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González A, Fullaondo A, Odriozola A. Host genetics-associated mechanisms in colorectal cancer. ADVANCES IN GENETICS 2024; 112:83-122. [PMID: 39396843 DOI: 10.1016/bs.adgen.2024.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Colorectal cancer (CRC) represents the second leading cause of cancer incidence and the third leading cause of cancer deaths worldwide. There is currently a lack of understanding of the onset of CRC, hindering the development of effective prevention strategies, early detection methods and the selection of appropriate therapies. This article outlines the key aspects of host genetics currently known about the origin and development of CRC. The organisation of the colonic crypts is described. It discusses how the transformation of a normal cell to a cancer cell occurs and how that malignant cell can populate an entire colonic crypt, promoting colorectal carcinogenesis. Current knowledge about the cell of origin of CRC is discussed, and the two morphological pathways that can give rise to CRC, the classical and alternative pathways, are presented. Due to the molecular heterogeneity of CRC, each of these pathways has been associated with different molecular mechanisms, including chromosomal and microsatellite genetic instability, as well as the CpG island methylator phenotype. Finally, different CRC classification systems are described based on genetic, epigenetic and transcriptomic alterations, allowing diagnosis and treatment personalisation.
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Affiliation(s)
- Adriana González
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | - Asier Fullaondo
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain
| | - Adrian Odriozola
- Hologenomics Research Group, Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country, Spain.
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Su MC, Hsu CH, Chen KC, Lin JR, Li HY, Fang YT, Huang RYJ, Jeng YM. Identification of Early Events in Serrated Pathway Colorectal Tumorigenesis by Using Digital Spatial Profiling. Pathobiology 2024; 91:393-410. [PMID: 38830348 PMCID: PMC11614314 DOI: 10.1159/000539612] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 05/30/2024] [Indexed: 06/05/2024] Open
Abstract
INTRODUCTION The colorectal serrated pathway involves precursor lesions known as sessile serrated lesions (SSL) and traditional serrated adenomas (TSA). Mutations in BRAF or KRAS are crucial early events in this pathway. Additional genetic and epigenetic changes contribute to the progression of these lesions into high-grade lesions and, eventually, invasive carcinoma. METHODS We employed digital spatial profiling to investigate the transcriptional changes associated with SSL and TSA. The genes identified are confirmed by immunohistochemical (IHC) staining. Colorectal cancer (CRC) cell lines with CEACAM6 overexpression and knockdown were established to study the roles of CEACAM6 on tumorigenesis of CRC. RESULTS Ten genes were upregulated in SSL and TSA, and seven were upregulated in both types of lesions. IHC staining confirmed overexpression of CEACAM6, LCN2, KRT19, and lysozyme in SSL and TSA. CEACAM6 expression is an early event in the serrated pathway but a late event in the conventional pathway. Using cell line models, we confirmed that CEACAM6 promotes CRC cells' proliferation, migration, and invasion abilities. CONCLUSION These results highlight that the transcriptional changes in the early stages of tumorigenesis exhibit relative uniformity. Identifying these early events may hold significant promise in elucidating the mechanisms behind tumor initiation.
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Affiliation(s)
- Min-Cheng Su
- Department of Pathology, Min-Sheng General Hospital, Taoyuan, Taiwan
| | - Ching-Hsiang Hsu
- Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan
| | - Ko-Chen Chen
- School of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
| | - Jun-Ru Lin
- Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan
| | - Huei-Ying Li
- Medical Microbiota Center of the First Core Laboratory, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Ting Fang
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
| | - Ruby Yun-Ju Huang
- School of Medicine, National Taiwan University, Taipei, Taiwan
- Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
| | - Yung-Ming Jeng
- Graduate Institute of Pathology, National Taiwan University, Taipei, Taiwan
- Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan
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Yoshida N, Suzuki S, Inoue K, Aniwan S, Chiu HM, Laohavichitra K, Chirapongsathorn S, Yamamura T, Kuo CY, Ang TL, Takezawa T, Rerknimitr R, Ishikawa H. Analysis of the Characteristics of Coexisting Lesions in Colorectal Cancer Patients in an International Study: A Subgroup Analysis of the ATLAS Trial. Digestion 2024; 105:280-290. [PMID: 38631318 DOI: 10.1159/000538955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 04/16/2024] [Indexed: 04/19/2024]
Abstract
INTRODUCTION We investigated coexisting lesion types in patients with invasive colorectal cancer (CRC) in a multinational study for comprehending the adenoma-carcinoma and serrated pathway about the development of CRC. METHODS We retrospectively reviewed 3,050 patients enrolled in the international randomized controlled trial (ATLAS study) to evaluate the colorectal polyp detection performance of image-enhanced endoscopy in 11 institutions in four Asian countries/regions. In the current study, as a subgroup analysis of the ATLAS study, 92 CRC patients were extracted and compared to 2,958 patients without CRC to examine the effects of age, sex, and coexisting lesion types (high-grade adenoma [HGA], low-grade adenoma with villous component [LGAV], 10 adenomas, adenoma ≥10 mm, sessile serrated lesions [SSLs], and SSLs with dysplasia [SSLD]). Additional analyses of coexisting lesion types were performed according to sex and location of CRC (right- or left-sided). RESULTS A multivariate analysis showed that HGA (odds ratio [95% confidence interval] 4.29 [2.16-8.18]; p < 0.01), LGAV (3.02 [1.16-7.83], p = 0.02), and age (1.04 [1.01-1.06], p = 0.01) were independently associated with CRC. According to sex, the coexisting lesion types significantly associated with CRC were LGAV (5.58 [1.94-16.0], p < 0.01) and HGA (4.46 [1.95-10.20], p < 0.01) in males and HGA (4.82 [1.47-15.80], p < 0.01) in females. Regarding the location of CRC, SSLD (21.9 [1.31-365.0], p = 0.03) was significant for right-sided CRC, and HGA (5.22 [2.39-11.4], p < 0.01) and LGAV (3.46 [1.13-10.6], p = 0.02) were significant for left-sided CRC. CONCLUSIONS The significant coexisting lesions in CRC differed according to sex and location. These findings may contribute to comprehending the pathogenesis of CRC.
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Affiliation(s)
- Naohisa Yoshida
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan,
| | - Sho Suzuki
- Department of Gastroenterology and Hepatology, International University of Health and Welfare, School of Medicine, Chiba, Japan
| | - Ken Inoue
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Satimai Aniwan
- Center of Excellence in Endoscopy for Gastrointestinal Oncology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Han-Mo Chiu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | | | - Sakkarin Chirapongsathorn
- Division of Gastroenterology and Hepatology, Department of Medicine, Phramongkutklao Hospital and College of Medicine, Bangkok, Thailand
| | - Takeshi Yamamura
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Chen-Ya Kuo
- Department of Internal Medicine, Fu Jen Catholic University Hospital, New Taipei City, Taiwan
| | - Tiing Leong Ang
- Department of Gastroenterology and Hepatology, Changi General Hospital, SingHealth, Singapore, Singapore
| | - Takahito Takezawa
- Division of Gastroenterology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Rungsun Rerknimitr
- Center of Excellence in Endoscopy for Gastrointestinal Oncology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Hideki Ishikawa
- Department of Molecular-Targeting Cancer Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan
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Soo JMP, Koh FHX. Detection of sessile serrated adenoma using artificial intelligence-enhanced endoscopy: an Asian perspective. ANZ J Surg 2024; 94:362-365. [PMID: 38149749 DOI: 10.1111/ans.18785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Accepted: 11/04/2023] [Indexed: 12/28/2023]
Abstract
BACKGROUND As the serrated pathway has gained prominence as an alternative colorectal carcinogenesis pathway, sessile serrated adenomas or polyps (SSA/P) have been highlighted as lesions to rule out during colonoscopy. These lesions are however morphologically difficult to detect on endoscopy and can be mistaken for hyperplastic polyps due to similar endoscopic features. With the underlying nature of rapid progression and malignant transformation, interval cancer is a likely consequence of undetected or overlooked SSA/P. Real-time artificial intelligence (AI)-assisted colonoscopy via the computer-assisted detection system (CADe) is an increasingly useful tool in improving adenoma detection rate by providing a second eye during the procedure. In this article, we describe a guide through a video to illustrate the detection of SSA/P during AI-assisted colonoscopy. METHODS Consultant-grade endoscopists utilized real-time AI-assisted colonoscopy device, as part of a larger prospective study, to detect suspicious lesions which were later histopathologically confirmed to be SSA/P. RESULTS All lesions were picked up by the CADe where a real-time green box highlighted suspicious polyps to the clinician. Three SSA/P of varying morphology are described with reference to classical SSA/P features and with comparison to the features of the hyperplastic polyp found in our study. All three SSA/P observed are in keeping with the JNET Classification (Type 1). CONCLUSION In conclusion, CADe is a most useful aid to clinicians during endoscopy in the detection of SSA/P but must be complemented with factors such as good endoscopy skill and bowel prep for effective detection, and biopsy coupled with subsequent accurate histological diagnosis.
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Affiliation(s)
- Joycelyn Mun-Peng Soo
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Frederick Hong-Xiang Koh
- Colorectal Service, Department of General Surgery, Sengkang General Hospital, SingHealth Services, Singapore, Singapore
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Tong K, Bandari M, Carrick JN, Zenkevich A, Kothari OA, Shamshad E, Stefanik K, Haro KS, Perekatt AO, Verzi MP. In Vitro Organoid-Based Assays Reveal SMAD4 Tumor-Suppressive Mechanisms for Serrated Colorectal Cancer Invasion. Cancers (Basel) 2023; 15:5820. [PMID: 38136364 PMCID: PMC10742020 DOI: 10.3390/cancers15245820] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 12/08/2023] [Accepted: 12/11/2023] [Indexed: 12/24/2023] Open
Abstract
Colon cancer is the third most prominent cancer and second leading cause of cancer-related deaths in the United States. Up to 20% of colon cancers follow the serrated tumor pathway driven by mutations in the MAPK pathway. Loss of SMAD4 function occurs in the majority of late-stage colon cancers and is associated with aggressive cancer progression. Therefore, it is important to develop technology to accurately model and better understand the genetic mechanisms behind cancer invasion. Organoids derived from tumors found in the Smad4KO BRAFV600E/+ mouse model present multiple phenotypes characteristic of invasion both in ex vivo and in vivo systems. Smad4KO BRAFV600E/+ tumor organoids can migrate through 3D culture and infiltrate through transwell membranes. This invasive behavior can be suppressed when SMAD4 is re-expressed in the tumor organoids. RNA-Seq analysis reveals that SMAD4 expression in organoids rapidly regulates transcripts associated with extracellular matrix and secreted proteins, suggesting that the mechanisms employed by SMAD4 to inhibit invasion are associated with regulation of extracellular matrix and secretory pathways. These findings indicate new models to study SMAD4 regulation of tumor invasion and an additional layer of complexity in the tumor-suppressive function of the SMAD4/Tgfβ pathway.
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Affiliation(s)
- Kevin Tong
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
- Human Genetics Institute of New Jersey, Piscataway, NJ 08854, USA
- Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
- Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USA
- Department of Medical Sciences, Hackensack Meridian Health School of Medicine, Nutley, NJ 07110, USA
| | - Manisha Bandari
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
| | - Jillian N. Carrick
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
- Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USA
| | - Anastasia Zenkevich
- Hackensack Meridian Health Center for Discovery and Innovation, Nutley, NJ 07110, USA
| | - Om A. Kothari
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
| | - Eman Shamshad
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
| | - Katarina Stefanik
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
- Department of Biology, The College of New Jersey, Ewing Township, NJ 08618, USA
| | - Katherine S. Haro
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
| | - Ansu O. Perekatt
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
- Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ 07030, USA
| | - Michael P. Verzi
- Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA (A.O.P.)
- Human Genetics Institute of New Jersey, Piscataway, NJ 08854, USA
- Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
- Rutgers Center for Lipid Research, New Brunswick, NJ 08901, USA
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Kasprzak A. Prognostic Biomarkers of Cell Proliferation in Colorectal Cancer (CRC): From Immunohistochemistry to Molecular Biology Techniques. Cancers (Basel) 2023; 15:4570. [PMID: 37760539 PMCID: PMC10526446 DOI: 10.3390/cancers15184570] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/04/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and severe malignancies worldwide. Recent advances in diagnostic methods allow for more accurate identification and detection of several molecular biomarkers associated with this cancer. Nonetheless, non-invasive and effective prognostic and predictive testing in CRC patients remains challenging. Classical prognostic genetic markers comprise mutations in several genes (e.g., APC, KRAS/BRAF, TGF-β, and TP53). Furthermore, CIN and MSI serve as chromosomal markers, while epigenetic markers include CIMP and many other candidates such as SERP, p14, p16, LINE-1, and RASSF1A. The number of proliferation-related long non-coding RNAs (e.g., SNHG1, SNHG6, MALAT-1, CRNDE) and microRNAs (e.g., miR-20a, miR-21, miR-143, miR-145, miR-181a/b) that could serve as potential CRC markers has also steadily increased in recent years. Among the immunohistochemical (IHC) proliferative markers, the prognostic value regarding the patients' overall survival (OS) or disease-free survival (DFS) has been confirmed for thymidylate synthase (TS), cyclin B1, cyclin D1, proliferating cell nuclear antigen (PCNA), and Ki-67. In most cases, the overexpression of these markers in tissues was related to worse OS and DFS. However, slowly proliferating cells should also be considered in CRC therapy (especially radiotherapy) as they could represent a reservoir from which cells are recruited to replenish the rapidly proliferating population in response to cell-damaging factors. Considering the above, the aim of this article is to review the most common proliferative markers assessed using various methods including IHC and selected molecular biology techniques (e.g., qRT-PCR, in situ hybridization, RNA/DNA sequencing, next-generation sequencing) as prognostic and predictive markers in CRC.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Swiecicki Street 6, 60-781 Poznan, Poland
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Cheng HR, van Vorstenbosch RW, Pachen DM, Meulen LW, Straathof JWA, Dallinga JW, Jonkers DM, Masclee AA, van Schooten FJ, Mujagic Z, Smolinska A. Detecting Colorectal Adenomas and Cancer Using Volatile Organic Compounds in Exhaled Breath: A Proof-of-Principle Study to Improve Screening. Clin Transl Gastroenterol 2022; 13:e00518. [PMID: 35981245 PMCID: PMC10476860 DOI: 10.14309/ctg.0000000000000518] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 05/16/2022] [Accepted: 06/30/2022] [Indexed: 01/31/2023] Open
Abstract
INTRODUCTION Early detection of colorectal cancer (CRC) by screening programs is crucial because survival rates worsen at advanced stages. However, the currently used screening method, the fecal immunochemical test (FIT), suffers from a high number of false-positives and is insensitive for detecting advanced adenomas (AAs), resulting in false-negatives for these premalignant lesions. Therefore, more accurate, noninvasive screening tools are needed. In this study, the utility of analyzing volatile organic compounds (VOCs) in exhaled breath in a FIT-positive population to detect the presence of colorectal neoplasia was studied. METHODS In this multicenter prospective study, breath samples were collected from 382 FIT-positive patients with subsequent colonoscopy participating in the national Dutch bowel screening program (n = 84 negative controls, n = 130 non-AAs, n = 138 AAs, and n = 30 CRCs). Precolonoscopy exhaled VOCs were analyzed using thermal desorption-gas chromatography-mass spectrometry, and the data were preprocessed and analyzed using machine learning techniques. RESULTS Using 10 discriminatory VOCs, AAs could be distinguished from negative controls with a sensitivity and specificity of 79% and 70%, respectively. Based on this biomarker profile, CRC and AA combined could be discriminated from controls with a sensitivity and specificity of 77% and 70%, respectively, and CRC alone could be discriminated from controls with a sensitivity and specificity of 80% and 70%, respectively. Moreover, the feasibility to discriminate non-AAs from controls and AAs was shown. DISCUSSION VOCs in exhaled breath can detect the presence of AAs and CRC in a CRC screening population and may improve CRC screening in the future.
