, CDKN2A (encoding the p16 protein) is silenced nearly exclusively in the advanced areas of the BRAF mutant traditional serrated adenomas. Thus, the BRAF mutant traditional serrated adenoma represents an important precursor of the aggressive BRAF mutant, microsatellite-stable subtype of colorectal carcinoma.
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Affiliation(s)
- Mark L Bettington
- 1] The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia [2] The School of Medicine, The University of Queensland, Brisbane, QLD, Australia [3] Envoi Specialist Pathologists, Brisbane, QLD, Australia
| | - Neal I Walker
- 1] The School of Medicine, The University of Queensland, Brisbane, QLD, Australia [2] Envoi Specialist Pathologists, Brisbane, QLD, Australia
| | - Christophe Rosty
- 1] The School of Medicine, The University of Queensland, Brisbane, QLD, Australia [2] Envoi Specialist Pathologists, Brisbane, QLD, Australia [3] Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Carlton, VIC, Australia
| | - Ian S Brown
- 1] Envoi Specialist Pathologists, Brisbane, QLD, Australia [2] Department of Anatomical Pathology, Pathology Queensland, Brisbane, QLD, Australia
| | - Andrew D Clouston
- 1] The School of Medicine, The University of Queensland, Brisbane, QLD, Australia [2] Envoi Specialist Pathologists, Brisbane, QLD, Australia [3] Department of Anatomical Pathology, Pathology Queensland, Brisbane, QLD, Australia
| | - Diane M McKeone
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Sally-Ann Pearson
- The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Kerenaftali Klein
- Statistics Unit, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Barbara A Leggett
- 1] The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia [2] The School of Medicine, The University of Queensland, Brisbane, QLD, Australia [3] The Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
| | - Vicki L J Whitehall
- 1] The Conjoint Gastroenterology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia [2] The School of Medicine, The University of Queensland, Brisbane, QLD, Australia [3] Department of Chemical Pathology, Pathology Queensland, Brisbane, QLD, Australia
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Murakami T, Mitomi H, Saito T, Takahashi M, Sakamoto N, Fukui N, Yao T, Watanabe S. Distinct WNT/β-catenin signaling activation in the serrated neoplasia pathway and the adenoma-carcinoma sequence of the colorectum. Mod Pathol 2015; 28:146-58. [PMID: 24925057 DOI: 10.1038/modpathol.2014.41] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2013] [Revised: 01/14/2014] [Accepted: 01/15/2014] [Indexed: 12/14/2022]
Abstract
Sessile serrated adenoma/polyp (SSA/P) is considered as an early precursor in the serrated neoplasia pathway leading to colorectal cancer development. The conventional adenoma-carcinoma sequence is associated with activation of the WNT signaling pathway, although its role in serrated lesions is still controversial. To clarify differences in WNT signaling activation in association with MLH1 methylation or BRAF/KRAS mutations between serrated and conventional routes, we performed β-catenin immunostaining, methylation-specific PCR for MLH1 and WNT signaling associated genes such as AXIN2, APC, and MCC and secreted frizzled-related proteins (SFRPs), and direct sequencing of BRAF/KRAS in 27 SSA/Ps, 14 SSA/Ps with high-grade dysplasia and 9 SSA/Ps with submucosal carcinoma, as well as 19 conventional adenomas, 26 adenomas with high-grade dysplasia and 25 adenomas with submucosal carcinoma. Nuclear β-catenin labelings were significantly lower in the serrated series than in their adenoma counterparts, and a significant increment in those labelings was found from SSA/Ps to those with high-grade dysplasia or submucosal carcinoma. The frequency of MLH1 and SFRP4 methylation was significantly higher in SSA/P series, as compared with corresponding adenoma series. AXIN2 and MCC were more frequently methylated in SSA/Ps with high-grade dysplasia and those with submucosal carcinoma than in adenoma counterparts. Stepwise increment of AXIN2 and MCC methylation was identified from SSA/Ps through those with high-grade dysplasia to those with submucosal carcinoma. A significant correlation was seen between nuclear β-catenin expression and methylation of AXIN2 or MCC in the SSA/P series. BRAF mutation was more frequent, whereas KRAS mutation was less frequent in the SSA/P series as compared with the adenoma series. There was an inverse association of BRAF mutation with AXIN2 methylation in SSA/P series. In conclusion, WNT/β-catenin signal activation mediated by the methylation of SFRP4, MCC, and AXIN2 may make different contributions to colorectal neoplasia between the serrated and conventional routes.
