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Greco L, Rubbino F, Ferrari C, Cameletti M, Grizzi F, Bonelli F, Malesci A, Mazzone M, Ricciardiello L, Laghi L. Association of Fusobacterium nucleatum with colorectal cancer molecular subtypes and its outcome: a systematic review. GUT MICROBIOME (CAMBRIDGE, ENGLAND) 2025; 6:e5. [PMID: 40297307 PMCID: PMC12035788 DOI: 10.1017/gmb.2025.3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 03/27/2025] [Accepted: 03/28/2025] [Indexed: 04/30/2025]
Abstract
Colorectal cancer (CRC) represents a relevant public health problem, with high incidence and mortality in Western countries. CRC can occur as sporadic (65%-75%), common familial (25%), or as a consequence of an inherited predisposition (up to 10%). While unravelling its genetic basis has been a long trip leading to relevant clinical implementation over more than 30 years, other contributing factors remain to be clarified. Among these, micro-organisms have emerged as critical players in the development and progression of the disease, as well as for CRC treatment response. Fusobacterium nucleatum (Fn) has been associated with CRC development in both pre-clinical models and clinical settings. Fusobacteria are core members of the human oral microbiome, while being less prevalent in the healthy gut, prompting questions about their localization in CRC and its precursor lesions. This review aims to critically discuss the evidence connecting Fn with CRC pathogenesis, its molecular subtypes and clinical outcomes.
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Affiliation(s)
- Luana Greco
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Federica Rubbino
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Clarissa Ferrari
- Research and Clinical Trials Office, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
| | | | - Fabio Grizzi
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital, Milan, Italy
| | | | | | - Massimiliano Mazzone
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Macrophage Dynamics Lab, IRCCS Humanitas Research Hospital, Milan, Italy
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Luigi Ricciardiello
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas at MD Anderson Cancer Center, Houston, TX, USA
| | - Luigi Laghi
- Laboratory of Molecular Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Medicine and Surgery, University of Parma, Parma, Italy
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Golozar M, Motlagh AV, Mahdevar M, Peymani M, InanlooRahatloo K, Ghaedi K. TBX15 and SDHB expression changes in colorectal cancer serve as potential prognostic biomarkers. Exp Mol Pathol 2024; 136:104890. [PMID: 38378070 DOI: 10.1016/j.yexmp.2024.104890] [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: 02/14/2023] [Revised: 01/07/2024] [Accepted: 02/16/2024] [Indexed: 02/22/2024]
Abstract
Alterations in the expression of certain genes could be associated with both patient mortality rates and drug resistance. This study aimed to identify genes in colorectal cancer (CRC) that potentially serve as hub genes influencing patient survival rates. RNA-Seq data were downloaded from the cancer genome atlas database, and differential expression analysis was performed between tumors and healthy controls. Through the utilization of univariate and multivariate Cox regression analyses, in combination with the MCODE clustering module, the genes whose expression changes were related to survival rate and the hub genes related to them were identified. The mortality risk model was computed using the hub genes. CRC samples and the RT-qPCR method were utilized to confirm the outcomes. PharmacoGx data were employed to link the expression of potential genes to medication resistance and sensitivity. The results revealed the discovery of seven hub genes, which emerged as independent prognostic markers. These included HOXC6, HOXC13, HOXC8, and TBX15, which were associated with poor prognosis and overexpression, as well as SDHB, COX5A, and UQCRC1, linked to favorable prognosis and downregulation. Applying the risk model developed with the mentioned genes revealed a markedly higher incidence of deceased patients in the high-risk group compared to the low-risk group. RT-qPCR results indicated a decrease in SDHB expression and an elevation in TBX15 levels in cancer samples relative to adjacent healthy tissue. Also, PharmacoGx data indicated that the expression level of SDHB was correlated with drug sensitivity to Crizotinib and Dovitinib. Our findings highlight the potential association between alterations in the expression of genes such as HOXC6, HOXC13, HOXC8, TBX15, SDHB, COX5A, and UQCRC1 and increased mortality rates in CRC patients. As revealed by the PPI network, these genes exhibited the most connections with other genes linked to survival.
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Affiliation(s)
- Melika Golozar
- Kish International Campus, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Ali Valipour Motlagh
- Department of Animal Biotechnology, Cell Science Research Center, Royan Institute for Biotechnology, ACECR, Isfahan 8165131378, Iran
| | - Mohammad Mahdevar
- Genius Gene, Genetics and Biotechnology Company, Tehran, Iran; Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Kolsoum InanlooRahatloo
- Kish International Campus, School of Biology, College of Science, University of Tehran, Tehran, Iran
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
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Chorawala MR, Postwala H, Prajapati BG, Shah Y, Shah A, Pandya A, Kothari N. Impact of the microbiome on colorectal cancer development. COLORECTAL CANCER 2024:29-72. [DOI: 10.1016/b978-0-443-13870-6.00021-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Mohammadpour S, Noukabadi FN, Esfahani AT, Kazemi F, Esmaeili S, Zafarjafarzadeh N, Sarpash S, Nazemalhosseini-Mojarad E. Non-coding RNAs in Precursor Lesions of Colorectal Cancer: Their Role in Cancer Initiation and Formation. Curr Mol Med 2024; 24:565-575. [PMID: 37226783 DOI: 10.2174/1566524023666230523155719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 04/01/2023] [Accepted: 04/04/2023] [Indexed: 05/26/2023]
Abstract
Colorectal cancer (CRC) is one of the world's most common types of malignancy. The proliferation of precancerous lesions causes this type of cancer. Two distinct pathways for CRC carcinogenesis have been identified: the conventional adenoma-carcinoma pathway and the serrated neoplasia pathway. Recently, evidence has demonstrated the regulatory roles of noncoding RNAs (ncRNAs) in the initiation and progression of precancerous lesions, especially in the adenoma-carcinoma pathway and serrated neoplasia pathway. By expanding the science of molecular genetics and bioinformatics, several studies have identified dysregulated ncRNAs that function as oncogenes or tumor suppressors in cancer initiation and formation by diverse mechanisms via intracellular signaling pathways known to act on tumor cells. However, many of their roles are still unclear. This review summarizes the functions and mechanisms of ncRNAs (such as long non-coding RNAs, microRNAs, long intergenic non-coding RNAs, small interfering RNAs, and circRNAs) in the initiation and formation of precancerous lesions.