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Affiliation(s)
- Hao Ran Cheng
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, the Netherlands;
- Department of Gastroenterology and Hepatology, Máxima Medical Center, Veldhoven, the Netherlands;
- GROW, School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands;
| | - Robert W.R. van Vorstenbosch
- NUTRIM, School of Nutrition & Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands;
- Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
| | - Daniëlle M. Pachen
- NUTRIM, School of Nutrition & Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands;
- Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
| | - Lonne W.T. Meulen
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, the Netherlands;
- GROW, School for Oncology and Reproduction, Maastricht University, Maastricht, the Netherlands;
| | - Jan Willem A. Straathof
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, the Netherlands;
- Department of Gastroenterology and Hepatology, Máxima Medical Center, Veldhoven, the Netherlands;
| | - Jan W. Dallinga
- NUTRIM, School of Nutrition & Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands;
- Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
| | - Daisy M.A.E. Jonkers
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, the Netherlands;
- NUTRIM, School of Nutrition & Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands;
| | - Ad A.M. Masclee
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, the Netherlands;
- NUTRIM, School of Nutrition & Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands;
| | - Frederik-Jan van Schooten
- NUTRIM, School of Nutrition & Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands;
- Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
| | - Zlatan Mujagic
- Division of Gastroenterology-Hepatology, Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, the Netherlands;
- NUTRIM, School of Nutrition & Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands;
| | - Agnieszka Smolinska
- NUTRIM, School of Nutrition & Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands;
- Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
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O'Sullivan DE, Ruan Y, Forbes N, Heitman SJ, Hilsden RJ, Pader J, Brenner DR. Long-term Use of Hormone Replacement Therapy is Associated With a Lower Risk of Developing High-risk Serrated Polyps in Women. J Clin Gastroenterol 2022; 56:697-704. [PMID: 34406174 DOI: 10.1097/mcg.0000000000001606] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 07/20/2021] [Indexed: 01/25/2023]
Abstract
GOALS/BACKGROUND Hormone replacement therapy (HRT) and parity have been suggested protective factors against the development of colorectal polyps. However, there are a limited number of studies that have examined the relationship of these factors with high-risk adenomatous polyps (HRAP) or high-risk serrated polyps (HRSP), which may have different causes and therefore implications for screening programs. STUDY Data from a cross-sectional study of 1384 women undergoing screening-related colonoscopy between 2008 and 2016 were analyzed. Modified Poisson regression models with robust error variance were used to determine the relative risk of developing adenomatous polyps, serrated polyps, HRAPs, and HRSPs associated with pregnancy, menopausal status, and the use of HRT (duration and type). RESULTS Women that used HRT for ≥6 years were at a significantly lower risk of developing a HRSP [risk ratios (RR): 0.53; 95% confidence interval (CI): 0.29-0.97]. Irrespective of the duration of use, the use of HRT that included progesterone alone or with estrogen was associated with a significantly lower risk of developing a HRSP (RR: 0.54; 95% CI: 0.30-0.95). The use HRT with progesterone for ≥6 years was associated with a nonsignificant lower risk of developing a HRSP (RR: 0.42; 95% CI: 0.17-1.04). None of the reproductive factors assessed or HRT were associated with the development of adenomatous polyps or HRAPs. CONCLUSIONS The results of this study suggests that the long-term use of HRT, and therapies that include progesterone are associated with a lower risk of developing HRSPs. These results could have implications for targeted screening for serrated polyps among women.
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Affiliation(s)
- Dylan E O'Sullivan
- Departments of Community Health Sciences
- Oncology
- Forzani and MacPhail Colon Cancer Screening Centre, Alberta Health Services, Calgary, AB, Canada
| | - Yibing Ruan
- Department of Cancer Epidemiology and Prevention Research, Alberta Health Services
| | - Nauzer Forbes
- Departments of Community Health Sciences
- Medicine, Cumming School of Medicine, University of Calgary
- Forzani and MacPhail Colon Cancer Screening Centre, Alberta Health Services, Calgary, AB, Canada
| | - Steven J Heitman
- Departments of Community Health Sciences
- Medicine, Cumming School of Medicine, University of Calgary
- Forzani and MacPhail Colon Cancer Screening Centre, Alberta Health Services, Calgary, AB, Canada
| | - Robert J Hilsden
- Departments of Community Health Sciences
- Medicine, Cumming School of Medicine, University of Calgary
- Forzani and MacPhail Colon Cancer Screening Centre, Alberta Health Services, Calgary, AB, Canada
| | - Joy Pader
- Department of Cancer Epidemiology and Prevention Research, Alberta Health Services
| | - Darren R Brenner
- Departments of Community Health Sciences
- Oncology
- Department of Cancer Epidemiology and Prevention Research, Alberta Health Services
- Forzani and MacPhail Colon Cancer Screening Centre, Alberta Health Services, Calgary, AB, Canada
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dos Santos W, dos Reis MB, Porto J, de Carvalho AC, Matsushita M, Oliveira G, Syrjänen K, Reis RM, Guimarães DP. Somatic targeted mutation profiling of colorectal cancer precursor lesions. BMC Med Genomics 2022; 15:143. [PMID: 35761395 PMCID: PMC9238170 DOI: 10.1186/s12920-022-01294-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Accepted: 06/16/2022] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Most colorectal cancers (CRC) arise from precursor lesions. This study aimed to characterize the mutation profile of colorectal cancer precursor lesions in a Brazilian population.
Methods
In total, 90 formalin-fixed paraffin-embedded colorectal precursor lesions, including 67 adenomas, 7 sessile serrated lesions, and 16 hyperplastic polyps, were analyzed by next-generation sequencing using a panel of 50 oncogenes and tumor suppressor genes. The genetic ancestry of the patients was estimated.
Results
Somatic driver mutations were identified in 66.7% of cases, including alterations in APC (32.2%), TP53 (20.0%), KRAS (18.9%), BRAF (13.3%) and EGFR (7.8%). Adenomas displayed a higher number of mutations, mainly in APC, compared to serrated polyps (73.1% vs. 47.8%, p = 0.026). Advanced adenomas had a significantly higher frequency of mutation in KRAS and a high overall mutation rate than early adenomas (92.9% vs. 59%, p = 0.006). A high degree of ancestry admixture was observed in the population studied, with a predominance of European components (mean of 73%) followed by African (mean of 11.3%). No association between genetic ancestry and type of lesions was found. The mutation profile of Brazilian colorectal precursor lesions exhibits alteration in APC, KRAS, TP53, and BRAF at different frequencies according to lesion type.
Conclusions
These results bestow the knowledge of CRC's biologic history and support the potential of these biomarkers for precursor lesions detection in CRC screening of the Brazilian population.
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Serrated Colorectal Lesions: An Up-to-Date Review from Histological Pattern to Molecular Pathogenesis. Int J Mol Sci 2022; 23:ijms23084461. [PMID: 35457279 PMCID: PMC9032676 DOI: 10.3390/ijms23084461] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/16/2022] [Accepted: 04/17/2022] [Indexed: 12/10/2022] Open
Abstract
Until 2010, colorectal serrated lesions were generally considered as harmless lesions and reported as hyperplastic polyps (HPs) by pathologists and gastroenterologists. However, recent evidence showed that they may bear the potential to develop into colorectal carcinoma (CRC). Therefore, the World Health Organization (WHO) classification has identified four categories of serrated lesions: hyperplastic polyps (HPs), sessile serrated lesions (SSLs), traditional serrated adenoma (TSAs) and unclassified serrated adenomas. SSLs with dysplasia and TSAs are the most common precursors of CRC. CRCs arising from serrated lesions originate via two different molecular pathways, namely sporadic microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP), the latter being considered as the major mechanism that drives the serrated pathway towards CRC. Unlike CRCs arising through the adenoma-carcinoma pathway, APC-inactivating mutations are rarely shown in the serrated neoplasia pathway.
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Micsik T, Jakab A, Lehoczki C, Patai ÁV. Traditional Serrated Adenoma of the Gallbladder, a Case Report. Pathol Oncol Res 2022; 28:1610133. [PMID: 35185394 PMCID: PMC8854181 DOI: 10.3389/pore.2022.1610133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 01/13/2022] [Indexed: 11/25/2022]
Abstract
While overwhelming majority of laparoscopic cholecystectomy specimens performed for gallstones or cholecystitis show rather typical findings, sometimes polypoid structures are also removed. These can be related to cholesterolosis or conventional adenomas, but occasionally extraordinary findings do emerge. In our case, a 67-year old lady with typical complaints of cholecystitis underwent routine laparoscopic cholecystectomy. Preoperative ultrasound revealed a polypoid mass with inflammation and without suspicion for malignancy. Microscopic examination showed partly conventional, low-grade dysplastic crypts forming a villous and rather complex structure. Ectopic crypt foci, slit-like serration pattern and serrated dysplasia with eosinophylic cytoplasm and centrally located nuclei were seen throughout the lesion, thus a traditional serrated adenoma (TSA) of the gallbladder was diagnosed. TSA represents the rarest subtype of serrated lesions in the colon and extracolonic manifestations are sporadically reported. Until now only a single case of a serrated adenoma was reported from the gallbladder. Here we describe the detailed clinical, pathological and molecular findings of our case and discuss these in the light of current literature data regarding this field.
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Affiliation(s)
- Tamás Micsik
- St. Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.,Pathology Department, St. George University Teaching Hospital at Fejér County, Székesfehérvár, Hungary.,Interdisciplinary Gastroenterology Working Group, Semmelweis University, Budapest, Hungary
| | - Anna Jakab
- St. Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.,Interdisciplinary Gastroenterology Working Group, Semmelweis University, Budapest, Hungary
| | - Csaba Lehoczki
- Surgery Department of Bajcsy-Zsilinszky Hospital, Budapest, Hungary
| | - Árpád V Patai
- Interdisciplinary Gastroenterology Working Group, Semmelweis University, Budapest, Hungary.,Department of Surgery, Transplantation and Gastroenterology, Semmelweis University, Budapest, Hungary
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Wang X, Amitay E, Harrison TA, Banbury BL, Berndt SI, Brenner H, Buchanan DD, Campbell PT, Cao Y, Chan AT, Chang-Claude J, Gallinger SJ, Giannakis M, Giles GG, Gunter MJ, Hopper JL, Jenkins MA, Lin Y, Moreno V, Nishihara R, Newcomb PA, Ogino S, Phipps AI, Sakoda LC, Schoen RE, Slattery ML, Song M, Sun W, Thibodeau SN, Toland AE, Van Guelpen B, Woods MO, Hsu L, Hoffmeister M, Peters U. Association Between Smoking and Molecular Subtypes of Colorectal Cancer. JNCI Cancer Spectr 2021; 5:pkab056. [PMID: 34377935 PMCID: PMC8346704 DOI: 10.1093/jncics/pkab056] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/25/2021] [Accepted: 04/30/2021] [Indexed: 12/24/2022] Open
Abstract
Background Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking. Methods A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study-specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including BRAF mutation, KRAS mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction. Results Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers (P trend < .001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and BRAF. Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio = 1.90, 95% confidence interval = 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio = 1.35, 95% confidence interval = 1.22 to 1.49; P difference = 2.1 x 10-6). The association was also stronger in tumors that were CIMP positive, MSI high, or KRAS wild type when combined (P difference < .001). Conclusion Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.