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Affiliation(s)
- Takashi Murakami
- 1] Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan [2] Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Hiroyuki Mitomi
- Department of Surgical and Molecular Pathology, Dokkyo Medical University School of Medicine, Tochigi, Japan
| | - Tsuyoshi Saito
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Michiko Takahashi
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoto Sakamoto
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Naoshi Fukui
- Clinical Research Center, National Hospital Organization Sagamihara Hospital, Kanagawa, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Sumio Watanabe
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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Ito M, Mitsuhashi K, Igarashi H, Nosho K, Naito T, Yoshii S, Takahashi H, Fujita M, Sukawa Y, Yamamoto E, Takahashi T, Adachi Y, Nojima M, Sasaki Y, Tokino T, Baba Y, Maruyama R, Suzuki H, Imai K, Yamamoto H, Shinomura Y. MicroRNA-31 expression in relation to BRAF mutation, CpG island methylation and colorectal continuum in serrated lesions. Int J Cancer 2014; 135:2507-2515. [PMID: 24752710 DOI: 10.1002/ijc.28920] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2014] [Revised: 03/26/2014] [Accepted: 04/09/2014] [Indexed: 12/18/2022]
Abstract
The CpG island methylator phenotype (CIMP) is a distinct form of epigenomic instability. Many CIMP-high colorectal cancers (CRCs) with BRAF mutation are considered to arise from serrated pathway. We recently reported that microRNA-31 (miR-31) is associated with BRAF mutation in colorectal tumors. Emerging new approaches have revealed gradual changes in BRAF mutation and CIMP-high throughout the colorectum in CRCs. Here, we attempted to identify a possible association between miR-31 and epigenetic features in serrated pathway, and hypothesized that miR-31 supports the "colorectal continuum" concept. We evaluated miR-31 expression, BRAF mutation and epigenetic features including CIMP status in 381 serrated lesions and 222 non-serrated adenomas and examined associations between them and tumor location (rectum; sigmoid, descending, transverse and ascending colon and cecum). A significant association was observed between high miR-31 expression and CIMP-high status in serrated lesions with BRAF mutation (p = 0.0001). In contrast, miR-31 was slightly but insignificantly associated with CIMP status in the cases with wild-type BRAF. miR-31 expression in sessile serrated adenomas (SSAs) with cytological dysplasia was higher than that in SSAs, whereas, no significant difference was observed between traditional serrated adenomas (TSAs) and TSAs with high-grade dysplasia. The frequency of miR-31, BRAF mutation CIMP-high and MLH1 methylation increased gradually from the rectum to cecum in serrated lesions. In conclusion, miR-31 expression was associated with CIMP-high status in serrated lesions with BRAF mutation. Our data also suggested that miR-31 plays an important role in SSA evolution and may be a molecule supporting the colorectal continuum.
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Affiliation(s)
- Miki Ito
- Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo, Japan
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Liu CX, Liu HY, Li XF, Niu Q, Jia XF. Expression of EphB2/EphrinB2 in canceration of serrated polyps. Shijie Huaren Xiaohua Zazhi 2014; 22:4872-4877. [DOI: 10.11569/wcjd.v22.i31.4872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore the role of EphB2 and its ligand EphrinB2 in colorectal tumorigenesis.
METHODS: The expression of EphB2 and EphrinB2 in 72 colorectal cancer, 64 serrated polyp and 33 normal colon tissues was detected by immunohistochemistry.
RESULTS: The area of EphB2 positive signal was located in the crypt base and the lower 2/3 region, while the positive area of EphrinB2 was mainly located throughout the crypt. EphB2 was expressed in the majority of normal colonic mucosa tissues, but showed a decreasing trend in serrated polyps and colorectal cancer. The positive rate of EphrinB2 in the normal mucosa was significantly lower than those in colorectal cancer and serrated polyps (P < 0.05). The expression rate of EphrinB2 in the normal colonic mucosa was significantly higher than those in serrated polyps and colorectal cancer (P < 0.05).
CONCLUSION: EphB2 may inhibit the occurrence of colorectal cancer. EphrinB2 may promote intestinal tumor growth.