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Affiliation(s)
- Somayeh Mohammadpour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences. Tehran, Iran
| | - Fatemeh Naderi Noukabadi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences. Tehran, Iran
| | - Amir Torshizi Esfahani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences. Tehran, Iran
| | - Fatemeh Kazemi
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University Tehran, Tehran, Iran
| | - Sahar Esmaeili
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University Tehran, Tehran, Iran
| | - Nikta Zafarjafarzadeh
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University Tehran, Tehran, Iran
| | - SeyedKasra Sarpash
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Medical Sciences, Islamic Azad University Tehran, Tehran, Iran
| | - Ehsan Nazemalhosseini-Mojarad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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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: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [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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Paweł K, Maria Małgorzata S. CpG Island Methylator Phenotype-A Hope for the Future or a Road to Nowhere? Int J Mol Sci 2022; 23:ijms23020830. [PMID: 35055016 PMCID: PMC8777692 DOI: 10.3390/ijms23020830] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/01/2021] [Accepted: 12/07/2021] [Indexed: 02/06/2023] Open
Abstract
The CpG island methylator phenotype (CIMP) can be regarded as the most notable emanation of epigenetic instability in cancer. Since its discovery in the late 1990s, CIMP has been extensively studied, mainly in colorectal cancers (CRC) and gliomas. Consequently, knowledge on molecular and pathological characteristics of CIMP in CRC and other tumour types has rapidly expanded. Concordant and widespread hypermethylation of multiple CpG islands observed in CIMP in multiple cancers raised hopes for future epigenetically based diagnostics and treatments of solid tumours. However, studies on CIMP in solid tumours were hampered by a lack of generalisability and reproducibility of epigenetic markers. Moreover, CIMP was not a satisfactory marker in predicting clinical outcomes. The idea of targeting epigenetic abnormalities such as CIMP for cancer therapy has not been implemented for solid tumours, either. Twenty-one years after its discovery, we aim to cover both the fundamental and new aspects of CIMP and its future application as a diagnostic marker and target in anticancer therapies.
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Shi J, Li S, Qi Y, Li P, Sun W, He P, Ji H, Hou Z. Effects of Insulin Pathway on Glucose and Lipid Metabolism Disorder in Different Pathological Types of Colorectal Adenomas. EXPLORATORY RESEARCH AND HYPOTHESIS IN MEDICINE 2021; 000:000-000. [DOI: 10.14218/erhm.2021.00018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Zhu L, Sun H, Tian G, Wang J, Zhou Q, Liu P, Tang X, Shi X, Yang L, Liu G. Development and validation of a risk prediction model and nomogram for colon adenocarcinoma based on methylation-driven genes. Aging (Albany NY) 2021; 13:16600-16619. [PMID: 34182539 PMCID: PMC8266312 DOI: 10.18632/aging.203179] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 05/13/2021] [Indexed: 12/13/2022]
Abstract
Evidence suggests that abnormal DNA methylation patterns play a crucial role in the etiology and pathogenesis of colon adenocarcinoma (COAD). In this study, we identified a total of 97 methylation-driven genes (MDGs) through a comprehensive analysis of the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Univariate Cox regression analysis identified four MDGs (CBLN2, RBM47, SLCO4C1, and TMEM220) associated with overall survival (OS) in COAD patients. A risk prediction model was then developed based on these four MDGs to predict the prognosis of COAD patients. We also created a nomogram that incorporated risk scores, age, and TNM stage to promote a personalized prediction of OS in COAD patients. Compared with the traditional TNM staging system, our new nomogram was better at predicting the OS of COAD patients. In cell experiments, we confirmed that the mRNA expression levels of CLBN2 and TMEM220 were regulated by the methylation of their promoter regions. Moreover, immunohistochemistry showed that CBLN2 and TMEM220 were potential prognostic biomarkers for COAD patients. In summary, we have established a risk prediction model and nomogram that might be effectively utilized to promote the prediction of OS in COAD patients.
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Affiliation(s)
- Liangyu Zhu
- Department of Epidemiology and Statistics, School of Public Health, Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Shijiazhuang 050017, P.R. China
| | - Hongyu Sun
- Department of Epidemiology and Statistics, School of Public Health, Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Shijiazhuang 050017, P.R. China
| | - Guo Tian
- Department of Medical Record, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, P.R. China
| | - Juan Wang
- Department of Pathology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, P.R. China
| | - Qian Zhou
- Department of Clinical Pharmacology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, P.R. China
| | - Pu Liu
- Department of Epidemiology and Statistics, School of Public Health, Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Shijiazhuang 050017, P.R. China
| | - Xuejiao Tang
- Department of Epidemiology and Statistics, School of Public Health, Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Shijiazhuang 050017, P.R. China
| | - Xinrui Shi
- Department of Epidemiology and Statistics, School of Public Health, Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Shijiazhuang 050017, P.R. China
| | - Lei Yang
- Department of Epidemiology and Statistics, School of Public Health, Hebei Key Laboratory of Environment and Human Health, Hebei Medical University, Shijiazhuang 050017, P.R. China
| | - Guangjie Liu
- Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, P.R. China
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Labadie JD, Harrison TA, Banbury B, Amtay EL, Bernd S, Brenner H, Buchanan DD, Campbell PT, Cao Y, Chan AT, Chang-Claude J, English D, Figueiredo JC, Gallinger SJ, Giles GG, Gunter MJ, Hoffmeister M, Hsu L, Jenkins MA, Lin Y, Milne RL, Moreno V, Murphy N, Ogino S, Phipps AI, Sakoda LC, Slattery ML, Southey MC, Sun W, Thibodeau SN, Van Guelpen B, Zaidi SH, Peters U, Newcomb PA. Postmenopausal Hormone Therapy and Colorectal Cancer Risk by Molecularly Defined Subtypes and Tumor Location. JNCI Cancer Spectr 2020; 4:pkaa042. [PMID: 32923935 PMCID: PMC7477374 DOI: 10.1093/jncics/pkaa042] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 04/20/2020] [Accepted: 05/12/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Postmenopausal hormone therapy (HT) is associated with a decreased colorectal cancer (CRC) risk. As CRC is a heterogeneous disease, we evaluated whether the association of HT and CRC differs across etiologically relevant, molecularly defined tumor subtypes and tumor location. METHODS We pooled data on tumor subtypes (microsatellite instability status, CpG island methylator phenotype status, BRAF and KRAS mutations, pathway: adenoma-carcinoma, alternate, serrated), tumor location (proximal colon, distal colon, rectum), and HT use among 8220 postmenopausal women (3898 CRC cases and 4322 controls) from 8 observational studies. We used multinomial logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CIs) for the association of ever vs never HT use with each tumor subtype compared with controls. Models were adjusted for study, age, body mass index, smoking status, and CRC family history. All statistical tests were 2-sided. RESULTS Among postmenopausal women, ever HT use was associated with a 38% reduction in overall CRC risk (OR =0.62, 95% CI = 0.56 to 0.69). This association was similar according to microsatellite instability, CpG island methylator phenotype and BRAF or KRAS status. However, the association was attenuated for tumors arising through the serrated pathway (OR = 0.81, 95% CI = 0.66 to 1.01) compared with the adenoma-carcinoma pathway (OR = 0.63, 95% CI = 0.55 to 0.73; P het =.04) and alternate pathway (OR = 0.61, 95% CI = 0.51 to 0.72). Additionally, proximal colon tumors had a weaker association (OR = 0.71, 95% CI = 0.62 to 0.80) compared with rectal (OR = 0.54, 95% CI = 0.46 to 0.63) and distal colon (OR = 0.57, 95% CI = 0.49 to 0.66; P het =.01) tumors. CONCLUSIONS We observed a strong inverse association between HT use and overall CRC risk, which may predominantly reflect a benefit of HT use for tumors arising through the adenoma-carcinoma and alternate pathways as well as distal colon and rectal tumors.