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Affiliation(s)
- Xiaoliang Wang
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Efrat Amitay
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Tabitha A Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Barbara L Banbury
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Department of Preventive Oncology, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniel D Buchanan
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
- Department of Clinical Pathology, Colorectal Oncogenomics Group, The University of Melbourne, Parkville, Victoria, Australia
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia
- Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Melbourne, Victoria, Australia
| | - Peter T Campbell
- Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA
| | - Yin Cao
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St Louis, MO, USA
- Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, St. Louis, MO, USA
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA
- Channing Division of Network Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
- Genetic Tumour Epidemiology Group, University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Steven J Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Marios Giannakis
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Graham G Giles
- Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, Australia
- Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - Marc J Gunter
- Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - John L Hopper
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia
| | - Yi Lin
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Victor Moreno
- Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain
| | - Reiko Nishihara
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Shuji Ogino
- Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Lori C Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA
| | - Robert E Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA
| | - Mingyang Song
- Division of Gastroenterology, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Wei Sun
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Steven N Thibodeau
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Amanda E Toland
- Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Bethany Van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden
| | - Michael O Woods
- Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland & Labrador, Canada
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
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Clinicopathological and Molecular Features of Patients with Early and Late Recurrence after Curative Surgery for Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13081883. [PMID: 33919924 PMCID: PMC8070938 DOI: 10.3390/cancers13081883] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 04/10/2021] [Accepted: 04/12/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Colorectal cancer patients with early recurrence had advanced pathological node categories, pathological tumor, node, metastasis stages, adjuvant chemotherapy treatment, a worse overall survival rate, more liver metastases and more APC mutations than those with late recurrence. Patients with right-sided colon cancer tended to have early recurrence than those with left-sided colon cancer or rectal cancer. The postrecurrence survival rates were not significantly different between patients with early and late recurrence, which was observed in right-sided colon, left-sided colon and rectum. Multivariate analysis showed that old age, early recurrence, multiple-site recurrence and BRAF and NRAS mutations were independent prognostic factors. Abstract Background: Few reports have investigated genetic alterations between patients with early and late recurrence following curative surgery for colorectal cancer (CRC). Methods: A total of 1227 stage I–III CRC patients who underwent curative resection were included retrospectively. Among them, 236 patients had tumor recurrence: 139 had early (<2 years after surgery) and 97 had late (≥2 years after surgery) recurrence. Clinicopathological features and genetic alterations were compared between the two groups. Results: Compared to those with late recurrence, patients with early recurrence were more likely to have advanced pathological node (N) categories; tumor, node, metastasis (TNM) stages; adjuvant chemotherapy treatment; liver metastases; APC mutations; and worse five-year overall survival rates. Patients with right-sided colon cancer were more likely to develop early recurrence than were those with left-sided colon cancer or rectal cancer. Regarding rectal cancer, patients with early recurrence were more likely to be at advanced pathological N categories and TNM stages than those with late recurrence. Multivariate analysis revealed old age, early recurrence, multiple-site recurrence, and BRAF and NRAS mutations to be independent prognostic factors. Conclusion: CRC patients with early recurrence have a worse OS rate and more APC mutations than those with late recurrence.
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Desai M, Anderson JC, Kaminski M, Thoguluva Chandrasekar V, Fathallah J, Hassan C, Lieberman D, Sharma P. Sessile serrated lesion detection rates during average risk screening colonoscopy: A systematic review and meta-analysis of the published literature. Endosc Int Open 2021; 9:E610-E620. [PMID: 33869735 PMCID: PMC8043815 DOI: 10.1055/a-1352-4095] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 12/10/2020] [Indexed: 12/17/2022] Open
Abstract
Background and study aims Sessile serrated lesion (SSL) detection rate has been variably reported and unlike adenoma detection rate (ADR) is not currently a quality indicator for screening colonoscopy. Composite detection rates of SSL in patients undergoing average risk screening colonoscopy are not available. Methods Electronic database search (Medline, Embase and Cochrane) was conducted for studies reporting detection rates of serrated polyps (SSL, Hyperplastic polyp, traditional serrated adenoma) among average risk subjects undergoing screening colonoscopy. Primary outcomes were pooled SDR (SSL detection rate) and proximal serrated polyp detection rate (PSPDR). Pooled proportion rates were calculated with 95 %CI with assessment of heterogeneity (I 2 ). Publication bias, regression test and 95 %prediction interval were calculated. Results A total of 280,370 screening colonoscopies among average risk subjects that were eligible with 48.9 % males and an average age of 58.7 years (± 3.2). The pooled SDR was available from 16 studies: 2.5 % (1.8 %-3.4 %) with significant heterogeneity (I 2 = 98.66 %) and the 95 % prediction interval ranging from 0.6 % to 9.89 %. When analysis was restricted to large (n > 1000) and prospective studies (n = 4), SDR was 2 % (1.1 %-3.3 %). Pooled PSPDR was 10 % (8.5 %-11.8 %; 12 studies). There was evidence of publication bias ( P < 0.01). Conclusion Definitions of SSL have been varying over years and there exists significant heterogeneity in prevalence reporting of serrated polyps during screening colonoscopy. Prevalence rate of 2 % for SSL and 10 % for proximal serrated polyps could serve as targets while robust high-quality data is awaited to find a future benchmark showing reduction in colorectal cancer arising from serrated pathway.
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Affiliation(s)
- Madhav Desai
- Department of Gastroenterology, Kansas City VA Medical Center, Kansas City, Missouri, United States
| | - Joseph C. Anderson
- Department of Veterans Affairs Medical Center, White River Junction, Vermont, United States,The Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States
| | - Michael Kaminski
- Department of Gastroenterological Oncology, the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland,Department of Gastroenterology, Hepatology and Oncology, Medical Center for Postgraduate Education, Warsaw, Poland,Institute of Health and Society, University of Oslo, Oslo, Norway
| | | | - Jihan Fathallah
- Department of Gastroenterology and hepatology, University of Kansas Medical Center, Kansas City, Kansas, United States
| | - Cesare Hassan
- Endoscopy Unit, Nuovo Regina Margherita Hospital, Rome, Italy
| | - David Lieberman
- Department of Gastroenterology and Hepatology, Oregon Health and Science University, Portland, Oregon, United States
| | - Prateek Sharma
- Department of Gastroenterology, Kansas City VA Medical Center, Kansas City, Missouri, United States,Department of Gastroenterology and hepatology, University of Kansas Medical Center, Kansas City, Kansas, United States
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15
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Pitchumoni CS. Colorectal Cancer. GERIATRIC GASTROENTEROLOGY 2021:1963-1989. [DOI: 10.1007/978-3-030-30192-7_80] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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16
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Trivieri N, Pracella R, Cariglia MG, Panebianco C, Parrella P, Visioli A, Giani F, Soriano AA, Barile C, Canistro G, Latiano TP, Dimitri L, Bazzocchi F, Cassano D, Vescovi AL, Pazienza V, Binda E. BRAF V600E mutation impinges on gut microbial markers defining novel biomarkers for serrated colorectal cancer effective therapies. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:285. [PMID: 33317591 PMCID: PMC7737386 DOI: 10.1186/s13046-020-01801-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 12/04/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) harboring BRAFV600E mutation exhibits low response to conventional therapy and poorest prognosis. Due to the emerging correlation between gut microbiota and CRC carcinogenesis, we investigated in serrated BRAFV600E cases the existence of a peculiar fecal microbial fingerprint and specific bacterial markers, which might represent a tool for the development of more effective clinical strategies. METHODS By injecting human CRC stem-like cells isolated from BRAFV600E patients in immunocompromised mice, we described a new xenogeneic model of this subtype of CRC. By performing bacterial 16S rRNA sequencing, the fecal microbiota profile was then investigated either in CRC-carrying mice or in a cohort of human CRC subjects. The microbial communities' functional profile was also predicted. Data were compared with Mann-Whitney U, Welch's t-test for unequal variances and Kruskal-Wallis test with Benjamini-Hochberg false discovery rate (FDR) correction, extracted as potential BRAF class biomarkers and selected as model features. The obtained mean test prediction scores were subjected to Receiver Operating characteristic (ROC) analysis. To discriminate the BRAF status, a Random Forest classifier (RF) was employed. RESULTS A specific microbial signature distinctive for BRAF status emerged, being the BRAF-mutated cases closer to healthy controls than BRAF wild-type counterpart. In agreement, a considerable score of correlation was also pointed out between bacteria abundance from BRAF-mutated cases and the level of markers distinctive of BRAFV600E pathway, including those involved in inflammation, innate immune response and epithelial-mesenchymal transition. We provide evidence that two candidate bacterial markers, Prevotella enoeca and Ruthenibacterium lactatiformans, more abundant in BRAFV600E and BRAF wild-type subjects respectively, emerged as single factors with the best performance in distinguishing BRAF status (AUROC = 0.72 and 0.74, respectively, 95% confidence interval). Furthermore, the combination of the 10 differentially represented microorganisms between the two groups improved performance in discriminating serrated CRC driven by BRAF mutation from BRAF wild-type CRC cases (AUROC = 0.85, 95% confidence interval, 0.69-1.01). CONCLUSION Overall, our results suggest that BRAFV600E mutation itself drives a distinctive gut microbiota signature and provide predictive CRC-associated bacterial biomarkers able to discriminate BRAF status in CRC patients and, thus, useful to devise non-invasive patient-selective diagnostic strategies and patient-tailored optimized therapies.
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Affiliation(s)
- Nadia Trivieri
- Cancer Stem Cells Unit, ISBReMIT, IRCSS Casa Sollievo della Sofferenza, Opera di San Pio da Pietrelcina, San Giovanni Rotondo, FG, Italy
| | - Riccardo Pracella
- Cancer Stem Cells Unit, ISBReMIT, IRCSS Casa Sollievo della Sofferenza, Opera di San Pio da Pietrelcina, San Giovanni Rotondo, FG, Italy
| | - Maria Grazia Cariglia
- Cancer Stem Cells Unit, ISBReMIT, IRCSS Casa Sollievo della Sofferenza, Opera di San Pio da Pietrelcina, San Giovanni Rotondo, FG, Italy
| | - Concetta Panebianco
- Gastroenterology Unit, IRCSS Casa Sollievo della Sofferenza, Opera di San Pio da Pietrelcina, San Giovanni Rotondo, FG, Italy
| | - Paola Parrella
- Oncology Laboratory, IRCSS Casa Sollievo della Sofferenza, Opera di San Pio da Pietrelcina, San Giovanni Rotondo, FG, Italy
| | | | | | - Amata Amy Soriano
- Cancer Stem Cells Unit, ISBReMIT, IRCSS Casa Sollievo della Sofferenza, Opera di San Pio da Pietrelcina, San Giovanni Rotondo, FG, Italy
| | - Chiara Barile
- Cancer Stem Cells Unit, ISBReMIT, IRCSS Casa Sollievo della Sofferenza, Opera di San Pio da Pietrelcina, San Giovanni Rotondo, FG, Italy
| | - Giuseppe Canistro
- Abdominal Surgery Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Tiziana Pia Latiano
- Division of Medical Oncology, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Lucia Dimitri
- Anatomical Pathology Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Francesca Bazzocchi
- Abdominal Surgery Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Dario Cassano
- Abdominal Surgery Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Angelo L Vescovi
- StemGen SpA, Milan, Italy.,Science Directorate, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
| | - Valerio Pazienza
- Gastroenterology Unit, IRCSS Casa Sollievo della Sofferenza, Opera di San Pio da Pietrelcina, San Giovanni Rotondo, FG, Italy
| | - Elena Binda
- Cancer Stem Cells Unit, ISBReMIT, IRCSS Casa Sollievo della Sofferenza, Opera di San Pio da Pietrelcina, San Giovanni Rotondo, FG, Italy. .,Cancer Stem Cells Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapeutics (ISBReMIT), 71013, San Giovanni Rotondo, FG, Italy.
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Sacco M, De Palma FDE, Guadagno E, Giglio MC, Peltrini R, Marra E, Manfreda A, Amendola A, Cassese G, Dinuzzi VP, Pegoraro F, Tropeano FP, Luglio G, De Palma GD. Serrated lesions of the colon and rectum: Emergent epidemiological data and molecular pathways. Open Med (Wars) 2020; 15:1087-1095. [PMID: 33336065 PMCID: PMC7718641 DOI: 10.1515/med-2020-0226] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Revised: 07/14/2020] [Accepted: 08/07/2020] [Indexed: 12/26/2022] Open
Abstract
In 2010, serrated polyps (SP) of the colon have been included in the WHO classification of digestive tumors. Since then a large corpus of evidence focusing on these lesions are available in the literature. This review aims to analyze the present data on the epidemiological and molecular aspects of SP. Hyperplastic polyps (HPs) are the most common subtype of SP (70–90%), with a minimal or null risk of malignant transformation, contrarily to sessile serrated lesions (SSLs) and traditional serrated adenomas (TSAs), which represent 10–20% and 1% of adenomas, respectively. The malignant transformation, when occurs, is supported by a specific genetic pathway, known as the serrated-neoplasia pathway. The time needed for malignant transformation is not known, but it may occur rapidly in some lesions. Current evidence suggests that a detection rate of SP ≥15% should be expected in a population undergoing screening colonoscopy. There are no differences between primary colonoscopies and those carried out after positive occult fecal blood tests, as this screening test fails to identify SP, which rarely bleed. Genetic similarities between SP and interval cancers suggest that these cancers could arise from missed SP. Hence, the detection rate of serrated-lesions should be evaluated as a quality indicator of colonoscopy. There is a lack of high-quality longitudinal studies analyzing the long-term risk of developing colorectal cancer (CRC), as well as the cancer risk factors and molecular tissue biomarkers. Further studies are needed to define an evidence-based surveillance program after the removal of SP, which is currently suggested based on experts’ opinions.