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Transgenic expression of oncogenic BRAF induces loss of stem cells in the mouse intestine, which is antagonized by β-catenin activity. Oncogene 2014; 34:3164-75. [DOI: 10.1038/onc.2014.247] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Revised: 06/19/2014] [Accepted: 06/24/2014] [Indexed: 12/17/2022]
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Naito T, Nosho K, Ito M, Igarashi H, Mitsuhashi K, Yoshii S, Aoki H, Nomura M, Sukawa Y, Yamamoto E, Adachi Y, Takahashi H, Hosokawa M, Fujita M, Takenouchi T, Maruyama R, Suzuki H, Baba Y, Imai K, Yamamoto H, Ogino S, Shinomura Y. IGF2 differentially methylated region hypomethylation in relation to pathological and molecular features of serrated lesions. World J Gastroenterol 2014; 20:10050-10061. [PMID: 25110432 PMCID: PMC4123334 DOI: 10.3748/wjg.v20.i29.10050] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2014] [Revised: 03/01/2014] [Accepted: 04/21/2014] [Indexed: 02/07/2023] Open
Abstract
AIM To investigate insulin-like growth factor 2 (IGF2) differentially methylated region (DMR)0 hypomethylation in relation to clinicopathological and molecular features in colorectal serrated lesions. METHODS To accurately analyze the association between the histological types and molecular features of each type of serrated lesion, we consecutively collected 1386 formalin-fixed paraffin-embedded tissue specimens that comprised all histological types [hyperplastic polyps (HPs, n = 121), sessile serrated adenomas (SSAs, n = 132), traditional serrated adenomas (TSAs, n = 111), non-serrated adenomas (n = 195), and colorectal cancers (CRCs, n = 827)]. We evaluated the methylation levels of IGF2 DMR0 and long interspersed nucleotide element-1 (LINE-1) in HPs (n = 115), SSAs (n = 120), SSAs with cytological dysplasia (n = 10), TSAs (n = 91), TSAs with high-grade dysplasia (HGD) (n = 15), non-serrated adenomas (n = 80), non-serrated adenomas with HGD (n = 105), and CRCs (n = 794). For the accurate quantification of the relative methylation levels (scale 0%-100%) of IGF2 DMR0 and LINE-1, we used bisulfite pyrosequencing method. Tumor specimens were analyzed for microsatellite instability, KRAS (codons 12 and 13), BRAF (V600E), and PIK3CA (exons 9 and 20) mutations; MLH1 and MGMT methylation; and IGF2 expression by immunohistochemistry. RESULTS The distribution of the IGF2 DMR0 methylation level in 351 serrated lesions and 185 non-serrated adenomas (with or without HGD) was as follows: mean 61.7, median 62.5, SD 18.0, range 5.0-99.0, interquartile range 49.5-74.4. The IGF2 DMR0 methylation level was divided into quartiles (Q1 ≥ 74.5, Q2 62.6-74.4, Q3 49.6-62.5, Q4 ≤ 49.5) for further analysis. With regard to the histological type, the IGF2 DMR0 methylation levels of SSAs (mean ± SD, 73.1 ± 12.3) were significantly higher than those of HPs (61.9 ± 20.5), TSAs (61.6 ± 19.6), and non-serrated adenomas (59.0 ± 15.8) (P < 0.0001). The IGF2 DMR0 methylation level was inversely correlated with the IGF2 expression level (r = -0.21, P = 0.0051). IGF2 DMR0 hypomethylation was less frequently detected in SSAs compared with HPs, TSAs, and non-serrated adenomas (P < 0.0001). Multivariate logistic regression analysis also showed that IGF2 DMR0 hypomethylation was inversely associated with SSAs (P < 0.0001). The methylation levels of IGF2 DMR0 and LINE-1 in TSAs with HGD (50.2 ± 18.7 and 55.7 ± 5.4, respectively) were significantly lower than those in TSAs (61.6 ± 19.6 and 58.8 ± 4.7, respectively) (IGF2 DMR0, P = 0.038; LINE-1, P = 0.024). CONCLUSION IGF2 DMR0 hypomethylation may be an infrequent epigenetic alteration in the SSA pathway. Hypomethylation of IGF2 DMR0 and LINE-1 may play a role in TSA pathway progression.
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