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Affiliation(s)
- Julia D Labadie
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, USA
| | - Tabitha A Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Barbara Banbury
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Efrat L Amtay
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sonja Bernd
- 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
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia
| | - Peter T Campbell
- Behavioral and Epidemiology Research Group, 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, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
- University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany
| | - Dallas English
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai, Los Angeles, CA, USA
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Steven J Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Graham G Giles
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Marc J Gunter
- Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Biostatistics, University of Washington, Seattle, WA, USA
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Yi Lin
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Roger L Milne
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Victor Moreno
- Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain
| | - Neil Murphy
- Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France
| | - Shuji Ogino
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, 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
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA
| | - Melissa C Southey
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
- Genetic Epidemiology Laboratory, Department of Clinical Pathology, University of Melbourne, Melbourne, Victoria, Australia
| | - Wei Sun
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Stephen N Thibodeau
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Bethany Van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Syed H Zaidi
- Ontario Institute for Cancer Research, Toronto, Ontario, Canada
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, University of Washington, Seattle, WA, 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
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Identification of Hub Genes Related to Carcinogenesis and Prognosis in Colorectal Cancer Based on Integrated Bioinformatics. Mediators Inflamm 2020; 2020:5934821. [PMID: 32351322 PMCID: PMC7171686 DOI: 10.1155/2020/5934821] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 03/20/2020] [Accepted: 03/20/2020] [Indexed: 12/15/2022] Open
Abstract
The high mortality of colorectal cancer (CRC) patients and the limitations of conventional tumor-node-metastasis (TNM) stage emphasized the necessity of exploring hub genes closely related to carcinogenesis and prognosis in CRC. The study is aimed at identifying hub genes associated with carcinogenesis and prognosis for CRC. We identified and validated 212 differentially expressed genes (DEGs) from six Gene Expression Omnibus (GEO) datasets and the Cancer Genome Atlas (TCGA) database. We investigated functional enrichment analysis for DEGs. The protein-protein interaction (PPI) network was constructed, and hub modules and genes in CRC carcinogenesis were extracted. A prognostic signature was developed and validated based on Cox proportional hazards regression analysis. The DEGs mainly regulated biological processes covering response to stimulus, metabolic process, and affected molecular functions containing protein binding and catalytic activity. The DEGs played important roles in CRC-related pathways involving in preneoplastic lesions, carcinogenesis, metastasis, and poor prognosis. Hub genes closely related to CRC carcinogenesis were extracted including six genes in model 1 (CXCL1, CXCL3, CXCL8, CXCL11, NMU, and PPBP) and two genes and Metallothioneins (MTs) in model 2 (SLC26A3 and SLC30A10). Among them, CXCL8 was also related to prognosis. An eight-gene signature was proposed comprising AMH, WBSCR28, SFTA2, MYH2, POU4F1, SIX4, PGPEP1L, and PAX5. The study identified hub genes in CRC carcinogenesis and proposed an eight-gene signature with good reproducibility and robustness at the molecular level for CRC, which might provide directive significance for treatment selection and survival prediction.
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Sabit H, Cevik E, Tombuloglu H. Colorectal cancer: The epigenetic role of microbiome. World J Clin Cases 2019; 7:3683-3697. [PMID: 31799293 PMCID: PMC6887622 DOI: 10.12998/wjcc.v7.i22.3683] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 10/23/2019] [Accepted: 10/30/2019] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer in men (746000 cases per year) and the second most common cancer in women globally (614000 cases per year). The incidence rate of CRC in developed countries (737000 cases per year) is higher than that in less developed countries (624000 cases per year). CRC can arise from genetic causes such as chromosomal instability and microsatellite instability. Several etiologic factors underlie CRC including age, diet, and lifestyle. Gut microbiota represent a proven cause of the disease, where they play pivotal roles in modulating and reshaping the host epigenome. Several active microbial metabolites have been found to drive carcinogenesis, invasion, and metastasis via modifying both the methylation landscape along with histone structure in intestinal cells. Gut microbiota, in response to diet, can exert both beneficial and harmful functions in humans, according to the intestinal balance of number and types of these bacteria. Although the intestinal microbial community is diverse among individuals, these microbes cumulatively produce 100-fold more proteins than the human genome itself, which calls for further studies to elaborate on the complicated interaction between these microorganisms and intestinal cells. Therefore, understanding the exact role that gut microbiota play in inducing CRC will help attain reliable strategies to precisely diagnose and treat this fatal disease.