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Affiliation(s)
- Michele Sacco
- Department of Clinical Medicine and Surgery, University of Naples Federico II via Sergio Pansini, 5 - 80131, Naples, Italy
| | - Fatima Domenica Elisa De Palma
- CEINGE Biotecnologie Avanzate s.c.ar.l., Via Comunale Margherita, 80131, Naples, Italy.,Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, via Sergio Pansini, 5 - 80131, Naples, Italy
| | - Elia Guadagno
- Department of Advanced Biomedical Sciences, Pathology Section, University of Naples Federico II, Naples, Italy
| | - Mariano Cesare Giglio
- Department of Clinical Medicine and Surgery, University of Naples Federico II via Sergio Pansini, 5 - 80131, Naples, Italy
| | - Roberto Peltrini
- Department of Clinical Medicine and Surgery, University of Naples Federico II via Sergio Pansini, 5 - 80131, Naples, Italy
| | - Ester Marra
- Department of Clinical Medicine and Surgery, University of Naples Federico II via Sergio Pansini, 5 - 80131, Naples, Italy
| | - Andrea Manfreda
- Department of Clinical Medicine and Surgery, University of Naples Federico II via Sergio Pansini, 5 - 80131, Naples, Italy
| | - Alfonso Amendola
- Department of Clinical Medicine and Surgery, University of Naples Federico II via Sergio Pansini, 5 - 80131, Naples, Italy
| | - Gianluca Cassese
- Department of Clinical Medicine and Surgery, University of Naples Federico II via Sergio Pansini, 5 - 80131, Naples, Italy
| | - Vincenza Paola Dinuzzi
- Department of Clinical Medicine and Surgery, University of Naples Federico II via Sergio Pansini, 5 - 80131, Naples, Italy
| | - Francesca Pegoraro
- Department of Clinical Medicine and Surgery, University of Naples Federico II via Sergio Pansini, 5 - 80131, Naples, Italy
| | - Francesca Paola Tropeano
- Department of Clinical Medicine and Surgery, University of Naples Federico II via Sergio Pansini, 5 - 80131, Naples, Italy
| | - Gaetano Luglio
- Department of Clinical Medicine and Surgery, University of Naples Federico II via Sergio Pansini, 5 - 80131, Naples, Italy
| | - Giovanni Domenico De Palma
- Department of Clinical Medicine and Surgery, University of Naples Federico II via Sergio Pansini, 5 - 80131, Naples, Italy
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18
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Warsinggih, Liliyanto, Marhamah, Kusuma MI, Uwuratuw JA, Syarifuddin E, Faruk M. Relationship between BRAF V600E and KRAS mutations in stool for identifying colorectal cancer: A cross-sectional study. Ann Med Surg (Lond) 2020; 60:121-125. [PMID: 33145020 PMCID: PMC7593265 DOI: 10.1016/j.amsu.2020.10.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/11/2020] [Accepted: 10/11/2020] [Indexed: 02/08/2023] Open
Abstract
Background With early diagnosis, colorectal cancer (CRC) is a curable disease. As studies in the past 15 years have shown, specific genetic changes occur in the neoplastic transformation of normal colonic epithelium to benign adenoma until becoming adenocarcinoma. Considering that dynamic, we aimed to determine how v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E and Kirsten rat sarcoma (KRAS) mutations relate to the location, histopathology, and degree of tumor differentiation in CRC. Methods With a cross-sectional design involving an observational analytical approach, we determined the relationship of BRAF V600E and KRAS mutations to the location, histopathology, and degree of tumor differentiation in CRC. Result The sample contained 43 patients with CRC aged 21-80 years, with an average age of 56.0 ± 11.2 years, 46.5% of whom were male and 53.5% female, for a male-to-female ratio of 1.0-1.15. Most tumors were located in the right colon (n = 18, 41.9%), followed by the rectum (n = 14, 32.6%) and left colon (n = 18, 25.6%). Non-mucinous adenocarcinoma was more prevalent than mucinous adenocarcinoma, with 22 (51.2%) and 21 (48.8%) patients, respectively. Nineteen tumors were poorly differentiated (44.2%), 15 were moderately differentiated (34.9%), and nine were well-differentiated (20.9%). BRAF V600E mutations totaled six (14%), whereas non-BRAF V600E mutations totaled 37 (86.0%). BRAF V600E mutations significantly related to tumor location, degree of differentiation, and histopathology (p < .01). Conclusion A significant relationship exists between BRAF V600E mutations in the stool of patients with CRC and location, histopathology, and degree of tumor differentiation.
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Affiliation(s)
- Warsinggih
- Division of Digestive, Department of Surgery, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Liliyanto
- Division of Digestive, Department of Surgery, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Marhamah
- Department of Pediatric Dentistry, Faculty of Dentistry, Hasanuddin University, Makassar, Indonesia
| | - M Ihwan Kusuma
- Division of Digestive, Department of Surgery, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Julianus Aboyaman Uwuratuw
- Division of Digestive, Department of Surgery, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Erwin Syarifuddin
- Division of Digestive, Department of Surgery, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
| | - Muhammad Faruk
- Department of Surgery, Faculty of Medicine, Hasanuddin University, Makassar, Indonesia
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Lee HS, Hwang DY, Han HS. Histology and its prognostic effect on KRAS-mutated colorectal carcinomas in Korea. Oncol Lett 2020; 20:655-666. [PMID: 32565990 PMCID: PMC7285809 DOI: 10.3892/ol.2020.11606] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 04/15/2020] [Indexed: 12/13/2022] Open
Abstract
KRAS mutation is frequently identified in advanced colorectal carcinoma (CRC); however, its prognostic significance and the associated histological features have remained to be clarified. In the present study, the precise histological results and prognostic value of KRAS-mutated CRCs were investigated in patients from South Korea. A retrospective review of the results from KRAS mutation testing, as well as evaluation of the histology of 310 cases of CRC at various stages, were performed. Cross-tabulation and survival analysis were performed according to the KRAS status. Patients with KRAS mutation more frequently exhibited serrated and papillary architectures (P=0.009 and P=0.014, respectively). KRAS mutation was an independent unfavorable prognostic factor for overall survival (OS) according to multivariate analysis (P=0.001), whereas no association was observed with disease-free survival (DFS) (P=0.611). Of note, in the subgroup of KRAS-mutated carcinomas, the presence of a solid component on histology was associated with less favorable OS (P=0.032). Furthermore, among the wild type cases, patients with a micropapillary component had a worse OS than those who did not (P=0.018). However, no subgroup or specific histological features were associated with DFS. In summary, KRAS-mutated CRCs had a moderate association with particular histological features, and according to the KRAS mutational status, there was a certain degree of association between histology and prognosis.
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Affiliation(s)
- Hye Seung Lee
- Department of Pathology, Korea Clinical Laboratory, Seoul 05396, Republic of Korea
| | - Dae Yong Hwang
- Department of Surgery, Konkuk University School of Medicine, Seoul 05030, Republic of Korea
| | - Hye Seung Han
- Department of Pathology, Konkuk University School of Medicine, Seoul 05030, Republic of Korea
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Kim BH, Kim JM, Kang GH, Chang HJ, Kang DW, Kim JH, Bae JM, Seo AN, Park HS, Kang YK, Lee KH, Cho MY, Do IG, Lee HS, Chang HK, Park DY, Kang HJ, Sohn JH, Chang MS, Jung ES, Jin SY, Yu E, Han HS, Kim YW. Standardized Pathology Report for Colorectal Cancer, 2nd Edition. J Pathol Transl Med 2019; 54:1-19. [PMID: 31722452 PMCID: PMC6986966 DOI: 10.4132/jptm.2019.09.28] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Accepted: 09/26/2019] [Indexed: 02/06/2023] Open
Abstract
The first edition of the 'Standardized Pathology Report for Colorectal Cancer,' which was developed by the Gastrointestinal Pathology Study Group (GIP) of the Korean Society of Pathologists, was published 13 years ago. Meanwhile, there have been many changes in the pathologic diagnosis of colorectal cancer (CRC), pathologic findings included in the pathology report, and immunohistochemical and molecular pathology required for the diagnosis and treatment of colorectal cancer. In order to reflect these changes, we (GIP) decided to make the second edition of the report. The purpose of this standardized pathology report is to provide a practical protocol for Korean pathologists, which could help diagnose and treat CRC patients. This report consists of "standard data elements" and "conditional data elements." Basic pathologic findings and parts necessary for prognostication of CRC patients are classified as "standard data elements," while other prognostic factors and factors related to adjuvant therapy are classified as "conditional data elements" so that each institution could select the contents according to the characteristics of the institution. The Korean version is also provided separately so that Korean pathologists can easily understand and use this report. We hope that this report will be helpful in the daily practice of CRC diagnosis.
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Affiliation(s)
- Baek-Hui Kim
- Department of Pathology, Korea University Guro Hospital, Seoul, Korea
| | - Joon Mee Kim
- Department of Pathology, Inha University School of Medicine, Incheon, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hee Jin Chang
- Department of Pathology, Research Institute and Hospital, National Cancer Center, Goyang, Korea
| | - Dong Wook Kang
- Department of Pathology, Eulji University Hospital, Eulji University School of Medicine, Daejeon, Korea
| | - Jung Ho Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Mo Bae
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - An Na Seo
- Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Ho Sung Park
- Department of Pathology, Chonbuk National University Medical School, Jeonju, Korea
| | - Yun Kyung Kang
- Department of Pathology, Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea
| | - Kyung-Hwa Lee
- Department of Pathology, Chonnam National University Medical School, Gwangju, Korea
| | - Mee Yon Cho
- Department of Pathology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - In-Gu Do
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hye Seung Lee
- Department of Pathology, Seoul National University, Bundang Hospital, Seongnam, Korea
| | - Hee Kyung Chang
- Department of Pathology, Kosin University College of Medicine, Busan, Korea
| | - Do Youn Park
- Department of Pathology, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea
| | - Hyo Jeong Kang
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin Hee Sohn
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Mee Soo Chang
- Department of Pathology, Seoul National University Boramae Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Eun Sun Jung
- Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - So-Young Jin
- Department of Pathology, Soonchunhyang University Seoul Hospital, Soonchunhyang UniversityCollege of Medicine, Seoul, Korea
| | - Eunsil Yu
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hye Seung Han
- Department of Pathology, Konkuk University Medical Center, Konkuk University School of Medicine, Seoul, Korea
| | - Youn Wha Kim
- Department of Pathology, Kyung Hee University College of Medicine, Seoul, Korea
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Hissong E, Fernandes H, Jessurun J. Colonic Mucosa With Polypoid Hyperplasia. Am J Clin Pathol 2019; 152:423-430. [PMID: 31152544 DOI: 10.1093/ajcp/aqz053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES Define the morphologic and molecular features of colonic polyps with subtle histologic features. METHODS Two hundred specimens were obtained of surveillance colonoscopies. Endoscopic findings were reviewed. Histologic features of the polyps were compared with the flat mucosa. Next-generation sequencing was performed on 30 study polyps and 20 control samples. RESULTS Polyps with subtle changes comprised 12% of all polyps. All polyps were sessile and small (<0.5 cm) and were located predominantly in the distal colon (60%). Synchronous hyperplastic, sessile serrated, and dysplastic polyps were found in 30%, 7%, and 51% of patients, respectively. A total of 169 (84.5%) polyps showed wide, nonserrated crypts, increased intraluminal mucus, and patent openings. KRAS alterations were present in 30% of polyps. CONCLUSIONS Most polyps with subtle histologic features have recognizable morphologic changes. About one-third harbored KRAS alterations. These polyps should not be regarded as variants of hyperplastic polyps.
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Affiliation(s)
- Erika Hissong
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
| | - Helen Fernandes
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY
| | - Jose Jessurun
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
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The Molecular Hallmarks of the Serrated Pathway in Colorectal Cancer. Cancers (Basel) 2019; 11:cancers11071017. [PMID: 31330830 PMCID: PMC6678087 DOI: 10.3390/cancers11071017] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 07/15/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer death worldwide. It includes different subtypes that differ in their clinical and prognostic features. In the past decade, in addition to the conventional adenoma-carcinoma model, an alternative multistep mechanism of carcinogenesis, namely the “serrated pathway”, has been described. Approximately, 15 to 30% of all CRCs arise from neoplastic serrated polyps, a heterogeneous group of lesions that are histologically classified into three morphologic categories: hyperplastic polyps, sessile serrated adenomas/polyps, and the traditional serrated adenomas/polyps. Serrated polyps are characterized by genetic (BRAF or KRAS mutations) and epigenetic (CpG island methylator phenotype (CIMP)) alterations that cooperate to initiate and drive malignant transformation from normal colon mucosa to polyps, and then to CRC. The high heterogeneity of the serrated lesions renders their diagnostic and pathological interpretation difficult. Hence, novel genetic and epigenetic biomarkers are required for better classification and management of CRCs. To date, several molecular alterations have been associated with the serrated polyp-CRC sequence. In addition, the gut microbiota is emerging as a contributor to/modulator of the serrated pathway. This review summarizes the state of the art of the genetic, epigenetic and microbiota signatures associated with serrated CRCs, together with their clinical implications.
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24
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Quintanilla I, López-Cerón M, Jimeno M, Cuatrecasas M, Zabalza M, Moreira L, Alonso V, Rodríguez de Miguel C, Muñoz J, Castellvi-Bel S, Llach J, Castells A, Balaguer F, Camps J, Pellisé M. Rectal Aberrant Crypt Foci in Humans Are Not Surrogate Markers for Colorectal Cancer Risk. Clin Transl Gastroenterol 2019; 10:e00047. [PMID: 31136360 PMCID: PMC6613864 DOI: 10.14309/ctg.0000000000000047] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 02/22/2019] [Indexed: 02/07/2023] Open
Abstract
INTRODUCTION Over the past 20 years, aberrant crypt foci (ACF) have emerged as potential precursors and biomarkers for colorectal cancer (CRC). However, data regarding their molecular pathogenesis, as well as their endoscopic and histological identification, remain inconsistent. METHODS A wide cohort of ACF from 100 control subjects and 100 case patients, including patients with adenoma and CRC, were characterized for endoscopic, morphologic, and molecular features. RESULTS We observed that among all the endoscopic features evaluated, only the number of large ACF correlated with CRC risk (P = 0.003), whereas the histological classification, as assessed by 2 different pathologists, was inconsistent and did not differ between control and case patients. Moreover, only a few APC and BRAF mutations and no microsatellite instability were detected in our samples. KRAS mutations were detected in 16.3% of ACF samples, which also exhibited increased MGMT hypermethylation. However, none of those events were found to be predictive of CRC risk. DISCUSSION Although ACF might be preneoplastic lesions of the colon, they are not suitable biomarkers for assessing CRC progression.