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Affiliation(s)
- Hussein Sabit
- Department of Genetics, Institute for Medical Research and Consultations, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Emre Cevik
- Department of Genetics, Institute for Medical Research and Consultations, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Huseyin Tombuloglu
- Department of Genetics, Institute for Medical Research and Consultations, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
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12
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Sun J, Zhao H, Lin S, Bao S, Zhang Y, Su J, Zhou M. Integrative analysis from multi-centre studies identifies a function-derived personalized multi-gene signature of outcome in colorectal cancer. J Cell Mol Med 2019; 23:5270-5281. [PMID: 31140730 PMCID: PMC6653159 DOI: 10.1111/jcmm.14403] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2019] [Revised: 04/25/2019] [Accepted: 05/06/2019] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) is highly heterogeneous leading to variable prognosis and treatment responses. Therefore, it is necessary to explore novel personalized and reproducible prognostic signatures to aid clinical decision-making. The present study combined large-scale gene expression profiles and clinical data of 1828 patients with CRC from multi-centre studies and identified a personalized gene prognostic signature consisting of 46 unique genes (called function-derived personalized gene signature [FunPGS]) from an integrated statistics and function-derived perspective. In the meta-training and multiple independent validation cohorts, the FunPGS effectively discriminated patients with CRC with significantly different prognosis at the individual level and remained as an independent factor upon adjusting for clinical covariates in multivariate analysis. Furthermore, the FunPGS demonstrated superior performance for risk stratification with respect to other recently reported signatures and clinical factors. The complementary value of the molecular signature and clinical factors was further explored, and it was observed that the composite signature called IMCPS greatly improved the predictive performance of survival estimation relative to molecular signatures or clinical factors alone. With further prospective validation in clinical trials, the FunPGS may become a promising and powerful personalized prognostic tool for stratifying patients with CRC in order to achieve an optimal systemic therapy.
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Affiliation(s)
- Jie Sun
- School of Ophthalmology & Optometry and Eye Hospital, School of Biomedical EngineeringWenzhou Medical UniversityWenzhouP. R. China
| | - Hengqiang Zhao
- School of Ophthalmology & Optometry and Eye Hospital, School of Biomedical EngineeringWenzhou Medical UniversityWenzhouP. R. China
| | - Shuting Lin
- School of Ophthalmology & Optometry and Eye Hospital, School of Biomedical EngineeringWenzhou Medical UniversityWenzhouP. R. China
| | - Siqi Bao
- School of Ophthalmology & Optometry and Eye Hospital, School of Biomedical EngineeringWenzhou Medical UniversityWenzhouP. R. China
| | - Yan Zhang
- School of Ophthalmology & Optometry and Eye Hospital, School of Biomedical EngineeringWenzhou Medical UniversityWenzhouP. R. China
| | - Jianzhong Su
- School of Ophthalmology & Optometry and Eye Hospital, School of Biomedical EngineeringWenzhou Medical UniversityWenzhouP. R. China
| | - Meng Zhou
- School of Ophthalmology & Optometry and Eye Hospital, School of Biomedical EngineeringWenzhou Medical UniversityWenzhouP. R. China
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13
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Fei F, Li C, Cao Y, Liu K, Du J, Gu Y, Wang X, Li Y, Zhang S. CK7 expression associates with the location, differentiation, lymph node metastasis, and the Dukes' stage of primary colorectal cancers. J Cancer 2019; 10:2510-2519. [PMID: 31258757 PMCID: PMC6584339 DOI: 10.7150/jca.29397] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 04/13/2019] [Indexed: 02/07/2023] Open
Abstract
Purpose: Most colorectal cancers (CRCs) show positive immunohistochemical (IHC) staining for CK20 and negative staining for CK7. However, in clinical settings, some CRCs show positive IHC staining for CK7, and the clinicopathological significance of this needs to be studied. This study investigated the clinicopathological significance of CK7 positivity in CRCs. Materials and Methods: A total of 178 patients with CRC were used to study the clinicopathological significance of CK7 positivity. Western blotting and immunocytochemical (ICC) staining were used to compare the expression levels of CK7 before and after CoCl2 treatment. Results: CK7 expression was associated with the location, differentiation, lymph node metastasis, and the Dukes' stage of CRCs. CK7 positive cells were mainly distributed at the edge of cancer nests, at the invasion front, as single stromal polyploid giant cancer cells (PGCCs), in tumor buds, in intravascular tumor emboli, and in a micropapillary pattern. Results of ICC staining showed that CK7 expression was almost negative in LoVo and HCT116 before CoCl2 treatment. After CoCl2 treatment, the PGCCs and their daughter cells of LoVo and HCT116 yielded positive results in CK7 ICC staining. Results of western blotting also confirmed that there was higher CK7 expression in LoVo and HCT116 after CoCl2 treatment than in the control. Conclusion: CRC cells expressing CK7 may have strong invasive and metastatic abilities. Some metastasis-related morphological characteristics in CRCs including the invasion front, micropapillary pattern, tumor emboli, and single stromal PGCCs associated with CK7 positive expression.
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Affiliation(s)
- Fei Fei
- Nankai University School of Medicine, Nankai University, Tianjin, P.R. China
- Department of Pathology, Tianjin Union Medical Center, Tianjin, P.R. China
| | - Chunyuan Li
- Nankai University School of Medicine, Nankai University, Tianjin, P.R. China
- Department of Pathology, Tianjin Union Medical Center, Tianjin, P.R. China
| | - Yuan Cao
- Department of Pathology, Tianjin Union Medical Center, Tianjin, P.R. China
| | - Kai Liu
- Tianjin Medical University, Tianjin, P.R. China
| | - Jiaxing Du
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China
| | - Yanjun Gu
- Department of pathology, Affiliated Hospital of Logistic University of People's Armed Police Force, Tianjin, P.R. China
| | - Xinlu Wang
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, P.R. China
| | - Yuwei Li
- Departments of colorectal surgery, Tianjin Union Medical Center, Tianjin, P.R. China
| | - Shiwu Zhang
- Nankai University School of Medicine, Nankai University, Tianjin, P.R. China
- Department of Pathology, Tianjin Union Medical Center, Tianjin, P.R. China
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14
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Gock M, Mullins CS, Bergner C, Prall F, Ramer R, Göder A, Krämer OH, Lange F, Krause BJ, Klar E, Linnebacher M. Establishment, functional and genetic characterization of three novel patient-derived rectal cancer cell lines. World J Gastroenterol 2018; 24:4880-4892. [PMID: 30487698 PMCID: PMC6250916 DOI: 10.3748/wjg.v24.i43.4880] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Revised: 10/22/2018] [Accepted: 11/02/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To establish patient-individual tumor models of rectal cancer for analyses of novel biomarkers, individual response prediction and individual therapy regimens. METHODS Establishment of cell lines was conducted by direct in vitro culturing and in vivo xenografting with subsequent in vitro culturing. Cell lines were in-depth characterized concerning morphological features, invasive and migratory behavior, phenotype, molecular profile including mutational analysis, protein expression, and confirmation of origin by DNA fingerprint. Assessment of chemosensitivity towards an extensive range of current chemotherapeutic drugs and of radiosensitivity was performed including analysis of a combined radio- and chemotherapeutic treatment. In addition, glucose metabolism was assessed with 18F-fluorodeoxyglucose (FDG) and proliferation with 18F-fluorothymidine. RESULTS We describe the establishment of ultra-low passage rectal cancer cell lines of three patients suffering from rectal cancer. Two cell lines (HROC126, HROC284Met) were established directly from tumor specimens while HROC239 T0 M1 was established subsequent to xenografting of the tumor. Molecular analysis classified all three cell lines as CIMP-0/ non-MSI-H (sporadic standard) type. Mutational analysis revealed following mutational profiles: HROC126: APCwt , TP53wt , KRASwt , BRAFwt , PTENwt ; HROC239 T0 M1: APCmut , P53wt , KRASmut , BRAFwt , PTENmut and HROC284Met: APCwt , P53mut , KRASmut , BRAFwt , PTENmut . All cell lines could be characterized as epithelial (EpCAM+) tumor cells with equivalent morphologic features and comparable growth kinetics. The cell lines displayed a heterogeneous response toward chemotherapy, radiotherapy and their combined application. HROC126 showed a highly radio-resistant phenotype and HROC284Met was more susceptible to a combined radiochemotherapy than HROC126 and HROC239 T0 M1. Analysis of 18F-FDG uptake displayed a markedly reduced FDG uptake of all three cell lines after combined radiochemotherapy. CONCLUSION These newly established and in-depth characterized ultra-low passage rectal cancer cell lines provide a useful instrument for analysis of biological characteristics of rectal cancer.
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Affiliation(s)
- Michael Gock
- Department of General Surgery, University Medical Center, Rostock 18055, Germany
| | - Christina S Mullins
- Section of Molecular Oncology and Immunotherapy, University Medical Center, Rostock 18055, Germany
| | - Carina Bergner
- Department of Nuclear Medicine, University Medical Center, Rostock 18055, Germany
| | - Friedrich Prall
- Institute of Pathology, University Medical Center, Rostock 18055, Germany
| | - Robert Ramer
- Institute of Pharmacology, University Medical Center, Rostock 18055, Germany
| | - Anja Göder
- Institute of Toxicology, University Medical Center Mainz, Mainz 55131, Germany
| | - Oliver H Krämer
- Institute of Toxicology, University Medical Center Mainz, Mainz 55131, Germany
| | - Falko Lange
- Oscar-Langendorff-Institute of Physiology, University Medical Center, Rostock 18055, Germany
| | - Bernd J Krause
- Department of Nuclear Medicine, University Medical Center, Rostock 18055, Germany
| | - Ernst Klar
- Department of General Surgery, University Medical Center, Rostock 18055, Germany
| | - Michael Linnebacher
- Section of Molecular Oncology and Immunotherapy, University Medical Center, Rostock 18055, Germany
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15
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Xue W, Wu X, Wang F, Han P, Cui B. Genome-wide methylation analysis identifies novel prognostic methylation markers in colon adenocarcinoma. Biomed Pharmacother 2018; 108:288-296. [PMID: 30223100 DOI: 10.1016/j.biopha.2018.09.043] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Revised: 08/26/2018] [Accepted: 09/08/2018] [Indexed: 12/14/2022] Open
Abstract
Previous studies have indicated that abnormal methylation is a critical and early event in the pathogenesis of most types of human cancer, which contributes to tumorigenesis. However, there has been little focus on the potential of DNA methylation patterns as predictive markers for the prognosis of colon adenocarcinoma (COAD). In the present study, a genome-wide comparative analysis of DNA methylation profiles was performed between 315 COAD samples and 38 matched tumor-adjacent normal tissue samples. A total of 675 differentially methylated regions (DMRs) associated with 630 genes were identified, including 654 hypermethylated regions (UMRs) and 21 hypomethylated regions, which were capable of distinguishing COAD samples from non-malignant tissue samples. Although most of the DMRs appeared to be located within the gene body or promoter regions, UMRs were mostly located within CpG islands. Functional analysis suggested that genes associated with DMRs were enriched in many of the core cancer-signaling pathways known to be important in COAD biology. A survival analysis was also performed, which identified 7 DMRs as potential candidate markers with the ability to classify patients into high and low-risk groups with significantly different overall survival. The present study provides a better understanding of the molecular mechanisms underlying COAD, and demonstrates the utility of aberrant DNA methylation in the prognosis of COAD.
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Affiliation(s)
- Weinan Xue
- Department of Colorectal Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, 150081, China
| | - Xiangxin Wu
- Department of Colorectal Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, 150081, China
| | - Fan Wang
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, 150081, China
| | - Peng Han
- Department of Colorectal Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, 150081, China
| | - Binbin Cui
- Department of Colorectal Surgery, The Affiliated Tumor Hospital of Harbin Medical University, Harbin, 150081, China.
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16
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D’Arcy M, Stürmer T, Lund JL. The importance and implications of comparator selection in pharmacoepidemiologic research. CURR EPIDEMIOL REP 2018; 5:272-283. [PMID: 30666285 PMCID: PMC6338470 DOI: 10.1007/s40471-018-0155-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE OF REVIEW Pharmacoepidemiologic studies employing large databases are critical to evaluating the effectiveness and safety of drug exposures in large and diverse populations. Because treatment is not randomized, researchers must select a relevant comparison group for the treatment of interest. The comparator group can consist of individuals initiating: (1) a similarly indicated treatment (active comparator), (2) a treatment used for a different indication (inactive comparator) or (3) no particular treatment (non-initiators). Herein we review recent literature and describe considerations and implications of comparator selection in pharmacoepidemiologic studies. RECENT FINDINGS Comparator selection depends on the scientific question and feasibility constraints. Because pharmacoepidemiologic studies rely on the choice to initiate or not initiate a specific treatment, rather than randomization, they are at-risk for confounding related to the comparator choice including: by indication, disease severity and frailty. We describe forms of confounding specific to pharmacoepidemiologic studies and discuss each comparator along with informative examples and a case study. We provide commentary on potential issues relevant to comparator selection in each study, highlighting the importance of understanding the population in whom the treatment is given and how patient characteristics are associated with the outcome. SUMMARY Advanced statistical techniques may be insufficient for reducing confounding in observational studies. Evaluating the extent to which comparator selection may mitigate or induce systematic bias is a critical component of pharmacoepidemiologic studies.