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Affiliation(s)
- Isabel Quintanilla
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - María López-Cerón
- Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
| | - Mireya Jimeno
- Pathology Department, Centre de Diagnòstic Biomèdic, Hospital Clínic and Banc de Tumors-Biobanc Clinic-IDIBAPS-XBTC, Barcelona, Catalonia, Spain
| | - Miriam Cuatrecasas
- Pathology Department, Centre de Diagnòstic Biomèdic, Hospital Clínic and Banc de Tumors-Biobanc Clinic-IDIBAPS-XBTC, Barcelona, Catalonia, Spain
| | - Michel Zabalza
- Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
| | - Leticia Moreira
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Virginia Alonso
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Cristina Rodríguez de Miguel
- Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
| | - Jennifer Muñoz
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Sergi Castellvi-Bel
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Josep Llach
- Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
| | - Antoni Castells
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
- Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
| | - Francesc Balaguer
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
- Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
| | - Jordi Camps
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Maria Pellisé
- Institut d'Investigacions Biomèdiques August Pi i Sunyer, (IDIBAPS), University of Barcelona, Barcelona, Spain
- Gastroenterology Department, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd)
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Hodge R, Mandle HB, Ray S, Tandon S, Peterson M, Henry A, Jahan FA, Bostick RM, Baron JA, Barry EL, Yacoub R, Rutherford RE, Seabrook ME, Fedirko V. Effects of Supplemental Calcium and Vitamin D on Expression of Toll-Like Receptors and Phospho-IKKα/β in the Normal Rectal Mucosa of Colorectal Adenoma Patients. Cancer Prev Res (Phila) 2018; 11:707-716. [PMID: 30209117 PMCID: PMC6214739 DOI: 10.1158/1940-6207.capr-18-0123] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 07/19/2018] [Accepted: 08/28/2018] [Indexed: 02/06/2023]
Abstract
Chronic inflammation in the colorectum, a significant contributor to colorectal carcinogenesis, can be triggered by the activation of proinflammatory signaling pathways such as those initiated by Toll-like receptors (TLR) and nuclear factor κB (NF-κB). Although experimental evidence supports calcium and vitamin D potentially modifying these proinflammatory pathways in the colorectum, human data in these regards are scarce. We investigated supplemental calcium (1,200 mg daily) and/or vitamin D3 (1,000 IU daily) effects on inflammatory signaling pathway-related biomarkers in a subset of 105 participants from a colorectal adenoma recurrence chemoprevention clinical trial. We assessed expression of TLR4 and TLR5, which recognize the bacterial components lipopolysaccharides and flagellin, respectively, and phospho-IKKα/β (pIKKα/β), a biomarker of inflammation, in the normal-appearing rectal crypt epithelium and stroma using standardized, automated immunohistochemistry and quantitative image analysis. Following 1 year of treatment, TLR4, TLR5, and pIKKα/β expression in the rectal mucosa did not statistically significantly change with vitamin D or calcium supplementation, taken alone or in combination. Several baseline participant characteristics, including body mass index, history of sessile serrated adenomas, high red/processed meat intake, and high levels of rectal epithelial cell proliferation (as measured by MIB-1/Ki-67), were associated with higher baseline expression of TLRs or pIKKα/β. Our findings suggest that vitamin D and calcium may have no substantial effect on the investigated biomarkers. However, several modifiable lifestyle factors may be associated with TLRs and pIKKα/β expression in the normal rectal mucosa, supporting their future investigation as potentially treatable, preneoplastic risk factors for colorectal neoplasms. Cancer Prev Res; 11(11); 707-16. ©2018 AACR.
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Affiliation(s)
- Rebecca Hodge
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Hannah B Mandle
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Stephen Ray
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Sonia Tandon
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Meaghan Peterson
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Abigail Henry
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Ferdous A Jahan
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Roberd M Bostick
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
- Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - John A Baron
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
- Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
- University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Elizabeth L Barry
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
| | - Rami Yacoub
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Robin E Rutherford
- Division of Digestive Diseases, Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia
| | | | - Veronika Fedirko
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.
- Winship Cancer Institute, Emory University, Atlanta, Georgia
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Histopathologic study from a colorectal cancer screening in Chile: results from the first 2 years of an international collaboration between Chile and Japan. Eur J Cancer Prev 2018; 28:245-253. [PMID: 29958195 DOI: 10.1097/cej.0000000000000454] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
A national colorectal cancer (CRC) screening program began in Chile in 2012, which is an international collaboration between Japan and Chile and is based on a standardized protocol supported by Tokyo Medical and Dental University. We describe the results from the first 2 years of screening at one public hospital in Punta Arenas, Chile. Of 4124 asymptomatic individuals aged between 50 and 75 years, 485 participants with immunological fecal occult blood test values of at least 100 ng/ml and/or those with family histories of CRC underwent colonoscopies. Lesions were found in 291 participants, and 642 histologic samples were obtained. Chilean pathologists made the initial histologic diagnoses, and a Japanese pathologist reviewed the histologic slides and analyzed the results. Of the 291 participants with lesions, 60 (20.6%) were diagnosed with adenocarcinomas, of which 50 (83.3%) were early-phase adenocarcinomas (pTis or pT1), and 163 (56.0%) were diagnosed with conventional adenomas, of which 96 (58.9%) were high-risk adenomas. The cancer prevalence within the screened population was 1.5% (60 of 4124). The colonoscopy cancer detection rate was 12.4% (60 of 485). Notably, we detected one flat-depressed (0-IIc) lesion that measured 5 mm and had invaded the submucosa. The findings from this screening program are the first to show the histopathologic distributions of consecutive lesions and the high incidence of CRC in Chile. The high detection rates for high-risk adenomas and cancer support the feasibility of early CRC screening and its potential to reduce the mortality associated with CRC.
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Karpinski P, Patai AV, Hap W, Kielan W, Laczmanska I, Sasiadek MM. Multilevel omic data clustering reveals variable contribution of methylator phenotype to integrative cancer subtypes. Epigenomics 2018; 10:1289-1299. [PMID: 29896967 DOI: 10.2217/epi-2018-0057] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
AIM We aimed to assess to what extent CpG island methylator phenotype (CIMP) contributes to cancer subtypes obtained by multilevel omic data analysis. MATERIALS & METHODS 16 The Cancer Genome Atlas datasets encompassing three data layers in 4688 tumor samples were analyzed. We identified cancer integrative subtypes (ISs) by the use of similarity network fusion and consensus clustering. CIMP high (CIMP-H) associated ISs were profiled by gene sets and transcriptional regulators enrichment analysis. RESULTS & CONCLUSION In nine out of 16 cancer datasets CIMP-H clusters significantly overlaped with unique ISs. The contribution of CIMP-H on integrative molecular profiling is variable; therefore, only in a subset of cancer types does CIMP-H contribute to homogenous integrative subtype. CIMP-H associated ISs are heterogenous groups with regard to deregulated pathways and transcriptional regulators.
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Affiliation(s)
- Pawel Karpinski
- Department of Genetics; Wroclaw Medical University, Wroclaw, Poland
| | - Arpad V Patai
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Wojciech Hap
- 2nd Department of General & Oncological Surgery, Wroclaw Medical University, Wroclaw, Poland
| | - Wojciech Kielan
- 2nd Department of General & Oncological Surgery, Wroclaw Medical University, Wroclaw, Poland
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28
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Sugai T, Eizuka M, Fujita Y, Kawasaki K, Yamamoto E, Ishida K, Yamano H, Suzuki H, Matsumoto T. Molecular Profiling Based on KRAS/BRAF Mutation, Methylation, and Microsatellite Statuses in Serrated Lesions. Dig Dis Sci 2018; 63:2626-2638. [PMID: 29974407 PMCID: PMC6153566 DOI: 10.1007/s10620-018-5167-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 06/09/2018] [Indexed: 12/30/2022]
Abstract
AIM The aim of your study is to characterize serrated lesions according to their molecular patterns, specifically BRAF/KRAS mutation, methylation, and microsatellite statuses. We evaluated the molecular patterns of 163 serrated lesions, including 37 microvesicular hyperplastic polyps, 73 sessile serrated adenomas/polyps (SSA/Ps), 31 traditional serrated adenomas, and 22 SSA/Ps with cytological dysplasia/adenocarcinoma. METHODS Mutations in BRAF (V600E)/KRAS (exon 2) and microsatellite status [microsatellite stability (MSS) vs. MSI] were examined using a pyrosequencer and the PCR-based microsatellite method, respectively. DNA methylation status was classified as low (LME), intermediate (IME), or high methylation epigenotype (HME) according to a PCR-based two-step method. In addition, mucin and annexin A10 expression was examined. Finally, we performed a hierarchical clustering analysis of the BRAF/KRAS mutation, DNA methylation, and microsatellite statuses. RESULTS The molecular patterns observed in the serrated lesions could be divided into five subgroups: lesions characterized by (1) BRAF mutation, HME, and MSI; (2) BRAF mutation, HME, and MSS; (3) BRAF mutation, LME/IME, and MSS; (4) no BRAF/KRAS mutations, LME/IME, and MSS; and (5) KRAS mutation, LME/IME, and MSS. In addition, we demonstrated that these observed molecular patterns help identify the associations of the molecular patterns and markers (i.e., mucin and annexin A10) with the clinicopathological findings, including histological features and histological diagnosis. CONCLUSIONS We suggest that the identified molecular patterns play an important role in the pathway of serrated lesion development.
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Affiliation(s)
- Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Makoto Eizuka
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Yasuko Fujita
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Keisuke Kawasaki
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Eiichiro Yamamoto
- Department of Molecular Biology, School of Medicine, Sapporo Medical University, Cyuuouku, Sapporo, 060-0061 Japan
| | - Kazuyuki Ishida
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Hiroo Yamano
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Sapporo Medical University, 19-1, Cyuuouku, Sapporo, 060-0061 Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, School of Medicine, Sapporo Medical University, Cyuuouku, Sapporo, 060-0061 Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
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Fagunwa IO, Loughrey MB, Coleman HG. Alcohol, smoking and the risk of premalignant and malignant colorectal neoplasms. Best Pract Res Clin Gastroenterol 2017; 31:561-568. [PMID: 29195676 DOI: 10.1016/j.bpg.2017.09.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 08/31/2017] [Accepted: 09/16/2017] [Indexed: 01/31/2023]
Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide and has a complex aetiology consisting of environmental and genetic factors. In this review, we evaluate the roles of alcohol and tobacco smoking in colorectal neoplasia. Alcohol intake and tobacco smoking are associated with modest, but significantly, increased risks of CRC, adenomatous and serrated polyps. There is consistent evidence of dose-response relationships for both alcohol and smoking, and risk of these neoplasms. Alcohol and smoking appear to be more strongly associated with colorectal polyp than CRC development, suggesting roles in the initiation of neoplastic growths. These lifestyle factors also seem more strongly related to adenomas and sessile serrated lesions than hyperplastic polyps, but further confirmation is required. The gastroenterology community has an important, yet currently underexploited, role to play addressing the modifiable factors associated with CRC and polyps. These behaviours include, but are not limited to, alcohol and smoking.
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Affiliation(s)
- Ifewumi O Fagunwa
- Cancer Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Northern Ireland, United Kingdom.
| | - Maurice B Loughrey
- Department of Histopathology, Belfast Health and Social Care Trust, Northern Ireland, United Kingdom; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland, United Kingdom.
| | - Helen G Coleman
- Cancer Epidemiology Research Group, Centre for Public Health, Queen's University Belfast, Northern Ireland, United Kingdom; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland, United Kingdom.
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30
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De Maio G, Zama E, Rengucci C, Calistri D. What influences preneoplastic colorectal lesion recurrence? Oncotarget 2017; 8:12406-12416. [PMID: 27902488 PMCID: PMC5355354 DOI: 10.18632/oncotarget.13628] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 11/15/2016] [Indexed: 12/16/2022] Open
Abstract
The hypothesis of the local recurrence of preneoplastic lesions was first put forward in the 1950s. Disease recurrence may result from an inherent imbalance in cell proliferation that promotes carcinogenesis in apparently normal mucosa. Our review sheds light on how early preneoplastic lesions could be used to diagnose relapsed preneoplastic and, developing neoplastic lesions. We focus in detail on the clinical-pathological and molecular features of adenoma subtypes and their role in relapsed adenoma and their development into colorectal carcinoma. Moreover, we include the data available on microbiota and its metabolites and their role in recurrence. We strongly believe that a significant improvement could be achieved in colorectal screening by introducing personalized endoscopic surveillance for polyp-bearing patients on the basis of the presence of molecular markers that are predictive of recurrence.
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Affiliation(s)
- Giulia De Maio
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy
| | - Elisa Zama
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy
| | - Claudia Rengucci
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy
| | - Daniele Calistri
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy
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31
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MCM2 expression in serrated polyps demonstrates aberrant cellular proliferation. Hum Pathol 2017; 63:177-183. [PMID: 28302537 DOI: 10.1016/j.humpath.2017.02.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 02/06/2017] [Accepted: 02/24/2017] [Indexed: 01/06/2023]
Abstract
In normal colonic epithelium, the proliferative zone is limited to the lower half of the colonic crypt. Evaluating the changes in the colonic epithelial proliferation can be useful in understanding pathophysiology of various diseases. Our aim was to investigate the proliferative compartment of serrated polyps (SPs) using MCM2, a protein involved in DNA replication, and assess for changes along the SP spectrum. Immunohistochemistry was performed on serrated polyps (16 microvesicular-type hyperplastic polyps (HP), 58 sessile serrated adenomas (SSA), 7 SSAs with dysplasia) and 6 sections of normal colon using anti-MCM2 antibody. Multiple sections of normal colon showed the following pattern for MCM2 and Ki-67 staining: positive nuclear staining of the lower half of the colonic crypts and/or slightly expanded to the lower two-thirds of the crypt. By MCM2, SPs show expansion of the proliferative compartments; 81.3% of HPs and 100% of SSAs showed some degree of full crypt MCM2 staining. SSAs with dysplasia showed consistent diffuse polyp staining. Aberrant staining in adjacent normal mucosa was also seen in SSAs with dysplasia and in a subset of non-dysplastic SSAs. By using MCM2, we show that serrated polyps exhibit changes in proliferation during progression along the pathway. HPs and SSAs show a similar highly proliferative profile. Aberrant proliferative cell staining patterns in adjacent normal colonic mucosa as seen in SSAs with dysplasia and a subset of SSAs suggest a field effect phenomenon. This indicates that changes in the colonic micro-environment may promote adenoma morphogenesis and predisposition to malignancy.