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Affiliation(s)
- Monica D’Arcy
- Department of Epidemiology, Gillings School of Global
Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Til Stürmer
- Department of Epidemiology, Gillings School of Global
Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Jennifer L. Lund
- Department of Epidemiology, Gillings School of Global
Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
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17
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Leman JKH, Sandford SK, Rhodes JL, Kemp RA. Multiparametric analysis of colorectal cancer immune responses. World J Gastroenterol 2018; 24:2995-3005. [PMID: 30038466 PMCID: PMC6054948 DOI: 10.3748/wjg.v24.i27.2995] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Revised: 05/23/2018] [Accepted: 06/16/2018] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a heterogeneous disease, with a diverse and plastic immune cell infiltrate. These immune cells play an important role in regulating tumour growth - progression or elimination. Some populations of cells have a strong correlation with disease-free survival, making them useful prognostic markers. In particular, the infiltrate of CD3+ and CD8+ T cells into CRC tumours has been validated worldwide as a valuable indicator of patient prognosis. However, the heterogeneity of the immune response, both between patients with tumours of different molecular subtypes, and within the tumour itself, necessitates the use of multiparametric analysis in the investigation of tumour-specific immune responses. This review will outline the multiparametric analysis techniques that have been developed and applied to studying the role of immune cells in the tumour, with a focus on colorectal cancer. Because much of the data in this disease relates to T cell subsets and heterogeneity, we have used T cell populations as examples throughout. Flow and mass cytometry give a detailed representation of the cells within the tumour in a single-cell suspension on a per-cell basis. Imaging technologies, such as imaging mass cytometry, are used to investigate increasing numbers of markers whilst retaining the spatial and structural information of the tumour section and the infiltrating immune cells. Together, the analyses of multiple immune parameters can provide valuable information to guide clinical decision-making in CRC.
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Affiliation(s)
- Julia KH Leman
- Department of Microbiology and Immunology, University of Otago, Dunedin 9010, New Zealand
| | - Sarah K Sandford
- Department of Microbiology and Immunology, University of Otago, Dunedin 9010, New Zealand
| | - Janet L Rhodes
- Department of Microbiology and Immunology, University of Otago, Dunedin 9010, New Zealand
| | - Roslyn A Kemp
- Department of Microbiology and Immunology, University of Otago, Dunedin 9010, New Zealand
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18
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Hardikar S, Burnett-Hartman AN, Phipps AI, Upton MP, Zhu LC, Newcomb PA. Telomere length differences between colorectal polyp subtypes: a colonoscopy-based case-control study. BMC Cancer 2018; 18:513. [PMID: 29720120 PMCID: PMC5932759 DOI: 10.1186/s12885-018-4426-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 04/23/2018] [Indexed: 11/25/2022] Open
Abstract
Background Short telomeres have been associated with increased risk of many cancers, particularly cancers of the gastrointestinal tract including esophagus and stomach. However, the association between telomere length (TL) and colorectal cancer and its precursors, colorectal polyps, is not clear. Methods We investigated the relationship between TL and risk of colorectal polyp subtypes in a colonoscopy-based study in western Washington. Participants were 35–79 year-old enrollees at an integrated health care system, who underwent a colonoscopy between 1998 and 2007 (n = 190), completed a self-administered questionnaire, provided blood samples, and were distinguished as having adenomas, serrated polyps, or as polyp-free controls through a standardized pathology review. Telomere length (T) relative to a single copy gene (S) was measured in circulating leukocytes from stored buffy coat samples using quantitative polymerase chain reaction. Multivariable polytomous logistic regression was used to compare case groups with polyp-free controls and other case groups; adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated. Results TL in the shortest tertile (T/S ratio < 0.58) was associated with increased risk of adenomas and serrated polyps [OR (95%CI) were 1.77(0.81–3.88) and 2.98(1.15–7.77), respectively). When evaluated by lesion severity within each pathway, short TL was more strongly associated with advanced adenomas and sessile serrated polyps [OR (95% CI) = 1.90(0.76–4.73) and 3.82(0.86–16.86), respectively], although the associations were not statistically significant. Conclusions Our results suggest that short TL may be associated with an increased risk of colorectal polyps in both the adenoma-carcinoma and serrated pathways. The risk was particularly notable for sessile serrated polyps, although the association was not statistically significant and sample size was limited.
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Affiliation(s)
- Sheetal Hardikar
- Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope Dr. Room 4711, Salt Lake City, UT, 84112, USA. .,Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
| | - Andrea N Burnett-Hartman
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Kaiser Permanente, Colorado Institute for Health Research, Denver, CO, USA
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Melissa P Upton
- Department of Pathology, School of Medicine, University of Washington, Seattle, WA, USA
| | - Lee-Ching Zhu
- Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
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19
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Grizzi F, Basso G, Borroni EM, Cavalleri T, Bianchi P, Stifter S, Chiriva-Internati M, Malesci A, Laghi L. Evolving notions on immune response in colorectal cancer and their implications for biomarker development. Inflamm Res 2018; 67:375-389. [PMID: 29322204 DOI: 10.1007/s00011-017-1128-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Revised: 12/27/2017] [Accepted: 12/29/2017] [Indexed: 12/11/2022] Open
Abstract
INTRODUCTION Colorectal cancer (CRC) still represents the third most commonly diagnosed type of cancer in men and women worldwide. CRC is acknowledged as a heterogeneous disease that develops through a multi-step sequence of events driven by clonal selections; this observation is sustained by the fact that histologically similar tumors may have completely different outcomes, including a varied response to therapy. METHODS In "early" and "intermediate" stage of CRC (stages II and III, respectively) there is a compelling need for new biomarkers fit to assess the metastatic potential of their disease, selecting patients with aggressive disease that might benefit from adjuvant and targeted therapies. Therefore, we review the actual notions on immune response in colorectal cancer and their implications for biomarker development. RESULTS The recognition of the key role of immune cells in human cancer progression has recently drawn attention on the tumor immune microenvironment, as a source of new indicators of tumor outcome and response to therapy. Thus, beside consolidated histopathological biomarkers, immune endpoints are now emerging as potential biomarkers. CONCLUSIONS The introduction of immune signatures and cellular and molecular components of the immune system as biomarkers is particularly important considering the increasing use of immune-based cancer therapies as therapeutic strategies for cancer patients.
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Affiliation(s)
- Fabio Grizzi
- Department of Immunology and Inflammation, Humanitas Clinical and Research Center, Via Manzoni 56, 20089, Rozzano, Milan, Italy.
| | - Gianluca Basso
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Elena Monica Borroni
- Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Tommaso Cavalleri
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Paolo Bianchi
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Sanja Stifter
- Department of Pathology, School of Medicine, University of Rijeka, Rijeka, Croatia
| | | | - Alberto Malesci
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
- Department of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
- Department of Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Luigi Laghi
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
- Department of Gastroenterology, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
- Hereditary Cancer Genetics Clinic, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
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20
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Ashktorab H, Mokarram P, Azimi H, Olumi H, Varma S, Nickerson ML, Brim H. Targeted exome sequencing reveals distinct pathogenic variants in Iranians with colorectal cancer. Oncotarget 2018; 8:7852-7866. [PMID: 28002797 PMCID: PMC5341754 DOI: 10.18632/oncotarget.13977] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 12/01/2016] [Indexed: 12/12/2022] Open
Abstract
PURPOSE Next Generation Sequencing (NGS) is currently used to establish mutational profiles in many multigene diseases such as colorectal cancer (CRC), which is on the rise in many parts of the developing World including, Iran. Little is known about its genetic hallmarks in these populations. AIM To identify variants in 15 CRC-associated genes in patients of Iranian descent. RESULTS There were 51 validated variants distributed on 12 genes: 22% MSH3 (n = 11/51), 10% MSH6 (n = 5/51), 8% AMER1 (n = 4/51), 20% APC (n = 10/51), 2% BRAF (n = 1/51), 2% KRAS (n = 1/51), 12% PIK3CA (n = 6/51), 8% TGFβR2A (n = 4/51), 2% SMAD4 (n = 1/51), 4% SOX9 (n = 2/51), 6% TCF7L2 (n = 3/51), and 6% TP53 (n = 3/51). Most known and distinct variants were in mismatch repair genes (MMR, 32%) and APC (20%). Among oncogenes, PIK3CA was the top target (12%). MATERIALS AND METHODS CRC specimens from 63 Shirazi patients were used to establish the variant' profile on an Ion Torrent platform by targeted exome sequencing. To rule-out technical artifacts, the variants were validated in 13 of these samples using an Illumina NGS platform. Validated variants were annotated and compared to variants from publically available databases. An in-silico functional analysis was performed. MSI status of the analyzed samples was established. CONCLUSION These results illustrate for the first time CRC mutational profile in Iranian patients. MSH3, MSH6, APC and PIK3CA genes seem to play a bigger role in the path to cancer in this population. These findings will potentially lead to informed genetic diagnosis protocol and targeted therapeutic strategies.
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Affiliation(s)
- Hassan Ashktorab
- Department of Medicine and Cancer Center, Howard University College of Medicine, Washington, DC, USA
| | - Pooneh Mokarram
- Current address: Department of Biochemistry, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamed Azimi
- Department of Medicine and Cancer Center, Howard University College of Medicine, Washington, DC, USA
| | - Hasti Olumi
- Department of Medicine and Cancer Center, Howard University College of Medicine, Washington, DC, USA
| | | | - Michael L Nickerson
- Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD, USA
| | - Hassan Brim
- Department of Pathology, Howard University College of Medicine, Washington, DC, USA
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21
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Ashktorab H, Azimi H, Varma S, Tavakoli P, Nickerson ML, Brim H. Distinctive DNA mismatch repair and APC rare variants in African Americans with colorectal neoplasia. Oncotarget 2017; 8:99966-99977. [PMID: 29245953 PMCID: PMC5725144 DOI: 10.18632/oncotarget.21557] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 05/23/2017] [Indexed: 12/17/2022] Open
Abstract
PURPOSE African Americans have a higher incidence and mortality from colorectal cancer. This disparity might be due, in part, to the type of mutations in driver genes. In this study, we examined alterations specific to APC, MSH3, and MSH6 genes using targeted exome sequencing to determine distinctive variants in the course of neoplastic transformation. EXPERIMENTAL DESIGN A total of 140 African American colon samples (30 normal, 21 adenomas, 33 advanced adenomas and 56 cancers) were used as our discovery set on an Ion Torrent platform. A 36 samples subset was resequenced on an Illumina platform for variants' validation. Bioinformatics analyses were performed and novel validated variants are reported. RESULTS Two novel MSH6 variants were validated and mapped to the MutS-V region near the MSH2 binding site. For MSH3, 4 known variants were validated and were located in exon 10 (3 non-synonymous) and exon 18 (1 synonymous). As for APC, 20 variants were validated with 4 novel variants: 3 stopgain and 1 non-synonymous. These variants mapped prior to and on the Armadillo repeats region, to the 15-amino acid repeat region, and to the 20-amino acid repeats region, respectively. CONCLUSION We defined novel variants that target DNA mismatch repair and APC genes in African Americans with colorectal lesions. A greater frequency of variants in genes encoding DNA mismatch repair functions and APC likely plays major roles in colorectal cancer initiation and higher incidence of the disease in African Americans.
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Affiliation(s)
| | - Hamed Azimi
- Department of Medicine and Cancer Center, Washington, DC, USA
| | | | - Payaam Tavakoli
- Department of Medicine and Cancer Center, Washington, DC, USA
| | - Michael L. Nickerson
- Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD, USA
| | - Hassan Brim
- Department of Pathology, Howard University College of Medicine, Washington, DC, USA
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Blum-Guzman JP, Wanderley de Melo S. Location of colorectal cancer: colonoscopy versus surgery. Yield of colonoscopy in predicting actual location. Endosc Int Open 2017; 5:E642-E645. [PMID: 28691047 PMCID: PMC5500114 DOI: 10.1055/s-0043-110564] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 01/17/2017] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND AND STUDY AIMS Recent studies suggest that differences in biological characteristics and risk factors across cancer site within the colon and rectum may translate to differences in survival. It can be challenging at times to determine the precise anatomical location of a lesion with a luminal view during colonoscopy. The aim of this study is to determine if there is a significant difference between the location of colorectal cancers described by gastroenterologists in colonoscopies and the actual anatomical location noted on operative and pathology reports after colon surgery. PATIENTS AND METHODS A single-center retrospective analysis of colonoscopies of patient with reported colonic masses from January 2005 to April 2014 (n = 380) was carried. Assessed data included demography, operative and pathology reports. Findings were compared: between the location of colorectal cancers described by gastroenterologists in colonoscopies and the actual anatomical location noted on operative reports or pathology samples. RESULTS We identified 380 colonic masses, 158 were confirmed adenocarcinomas. Of these 123 underwent surgical resection, 27 had to be excluded since no specific location was reported on their operative or pathology report. An absolute difference between endoscopic and surgical location was found in 32 cases (33 %). Of these, 22 (23 %) differed by 1 colonic segment, 8 (8 %) differed by 2 colonic segments and 2 (2 %) differed by 3 colonic segments. CONCLUSION There is a significant difference between the location of colorectal cancers reported by gastroenterologists during endoscopy and the actual anatomical location noted on operative or pathology reports after colon surgery. Endoscopic tattooing should be used when faced with any luminal lesions of interest.