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32
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Li XL, Zhou J, Chan ZL, Chooi JY, Chen ZR, Chng WJ. PRIMA-1met (APR-246) inhibits growth of colorectal cancer cells with different p53 status through distinct mechanisms. Oncotarget 2017; 6:36689-99. [PMID: 26452133 PMCID: PMC4742204 DOI: 10.18632/oncotarget.5385] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2015] [Accepted: 09/17/2015] [Indexed: 12/25/2022] Open
Abstract
PRIMA-1met (APR-246) is a methylated derivative and structural analog of PRIMA-1 (p53 re-activation and induction of massive apoptosis). PRIMA-1met has been reported to restore both the wild type (wt) structure and function of mutant p53. Here, we show that PRIMA-1met is highly effective at limiting the growth of CRC cells regardless of p53 status. However, PRIMA-1met induces robust apoptosis only in CRC cells with mutant p53. Upregulation of Noxa, a proapoptotic molecule, is crucial for PRIMA-1met mediated activity. In human xenograft model of disease, PRIMA-1met effectively suppresses CRC tumor growth. Our results uncover distinct mechanisms of PRIMA-1met in CRC with different p53 status, thus providing a mechanistic rationale to evaluate the clinical efficacy of PRIMA-1met in CRC patients with different p53 status.
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Affiliation(s)
- Xiao-Lan Li
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore 117599, Republic of Singapore.,Department of Gastroenterology, Suzhou Municipal Hospital (Eastern), Suzhou City, Jiangsu Province, 215001, P.R. China
| | - Jianbiao Zhou
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore 117599, Republic of Singapore
| | - Zit-Liang Chan
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore 117599, Republic of Singapore
| | - Jing-Yuan Chooi
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore 117599, Republic of Singapore
| | - Zhi-Rong Chen
- Department of Gastroenterology, Suzhou Municipal Hospital (Eastern), Suzhou City, Jiangsu Province, 215001, P.R. China
| | - Wee-Joo Chng
- Cancer Science Institute of Singapore, National University of Singapore, Centre for Translational Medicine, Singapore 117599, Republic of Singapore.,Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Republic of Singapore.,Department of Hematology-Oncology, National University Hospital, Singapore 119228, Republic of Singapore
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Péterfia B, Kalmár A, Patai ÁV, Csabai I, Bodor A, Micsik T, Wichmann B, Egedi K, Hollósi P, Kovalszky I, Tulassay Z, Molnár B. Construction of a multiplex mutation hot spot PCR panel: the first step towards colorectal cancer genotyping on the GS Junior platform. J Cancer 2017; 8:162-173. [PMID: 28243320 PMCID: PMC5327365 DOI: 10.7150/jca.16037] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2016] [Accepted: 09/04/2016] [Indexed: 12/15/2022] Open
Abstract
Background: To support cancer therapy, development of low cost library preparation techniques for targeted next generation sequencing (NGS) is needed. In this study we designed and tested a PCR-based library preparation panel with limited target area for sequencing the top 12 somatic mutation hot spots in colorectal cancer on the GS Junior instrument. Materials and Methods: A multiplex PCR panel was designed to amplify regions of mutation hot spots in 12 selected genes (APC, BRAF, CTNNB1, EGFR, FBXW7, KRAS, NRAS, MSH6, PIK3CA, SMAD2, SMAD4, TP53). Amplicons were sequenced on a GS Junior instrument using ligated and barcoded adaptors. Eight samples were sequenced in a single run. Colonic DNA samples (8 normal mucosa; 33 adenomas; 17 adenocarcinomas) as well as HT-29 and Caco-2 cell lines with known mutation profiles were analyzed. Variants found by the panel on APC, BRAF, KRAS and NRAS genes were validated by conventional sequencing. Results: In total, 34 kinds of mutations were detected including two novel mutations (FBXW7 c.1740:C>G and SMAD4 c.413C>G) that have not been recorded in mutation databases, and one potential germline mutation (APC). The most frequently mutated genes were APC, TP53 and KRAS with 30%, 15% and 21% frequencies in adenomas and 29%, 53% and 29% frequencies in carcinomas, respectively. In cell lines, all the expected mutations were detected except for one located in a homopolymer region. According to re-sequencing results sensitivity and specificity was 100% and 92% respectively. Conclusions: Our NGS-based screening panel denotes a promising step towards low cost colorectal cancer genotyping on the GS Junior instrument. Despite the relatively low coverage, we discovered two novel mutations and obtained mutation frequencies comparable to literature data. Additionally, as an advantage, this panel requires less template DNA than sequence capture colon cancer panels currently available for the GS Junior instrument.
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Affiliation(s)
- Bálint Péterfia
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary;; Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, Hungary
| | - Alexandra Kalmár
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - Árpád V Patai
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary
| | - István Csabai
- Department of Physics of Complex Systems, Eötvös Loránd University, Budapest, Hungary
| | - András Bodor
- Department of Physics of Complex Systems, Eötvös Loránd University, Budapest, Hungary
| | - Tamás Micsik
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Barnabás Wichmann
- Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, Hungary
| | - Krisztina Egedi
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Péter Hollósi
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary;; Tumor Progression Research Group, Hungarian Academy of Sciences, Budapest, Hungary
| | - Ilona Kovalszky
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary
| | - Zsolt Tulassay
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary;; Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, Hungary
| | - Béla Molnár
- 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary;; Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, Hungary
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Bailie L, Loughrey MB, Coleman HG. Lifestyle Risk Factors for Serrated Colorectal Polyps: A Systematic Review and Meta-analysis. Gastroenterology 2017; 152:92-104. [PMID: 27639804 DOI: 10.1053/j.gastro.2016.09.003] [Citation(s) in RCA: 131] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 08/18/2016] [Accepted: 09/21/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Certain subsets of colorectal serrated polyps (SP) have malignant potential. We performed a systematic review and meta-analysis to investigate the association between modifiable lifestyle factors and risk for SPs. METHODS We conducted a systematic search of Medline, Embase, and Web of Science for observational or interventional studies that contained the terms risk or risk factor, and serrated or hyperplastic, and polyps or adenomas, and colorectal (or synonymous terms), published by March 2016. Titles and abstracts of identified articles were independently reviewed by at least 2 reviewers. Adjusted relative risk (RR) and 95% confidence interval (CI) were combined using random effects meta-analyses to assess the risk of SP, when possible. RESULTS We identified 43 studies of SP risk associated with 7 different lifestyle factors: smoking, alcohol, body fatness, diet, physical activity, medication, and hormone-replacement therapy. When we compared the highest and lowest categories of exposure, factors we found to significantly increase risk for SP included tobacco smoking (RR, 2.47; 95% CI, 2.12-2.87), alcohol intake (RR, 1.33; 95% CI, 1.17-1.52), body mass index (RR, 1.40; 95% CI, 1.22-1.61), and high intake of fat or meat. Direct associations for smoking and alcohol, but not body fat, tended to be stronger for sessile serrated adenomas/polyps than hyperplastic polyps. In contrast, factors we found to significantly decrease risks for SP included use of nonsteroidal anti-inflammatory drugs (RR, 0.77; 95% CI, 0.65-0.92) or aspirin (RR, 0.81; 95% CI, 0.67-0.99), as well as high intake of folate, calcium, or fiber. No significant associations were detected between SP risk and physical activity or hormone replacement therapy. CONCLUSIONS Several lifestyle factors, most notably smoking and alcohol, are associated with SP risk. These findings enhance our understanding of mechanisms of SP development and indicate that risk of serrated pathway colorectal neoplasms could be reduced with lifestyle changes.
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Affiliation(s)
- Lesley Bailie
- Cancer Epidemiology and Health Services Research Group, Centre for Public Health, Queens University Belfast, Belfast, Northern Ireland
| | - Maurice B Loughrey
- Department of Pathology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, Northern Ireland
| | - Helen G Coleman
- Cancer Epidemiology and Health Services Research Group, Centre for Public Health, Queens University Belfast, Belfast, Northern Ireland.
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Comprehensive DNA Methylation and Mutation Analyses Reveal a Methylation Signature in Colorectal Sessile Serrated Adenomas. Pathol Oncol Res 2016; 23:589-594. [PMID: 27896617 DOI: 10.1007/s12253-016-0154-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Accepted: 11/22/2016] [Indexed: 01/07/2023]
Abstract
Colorectal sessile serrated adenomas (SSA) are hypothesized to be precursor lesions of an alternative, serrated pathway of colorectal cancer, abundant in genes with aberrant promoter DNA hypermethylation. In our present pilot study, we explored DNA methylation profiles and examined selected gene mutations in SSA. Biopsy samples from patients undergoing screening colonoscopy were obtained during endoscopic examination. After DNA isolation and quality analysis, SSAs (n = 4) and healthy controls (n = 5) were chosen for further analysis. DNA methylation status of 96 candidate genes was screened by q(RT)PCR using Methyl-Profiler PCR array system. Amplicons for 12 gene mutations were sequenced by GS Junior Instrument using ligated and barcoded adaptors. Analysis of DNA methylation revealed 9 hypermethylated genes in both normal and SSA samples. 12 genes (CALCA, DKK2, GALR2, OPCML, PCDH10, SFRP1, SFRP2, SLIT3, SST, TAC1, VIM, WIF1) were hypermethylated in all SSAs and 2 additional genes (BNC1 and PDLIM4) were hypermethylated in 3 out of 4 SSAs, but in none of the normal samples. 2 SSAs exhibited BRAF mutation and synchronous MLH1 hypermethylation and were microsatellite instable by immunohistochemical analysis. Our combined mutation and DNA methylation analysis revealed that there is a common DNA methylation signature present in pre-neoplastic SSAs. This study advocates for the use of DNA methylation as a potential biomarker for the detection of SSA; however, further investigation is needed to better characterize the molecular background of these newly recognized colorectal lesions.
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36
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Liu Y, Sun H, Hu M, Zhang Y, Chen S, Tighe S, Zhu Y. The Role of Cyclooxygenase-2 in Colorectal Carcinogenesis. Clin Colorectal Cancer 2016; 16:165-172. [PMID: 27810226 DOI: 10.1016/j.clcc.2016.09.012] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 09/08/2016] [Accepted: 09/22/2016] [Indexed: 12/16/2022]
Abstract
Colorectal cancer is a major worldwide health care problem that accounts for 1 million new cases each year. The risk factors for this disease include hereditary factors, environmental agents, and inflammatory stimuli that affect the gastrointestinal tract. Among these risk factors, cyclooxygenase-2 (COX-2) is one of the major players in the progression of colorectal cancer; however, the detailed mechanism of its role in causing colorectal cancer is still not well understood. In addition, the role of COX-2 signaling through the interaction in the epithelial and stromal compartments on colorectal carcinogenesis has not been fully illustrated. In the present review, we provide published evidence to demonstrate that (1) COX-2 signaling plays a major role in the progression of colorectal cancer, (2) activation of COX-2 in the stromal compartment also contributes to colorectal carcinogenesis, and (3) inhibition of COX-2 signaling by COX-2 inhibitors might be an effective method to control colorectal cancer. We have also summarized recent advances and insights from mechanistic studies of colorectal cancer to help prevent and control this deadly disease and provide our opinion regarding the importance of risk reduction and disease prevention for colorectal cancer.
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Affiliation(s)
| | - Hong Sun
- The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Min Hu
- The Second People's Hospital of Yunnan Province, Kunming, China
| | - Yuan Zhang
- Research and Development Department, Tissue Tech, Inc., Miami, FL
| | - Shuangling Chen
- Research and Development Department, Tissue Tech, Inc., Miami, FL
| | - Sean Tighe
- Research and Development Department, Tissue Tech, Inc., Miami, FL
| | - Yingting Zhu
- Research and Development Department, Tissue Tech, Inc., Miami, FL.
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37
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Galamb O, Kalmár A, Péterfia B, Csabai I, Bodor A, Ribli D, Krenács T, Patai ÁV, Wichmann B, Barták BK, Tóth K, Valcz G, Spisák S, Tulassay Z, Molnár B. Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer. Epigenetics 2016; 11:588-602. [PMID: 27245242 DOI: 10.1080/15592294.2016.1190894] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The WNT signaling pathway has an essential role in colorectal carcinogenesis and progression, which involves a cascade of genetic and epigenetic changes. We aimed to analyze DNA methylation affecting the WNT pathway genes in colorectal carcinogenesis in promoter and gene body regions using whole methylome analysis in 9 colorectal cancer, 15 adenoma, and 6 normal tumor adjacent tissue (NAT) samples by methyl capture sequencing. Functional methylation was confirmed on 5-aza-2'-deoxycytidine-treated colorectal cancer cell line datasets. In parallel with the DNA methylation analysis, mutations of WNT pathway genes (APC, β-catenin/CTNNB1) were analyzed by 454 sequencing on GS Junior platform. Most differentially methylated CpG sites were localized in gene body regions (95% of WNT pathway genes). In the promoter regions, 33 of the 160 analyzed WNT pathway genes were differentially methylated in colorectal cancer vs. normal, including hypermethylated AXIN2, CHP1, PRICKLE1, SFRP1, SFRP2, SOX17, and hypomethylated CACYBP, CTNNB1, MYC; 44 genes in adenoma vs. NAT; and 41 genes in colorectal cancer vs. adenoma comparisons. Hypermethylation of AXIN2, DKK1, VANGL1, and WNT5A gene promoters was higher, while those of SOX17, PRICKLE1, DAAM2, and MYC was lower in colon carcinoma compared to adenoma. Inverse correlation between expression and methylation was confirmed in 23 genes, including APC, CHP1, PRICKLE1, PSEN1, and SFRP1. Differential methylation affected both canonical and noncanonical WNT pathway genes in colorectal normal-adenoma-carcinoma sequence. Aberrant DNA methylation appears already in adenomas as an early event of colorectal carcinogenesis.
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Affiliation(s)
- Orsolya Galamb
- a Molecular Medicine Research Group , Hungarian Academy of Sciences , Budapest , Hungary
| | - Alexandra Kalmár
- b 2nd Department of Internal Medicine , Semmelweis University , Budapest , Hungary
| | - Bálint Péterfia
- b 2nd Department of Internal Medicine , Semmelweis University , Budapest , Hungary
| | - István Csabai
- c Department of Physics of Complex Systems , Eötvös Loránd University , Budapest , Hungary
| | - András Bodor
- c Department of Physics of Complex Systems , Eötvös Loránd University , Budapest , Hungary
| | - Dezső Ribli
- c Department of Physics of Complex Systems , Eötvös Loránd University , Budapest , Hungary
| | - Tibor Krenács
- d 1st Department of Pathology and Experimental Cancer Research , Semmelweis University , Budapest , Hungary.,e Tumor Progression Research Group , Hungarian Academy of Sciences - Semmelweis University , Budapest , Hungary
| | - Árpád V Patai
- b 2nd Department of Internal Medicine , Semmelweis University , Budapest , Hungary
| | - Barnabás Wichmann
- a Molecular Medicine Research Group , Hungarian Academy of Sciences , Budapest , Hungary
| | - Barbara Kinga Barták
- b 2nd Department of Internal Medicine , Semmelweis University , Budapest , Hungary
| | - Kinga Tóth
- b 2nd Department of Internal Medicine , Semmelweis University , Budapest , Hungary
| | - Gábor Valcz
- a Molecular Medicine Research Group , Hungarian Academy of Sciences , Budapest , Hungary
| | - Sándor Spisák
- f Department of Medical Oncology , Dana-Farber Cancer Institute , Boston , MA , USA
| | - Zsolt Tulassay
- a Molecular Medicine Research Group , Hungarian Academy of Sciences , Budapest , Hungary.,b 2nd Department of Internal Medicine , Semmelweis University , Budapest , Hungary
| | - Béla Molnár
- a Molecular Medicine Research Group , Hungarian Academy of Sciences , Budapest , Hungary
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Murcia O, Juárez M, Hernández-Illán E, Egoavil C, Giner-Calabuig M, Rodríguez-Soler M, Jover R. Serrated colorectal cancer: Molecular classification, prognosis, and response to chemotherapy. World J Gastroenterol 2016; 22:3516-3530. [PMID: 27053844 PMCID: PMC4814638 DOI: 10.3748/wjg.v22.i13.3516] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 12/04/2015] [Accepted: 01/30/2016] [Indexed: 02/06/2023] Open
Abstract
Molecular advances support the existence of an alternative pathway of colorectal carcinogenesis that is based on the hypermethylation of specific DNA regions that silences tumor suppressor genes. This alternative pathway has been called the serrated pathway due to the serrated appearance of tumors in histological analysis. New classifications for colorectal cancer (CRC) were proposed recently based on genetic profiles that show four types of molecular alterations: BRAF gene mutations, KRAS gene mutations, microsatellite instability, and hypermethylation of CpG islands. This review summarizes what is known about the serrated pathway of CRC, including CRC molecular and clinical features, prognosis, and response to chemotherapy.
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39
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Amri R, Bordeianou LG, Berger DL. Effect of High-Grade Disease on Outcomes of Surgically Treated Colon Cancer. Ann Surg Oncol 2016; 23:1157-1163. [PMID: 26589501 DOI: 10.1245/s10434-015-4983-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Indexed: 01/06/2025]
Abstract
INTRODUCTION Tumor grade is one of the cardinal pathological characteristics of colon cancer. Despite a large body of evidence on disease grade in general, the exact impact of high-grade disease in the context of the simplified high/low-grade dichotomy that is based on glandular formation rate has yet to be quantified. METHODS Patients with sporadic colon cancer treated surgically at our center (2004-2011) were included in an institutional review board-approved database. We measured the rates of distant and nodal disease spread in baseline pathology and the multivariable hazard radio (mHR) of recurrence and overall- and disease-specific mortality. RESULTS Among 922 patients with specified tumor grade in baseline surgical pathology, 175 (19.0 %) had high-grade disease. These patients were at far higher risk of lymph node metastasis (63.8 vs. 39.6 %; P < 0.001) and metastatic presentation (31.4 vs. 15.8 %; P < 0.001). These baseline differences also led to significantly worse outcomes, including disease recurrence (17.1 vs. 10.6 %; mHR = 1.83; P = 0.026), overall mortality (57.7 vs. 33.3 %; mHR = 1.65; P < 0.001), and colon cancer-specific mortality (39.4 vs. 16.9 %; mHR = 1.57; P = 0.004). Most significantly, in stage II patients (n = 294), those with high-grade disease (16.0 %) had an mHR of 2.84 (P < 0.001) for mortality. CONCLUSIONS High-grade disease on baseline surgical pathology is associated with a considerably higher rate of nodal and distant metastasis in colon cancer. As a result, the colon cancer-related mortality doubles for patients with high-grade disease. These findings were independent of baseline staging and confirm that the high-/low-grade tumor dichotomy is an important prognostic factor greatly influencing colon cancer outcomes across stages.
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Affiliation(s)
- Ramzi Amri
- Division of General Surgery & Gastrointestinal Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Liliana G Bordeianou
- Division of General Surgery & Gastrointestinal Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - David L Berger
- Division of General Surgery & Gastrointestinal Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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40
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Sameer AS, Nissar S. Understanding Epigenetics: an Alternative Mechanism of Colorectal Carcinogenesis. CURRENT COLORECTAL CANCER REPORTS 2016. [DOI: 10.1007/s11888-016-0317-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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Disparities in prevalence, location, and shape characteristics of colorectal neoplasia between South Korean and U.S. patients. Gastrointest Endosc 2015; 82:1080-6. [PMID: 26024585 DOI: 10.1016/j.gie.2015.04.018] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 04/08/2015] [Indexed: 02/08/2023]
Abstract
BACKGROUND Colon cancer screening is being introduced in many countries, but standard Western screening approaches may not be appropriate for Asian societies if differences in colon cancer epidemiology exist. Comparative analysis of colorectal neoplasia patterns in South Korean and Western subjects has implications for appropriate screening approaches in non-Western societies. METHODS The results of concurrent screening colonoscopies performed in average-risk patients 50 to 69 years old in 2 teaching hospitals, Kyung Hee University Hospital (Seoul, South Korea) and Virginia Mason Medical Center (Seattle, Wash), were compared with respect to prevalence, histologic features, anatomic distribution, and shape characteristics of colorectal neoplasia. RESULTS The U.S. (n = 3460) and South Korean (n = 2193) cohorts were similar with regard to the prevalence of adenomas (28.5% vs 29.8%, respectively, P = .312) and advanced neoplasia (6.4% vs 5.4%, respectively, P = .102), but the proportion of proximal adenomas was greater in the U.S. cohort (62.8% vs 45.9%, P < .001). The prevalence of adenomas and advanced neoplasia was similar in male patients, but there was a greater prevalence of neoplasia (23.5% vs 18.8%, P = .006) and advanced neoplasia (5.1% vs 2.7%, P < .001) in U.S. women than South Korean women. When large (≥10 mm) adenomas were considered, proximal location and nonpolypoid (flat) shape were more common in the U.S. cohort (79.4% vs 37.1%, P = .003 and 43.5% vs 12.3%, P < .001, respectively). The overall prevalence of large flat adenomas in the U.S. cohort was 5 times that of the South Korean cohort (2.6% vs 0.5%, P < .001). Adjustment for sex ratio discrepancies (48.3% men in the U.S. cohort vs 60.8% in the South Korean cohort, P < .001) did not result in any significant changes in the conclusions. CONCLUSION Compared with Westerners, South Koreans have a more distal distribution of adenomas and advanced neoplasia and lower prevalence of large flat adenomas. South Korean women have a lower prevalence of colorectal neoplasia than Western women. Such disparities suggest that Western screening strategies cannot be directly adopted by other countries, but need to be customized by society.
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Peng X, Luo Z, Kang Q, Deng D, Wang Q, Peng H, Wang S, Wei Z. FOXQ1 mediates the crosstalk between TGF-β and Wnt signaling pathways in the progression of colorectal cancer. Cancer Biol Ther 2015; 16:1099-109. [PMID: 25955104 DOI: 10.1080/15384047.2015.1047568] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
A wide variety of signaling transduction pathways contribute to tumorigenesis. Forkhead box Q1 (FOXQ1) is a member of the forkhead transcription factor family and its upregulation is closely correlated with tumor progression and prognosis of multiple cancer types, including colorectal cancer. However, the molecular mechanisms by which FOXQ1 promotes tumorigenesis, especially cancer cell invasion and metastasis in colorectal cancer, have not been fully elucidated. In the present study, we demonstrate that FOXQ1 is overexpressed in colorectal tumor tissues and its expression level is closely correlated with the stage and lymph node metastasis of colorectal cancer. In in vitro cultured SW480 colorectal cancer cells, knockdown of FOXQ1 expression by small interfering RNA greatly diminished the aggressive tumor behaviors of SW480 cells, including angiogenesis, invasion, epithelial-mesenchymal transition, and resistance to chemotherapy drug-induced apoptosis. Further mechanistic investigation showed that FOXQ1 silencing prevents the nuclear translocation of β-catenin, thus reducing the activity of Wnt signaling. Moreover, TGF-β1 induced the expression of FOXQ1 as well as the migration and invasion of SW480 cells, which was partially prevented following knockdown of FOXQ1. Our results demonstrate that FOXQ1 plays a critical role during the tumorigenesis of colorectal cancer and is a mediator of the crosstalk between Wnt and TGF-β signaling pathways. Our findings provide further insight into the cancer biology of colorectal cancer and suggest that FOXQ1 is a potential therapeutic target for the development of therapies for colorectal cancer.
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Key Words
- 5-FU, 5-fluorouracil
- 7-AAD, 7-aminoactinomycin D
- DAPI, 4′,6-diamidino-2-phenylindole
- DEPC, Diethy pyrocarbonate
- DMSO, Dimethyl sulfoxide
- EMT, Epithelial-Mesenchymal transition
- FOXQ1
- FOXQ1, Forkhead Box Q1
- L-OHP, Oxaliplatin
- MMP2, Matrix metalloproteinase-2
- MiRNA, MicroRNA
- NC-shRNA, Negative Control-shRNA
- PBS, Phosphate buffer solution
- PBS, phosphate buffered saline
- PKA, proteinkinase A
- PVDF, Polyvinylidene fluoride
- RNAi, RNA interference
- SDS, Sodium dodecyl sulfonate
- TBS, Tris-buffered saline
- TEMED, Tetra methyl ethylene diamine
- TGF-β, Transformin growth β
- TGF-β1
- Tris, Trihydroxymethyl minomethane
- VEGF-A, Vascular endothelial growth factor-A
- Wnt signaling
- aggressive tumor behavior
- cDNA, Complementary DNA
- colorectal cancer
- ddH2O, double distilled H2O
- epithelial-mesenchymal transition
- qRT-PCR, Quantitative real-time PCR
- shRNA, Short hairpin RNA
- μg, Microgramme
- μl, Microliter
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Affiliation(s)
- Xudong Peng
- a Gastrointestinal Surgical Unit; The First Affiliated Hospital of Chongqing Medical University ; Chongqing , China
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Sethi A, Hanson JA. A morphologic reappraisal of endoscopically but not histologically apparent polyps and the emergence of the overlooked goblet cell--rich hyperplastic polyp. Hum Pathol 2015; 46:1147-52. [PMID: 26004372 DOI: 10.1016/j.humpath.2015.03.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 03/17/2015] [Accepted: 03/30/2015] [Indexed: 02/07/2023]
Abstract
Goblet cell--rich hyperplastic polyps (GCRHP) are morphologically subtle compared to microvesicular hyperplastic polyps (MVHP) and are believed to be the most commonly unrecognized serrated polyp, though this has not been systematically studied. We hypothesize that a gastrointestinal pathologist's review of endoscopically but not histologically apparent polyps will identify previously missed GCRHPs, a finding that may be clinically significant if the addition of this subtype of serrated polyp contributes to sufficient numeric criteria for a clinical diagnosis of serrated polyposis syndrome (SPS). Two blinded reviews were performed on 160 endoscopically but not histologically apparent polyps by a gastrointestinal pathologist, separated by a 6 month "washout period." A final review diagnosis of GCRHP was applied to all polyps with complete agreement on both reviews. Patient records were then searched to determine if the addition of a GCRHP resulted in sufficient numeric criteria for a clinical diagnosis of SPS. Fourteen (9%) polyps were reclassified as GCRHPs. The majority (n = 12, 86%) were originally called "colonic mucosa with surface hyperplastic change (CMWSHC)." Two polyps (1%) were re-classified as MVHPs. No other serrated or adenomatous polyps were identified. For each patient, the addition of a hyperplastic polyp did not result in a clinical diagnosis of SPS, though one patient fell short of this diagnosis by only one polyp. GCRHPs are the most commonly underdiagnosed serrated polyp and are often called CMWSHC. The addition of previously missed GCRHPs is unlikely to contribute to a diagnosis of SPS in an individual patient.
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Affiliation(s)
- Aisha Sethi
- Department of Pathology, University of New Mexico School of Medicine, Albuquerque, 87131, NM
| | - Joshua Anspach Hanson
- Department of Pathology, University of New Mexico School of Medicine, Albuquerque, 87131, NM.
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Serrated polyps and their alternative pathway to the colorectal cancer: a systematic review. Gastroenterol Res Pract 2015; 2015:573814. [PMID: 25945086 PMCID: PMC4405010 DOI: 10.1155/2015/573814] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 03/20/2015] [Accepted: 03/22/2015] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer (CRC) is the third most frequently diagnosed cancer in the world. For a long time, only one pathway of colorectal carcinogenesis was known. In recent years, a new “alternative” pathway through serrated adenoma was described. Recent meta-analysis estimated these cancers as about 10% to 30% of all CRCs. Serrated polyps are the second most popular groups of polyps (after conventional adenomas) found during colonoscopy. Serrated polyps of the colon are clinically and molecularly diverse changes that have common feature as crypt luminal morphology characterized by glandular serration. Evidence suggests that subtypes of serrated polyps, particularly TSA and SSA/P, can lead to adenocarcinoma through the serrated pathway. Moreover, the data indicate that the SSA/P are the precursors of colorectal carcinoma by MSI and may be subject to rapid progression to malignancy. An important step to reduce the incidence of CRC initiated by the serrated pathway is to improve the detection of serrated polyps and to ensure their complete removal during endoscopy. Understanding of the so-called serrated carcinogenesis pathway is an important step forward in expanding possibilities in the prevention of CRC.
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Moussata D, Boschetti G, Chauvenet M, Stroeymeyt K, Nancey S, Berger F, Lecomte T, Flourié B. Endoscopic and histologic characteristics of serrated lesions. World J Gastroenterol 2015; 21:2896-904. [PMID: 25780286 PMCID: PMC4356908 DOI: 10.3748/wjg.v21.i10.2896] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Revised: 08/25/2014] [Accepted: 10/14/2014] [Indexed: 02/07/2023] Open
Abstract
In recent years, a second pathway for colonic carcinogenesis, distinct from the adenomatous pathway, has been explored. This is referred to as serrated pathway and includes three types of polyp, characterised by a serrated appearance of the crypts: hyperplastic polyps (HP), sessile serrated adenomas (SSA) or lesions, and traditional serrated adenomas. Each lesion has its own genetic, as well as macroscopic and microscopic morphological features. Because of their flat aspect, their detection is easier with chromoendoscopy (carmin indigo or narrow-band imaging). However, as we show in this review, the distinction between SSA and HP is quite difficult. It is now recommended to resect in one piece as it is possible the serrated polyps with a control in a delay depending on the presence or not of dysplasia. These different types of lesion are described in detail in the present review in general population, in polyposis and in inflammatory bowel diseases patients. This review highlights the need to improve characterization and understanding of this way of colorectal cancerogenesis.
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Kumagai R, Kohashi K, Takahashi S, Yamamoto H, Hirahashi M, Taguchi K, Nishiyama K, Oda Y. Mucinous phenotype and CD10 expression of primary adenocarcinoma of the small intestine. World J Gastroenterol 2015; 21:2700-2710. [PMID: 25759539 PMCID: PMC4351221 DOI: 10.3748/wjg.v21.i9.2700] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2014] [Revised: 11/13/2014] [Accepted: 12/22/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To clarify the correlation with phenotypic expression, clinicopathological features, genetic alteration and microsatellite-instability status in small intestinal adenocarcinoma (SIA).
METHODS: The cases of 47 patients diagnosed with primary SIAs that were surgically resected at our institution in 1975-2005 were studied. We reviewed clinicopathological findings (age, gender, tumor size, gross appearance, histological morphologic type, invasion depth, lymphatic permeation, venous invasion, and lymph node metastasis), and the immunohistochemical expression of MUC5AC, MUC6, MUC2, CD10, and mismatch-repair (MMR) proteins (MLH1 and MSH2). We analyzed KRAS and BRAF gene mutations, and the microsatellite instability (MSI) status. The immunohistochemical staining of CD10, MUC2, MUC5AC and MUC6 was considered positive when distinct staining in > 5% of the adenocarcinoma cells was recorded. To evaluate of MMR protein expression, we used adjacent normal tissue including lymphoid follicles, inflammatory cells, and stromal cells as an internal positive control. Sections without nuclear staining in the tumor cells were considered to have lost the expression of the respective MMR protein.
RESULTS: There were 29 males and 18 females patients (mean age 59.9 years, range: 23-87 years). Tumors were located in the duodenum in 14 cases (30%), the jejunum in 21 cases (45%), and the ileum in 12 cases (25%). A phenotypic expression analysis revealed 20 MUC2-positive tumors (42.6%), 11 MUC5AC-positive (23.4%), 4 MUC6-positive (8.5%), and 7 CD10-positive (14.9%). The tumor sizes of the MUC2(+) tumors were significantly larger than those of the MUC2(-) tumors (mean, 5.7 ± 1.4 cm vs 4.7 ± 2.1 cm, P < 0.05). All three tumors with adenomatous component were positive for MUC2 (P < 0.05). Polypoid appearance was seen significantly more frequently in the CD10(+) group than in the CD10(-) group (P < 0.05). The tumor size was significantly larger in the CD10 (+) group than in the CD10(-) group (mean, 5.9 ± 1.4 cm vs 5.0 ± 2.1 cm, P < 0.05). Of 34 SIAs with successfully obtained MSI data, 4 were MSI-high. Of the 4 SIAs positive for both MUC5AC and MUC2, 3 showed MSI-H (75%) and 3 were mucinous adenocarcinoma (75%). KRAS mutations were detected in 4 SIAs. SIAs had KRAS mutation expressed only MUC2, but were negative for MUC5AC, MUC6 and CD10.
CONCLUSION: These findings suggest that the phenotypic expression of SIAs is correlated with their biological behavior, genetic alteration, and MSI status.
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MESH Headings
- Adenocarcinoma, Mucinous/genetics
- Adenocarcinoma, Mucinous/immunology
- Adenocarcinoma, Mucinous/pathology
- Adenocarcinoma, Mucinous/surgery
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/genetics
- Biopsy
- DNA Mutational Analysis
- Female
- Humans
- Immunohistochemistry
- Intestinal Neoplasms/genetics
- Intestinal Neoplasms/immunology
- Intestinal Neoplasms/pathology
- Intestinal Neoplasms/surgery
- Intestine, Small/immunology
- Intestine, Small/pathology
- Intestine, Small/surgery
- Male
- Microsatellite Instability
- Middle Aged
- Mucin 5AC/analysis
- Mucin-2/analysis
- Mucin-6/analysis
- Mucins/analysis
- Mutation
- Neprilysin/analysis
- Phenotype
- Prognosis
- Proto-Oncogene Proteins/genetics
- Proto-Oncogene Proteins B-raf/genetics
- Proto-Oncogene Proteins p21(ras)
- Retrospective Studies
- Young Adult
- ras Proteins/genetics
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Baker AM, Graham TA, Elia G, Wright NA, Rodriguez-Justo M. Characterization of LGR5 stem cells in colorectal adenomas and carcinomas. Sci Rep 2015; 5:8654. [PMID: 25728748 PMCID: PMC4345329 DOI: 10.1038/srep08654] [Citation(s) in RCA: 73] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 01/23/2015] [Indexed: 12/20/2022] Open
Abstract
LGR5 is known to be a stem cell marker in the murine small intestine and colon, however the localization of LGR5 in human adenoma samples has not been examined in detail, and previous studies have been limited by the lack of specific antibodies. Here we used in situ hybridization to specifically examine LGR5 mRNA expression in a panel of human adenoma and carcinoma samples (n = 66). We found that a small number of cells express LGR5 at the base of normal colonic crypts. We then showed that conventional adenomas widely express high levels of LGR5, and there is no evidence of stereotypic cellular hierarchy. In contrast, serrated lesions display basal localization of LGR5, and the cellular hierarchy resembles that of a normal crypt. Moreover, ectopic crypts found in traditional serrated adenomas show basal LGR5 mRNA, indicating that they replicate the stem cell organization of normal crypts with the development of a cellular hierarchy. These data imply differences in the stem cell dynamics between the serrated and conventional pathways of colorectal carcinogenesis. Furthermore we noted high LGR5 expression in invading cells, with later development of a stem cell niche in adenocarcinomas of all stages.
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Affiliation(s)
- Ann-Marie Baker
- Centre for Tumor Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK, EC1M 6BQ
| | - Trevor A. Graham
- Centre for Tumor Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK, EC1M 6BQ
| | - George Elia
- Centre for Tumor Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK, EC1M 6BQ
| | - Nicholas A. Wright
- Centre for Tumor Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK, EC1M 6BQ
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Kim HO, Kim BG, Cha SJ, Park YG, Lee TJ. Clinicopathologic Significance of BRAF Mutation and Extracellular Signal Regulated Kinase 1/2 Expression in Patients With a Colorectal Adenocarcinoma. Ann Coloproctol 2015; 31:9-15. [PMID: 25745621 PMCID: PMC4349919 DOI: 10.3393/ac.2015.31.1.9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Accepted: 01/03/2015] [Indexed: 02/06/2023] Open
Abstract
Purpose BRAF mutation and expression of extracellular signal regulated kinase (ERK) are linked with colorectal carcinogenesis through the serrated pathway. BRAF and ERK1/2 play important roles in the activation of mitogen-activated protein (MAP) kinase signaling pathways. The present study investigated the clinicopathologic outcomes of BRAF mutation and ERK1/2 expression in patients with colorectal cancer (CRC) and the possibility of using them as prognostic indicators. Methods Dual-priming oligonucleotide-based multiplex polymerase chain reaction for BRAFV600E mutation and immunohistochemical analysis of ERK1/2 were performed using 65 formalin-fixed, paraffin-embedded samples from patients with CRC. We analyzed the dependences of the clinicopathologic features on BRAF mutation and ERK1/2 expression. Results Out of 65 samples from CRC patients, BRAF mutation was detected in 3 (4.6%). The 3 patients with BRAF mutation presented with T3 CRC with lymph node metastasis (stage III) showing moderately or poorly differentiated histology. ERK1 and ERK2 were positively detected in 73.8% and 15.4% of the patients with CRC, respectively. ERK1 expression was significantly correlated with lymph node metastasis (P = 0.049). ERK2 expression was significantly correlated with tumor emboli (P < 0.05), tumor invasion (P = 0.035), lymph node metastasis (P = 0.017), and stage (P = 0.02). Conclusion BRAF mutation and ERK1/2 expression may be associated with advanced or more aggressive CRC. These molecular markers might play prognostic roles in CRC developed through the serrated pathway.
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Affiliation(s)
- Hyung Ook Kim
- Department of Surgery, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Beom Gyu Kim
- Department of Surgery, Chung-Ang University College of Medicine, Seoul, Korea
| | - Seong Jae Cha
- Department of Surgery, Chung-Ang University College of Medicine, Seoul, Korea
| | - Yong Gum Park
- Department of Surgery, Chung-Ang University College of Medicine, Seoul, Korea
| | - Tae Jin Lee
- Department of Pathology, Chung-Ang University College of Medicine, Seoul, Korea
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Pereira L, Mariadason JM, Hannan RD, Dhillon AS. Implications of epithelial-mesenchymal plasticity for heterogeneity in colorectal cancer. Front Oncol 2015; 5:13. [PMID: 25699236 PMCID: PMC4313606 DOI: 10.3389/fonc.2015.00013] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2014] [Accepted: 01/12/2015] [Indexed: 01/15/2023] Open
Abstract
Colorectal cancer (CRC) is a genetically heterogeneous disease that develops and progresses through several distinct pathways characterized by genomic instability. In recent years, it has emerged that inherent plasticity in some populations of CRC cells can contribute to heterogeneity in differentiation state, metastatic potential, therapeutic response, and disease relapse. Such plasticity is thought to arise through interactions between aberrant signaling events, including persistent activation of the APC/β-catenin and KRAS/BRAF/ERK pathways, and the tumor microenvironment. Here, we highlight key concepts and evidence relating to the role of epithelial–mesenchymal plasticity as a driver of CRC progression and stratification of the disease into distinct molecular and clinicopathological subsets.
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Affiliation(s)
- Lloyd Pereira
- Research Division, Peter MacCallum Cancer Centre , Melbourne, VIC , Australia
| | - John M Mariadason
- Olivia Newton-John Cancer Research Institute, Austin Hospital , Melbourne, VIC , Australia
| | - Ross D Hannan
- Research Division, Peter MacCallum Cancer Centre , Melbourne, VIC , Australia ; Sir Peter MacCallum Department of Oncology, The University of Melbourne , Melbourne, VIC , Australia ; Department of Biochemistry and Molecular Biology, The University of Melbourne , Melbourne, VIC , Australia
| | - Amardeep S Dhillon
- Research Division, Peter MacCallum Cancer Centre , Melbourne, VIC , Australia ; Sir Peter MacCallum Department of Oncology, The University of Melbourne , Melbourne, VIC , Australia ; Department of Pathology, The University of Melbourne , Melbourne, VIC , Australia
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Luo L, Song Q, Li YC, Yang Z, Chen Y, Tang LJ, Li XR, Yang YF, Yang S, Yan J, Huang Q. Protective effects of proanthocyanidins on intestinal smooth muscle contractility in rats with intestinal ischemia-reperfusion injury. Shijie Huaren Xiaohua Zazhi 2015; 23:409-414. [DOI: 10.11569/wcjd.v23.i3.409] [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 investigate the protective effects of proanthocyanidins (PA) on intestinal smooth muscle contractility in rats with ischemia-reperfusion (I/R) and explore the possible mechanism.
METHODS: Twenty-eight male SD rats were randomly divided into four groups (n = 7 for each group): A (sham group), B (I/R group), C (100 mg/kg PA group) and D (200 mg/kg PA group). Groups C and D were pretreated with 100 and 200 mg/(kg·d) PA for 5 days, group D was administrated 200 mg/(kg·d) PA, and the other two groups were administrated equal volume of physiological saline for the same duration. Intestinal I/R injury was induced by occlusion of the superior mesenteric artery (SMA) for 1 h and followed by a period of reperfusion for 4 h. Following reperfusion, the abdominal cavity was opened and segments of the ileum were quickly resected and equally separated into two parts to determine ileal smooth muscle contractility and tissue myeloperoxidse (MPO). Additionally, blood samples were collected to detect serum tumor necrosis factor-α (TNF-α).
RESULTS: The frequency, amplitude and vitality of intestinal smooth muscle contractility in group B were significantly decreased compared with group A (P < 0.01). Pretreatment with 200 mg/kg PA caused a significant increase in ileal smooth muscle contractility amplitude compared with group B (P < 0.05). Besides, both C and D groups showed an increasing trend in conparison with group B in the vitality of intestinal smooth muscle contractility. After I/R induction, the level of serum TNF-α was increased significantly (P < 0.05). Pretreatment with PA at 100 and 200 mg/kg significantly decreased the levels of serum TNF-α compared with group B (P < 0.05). Intestinal tissue MPO activity also showed a decreasing trend.
CONCLUSION: PA may reduce serum TNF-α levels and MPO activity and promote intestinal motility in rats with intestinal I/R injury.
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