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Affiliation(s)
- Juan Pablo Blum-Guzman
- University of Florida College of Medicine Jacksonville, Jacksonville, Florida, United States
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Slattery ML, Herrick JS, Wolff RK, Mullany LE, Stevens JR, Samowitz W. The miRNA landscape of colorectal polyps. Genes Chromosomes Cancer 2017; 56:347-353. [PMID: 27925331 PMCID: PMC5357145 DOI: 10.1002/gcc.22436] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Revised: 11/28/2016] [Accepted: 11/29/2016] [Indexed: 12/22/2022] Open
Abstract
The genomic landscape of adenomas and polyps may help define disease pathways. Expression of miRNAs in adenomas and polyps may importantly contribute to these pathways. We evaluated miRNA expression in 293 polyp-normal colorectal mucosa pairs. Polyps were classified as either adenomatous polyp (AD), hyperplastic polyp (HP), or sessile serrated polyp (SSP). We compared these miRNA expression profiles in polyps to miRNA expression in microsatellite unstable (MSI) and stable (MSS) tumors. A False Discovery Rate of 0.05 based on Benjamini and Hochberg was used to adjust for multiple comparisons. There were 70 miRNAs with differential expression by polyp type with a fold change <0.75 or >1.34 after adjusting for multiple comparisons. The major differences in miRNA expression were observed between AD and SSP and AD and HP, with few differences in expression noted for SSP and HP. AD polyps were more likely to be upregulated from normal colonic mucosa, while SSP and HP were more likely to be downregulated from normal colonic mucosa. MiRNA expression in the SSP and HP tumors almost uniformly go in opposite directions from the MSS tumor miRNA expression and was mixed with MSI tumors. We conclude that different types of polyps have unique miRNA expression profiles. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Martha L Slattery
- Department of Medicine, University of Utah, Salt Lake City, UT, 84108
| | | | - Roger K Wolff
- Department of Medicine, University of Utah, Salt Lake City, UT, 84108
| | - Lila E Mullany
- Department of Medicine, University of Utah, Salt Lake City, UT, 84108
| | - John R Stevens
- Department of Mathematics and Statistics, Utah State University, Logan, UT, 84322 3900
| | - Wade Samowitz
- Department of Pathology, University of Utah School, Salt Lake City, UT, 84108
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24
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25
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Gock M, Kühn F, Mullins CS, Krohn M, Prall F, Klar E, Linnebacher M. Tumor Take Rate Optimization for Colorectal Carcinoma Patient-Derived Xenograft Models. BIOMED RESEARCH INTERNATIONAL 2016; 2016:1715053. [PMID: 27999790 PMCID: PMC5141319 DOI: 10.1155/2016/1715053] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 09/23/2016] [Accepted: 11/07/2016] [Indexed: 12/21/2022]
Abstract
Background. For development of individualized treatment on a routine basis, transfer of patients' tumor tissue in a xenograft model (i.e., generation of patient-derived xenografts (PDX)) is desirable for molecular, biochemical, or functional analyses. Drawbacks are dissatisfactory tumor take rates, the necessity of fast tumor tissue processing, and extensive logistics demanding teamwork of surgeons, pathologists, and laboratory researchers. Methods. The take rates of ten colorectal cancer (CRC) tissue samples in immunodeficient mice were compared after direct cryopreservation and after a 24 h cooling period at 4°C prior to cryopreservation. Additionally, the effect of simultaneous Matrigel application on the take rates was investigated. Beside take rates, tumor growth characteristics and cell culture success were analyzed. Results. Tumor takes of CRC tissue samples were significantly improved after Matrigel application (8 versus 15 takes, p = 0.04). As expected, they diminished furthermore after 24 h cooling. Application of Matrigel could counteract this decrease significantly (2 versus 7 takes, p = 0.03). Cumulative take rate after cryopreservation was satisfactory (70%). Conclusion. Matrigel application after 24 h delay in tissue processing facilitates CRC PDX model development. These data help developing strategies for individualized tumor therapies in the context of multicenter clinical studies and for basic research on primary patient tumors.
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Affiliation(s)
- Michael Gock
- Department of General, Vascular, Thoracic and Transplantation Surgery, University of Rostock, Schillingallee 35, 18055 Rostock, Germany
| | - Florian Kühn
- Department of General, Vascular, Thoracic and Transplantation Surgery, University of Rostock, Schillingallee 35, 18055 Rostock, Germany
| | - Christina Susanne Mullins
- Department of General, Vascular, Thoracic and Transplantation Surgery, University of Rostock, Schillingallee 35, 18055 Rostock, Germany
| | - Mathias Krohn
- Department of General, Vascular, Thoracic and Transplantation Surgery, University of Rostock, Schillingallee 35, 18055 Rostock, Germany
| | - Friedrich Prall
- Institute of Pathology, University of Rostock, Strempelstraße 14, 18055 Rostock, Germany
| | - Ernst Klar
- Department of General, Vascular, Thoracic and Transplantation Surgery, University of Rostock, Schillingallee 35, 18055 Rostock, Germany
| | - Michael Linnebacher
- Department of General, Vascular, Thoracic and Transplantation Surgery, University of Rostock, Schillingallee 35, 18055 Rostock, Germany
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Jandova J, Xu W, Nfonsam V. Sporadic early-onset colon cancer expresses unique molecular features. J Surg Res 2016; 204:251-60. [PMID: 27451894 DOI: 10.1016/j.jss.2016.04.068] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2015] [Revised: 03/31/2016] [Accepted: 04/28/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND The overall incidence of colon cancer (CC) has steadily declined in the last decades but has increased in patients under age 50 y. The etiology of early-onset (EO) CC is not understood. The aim of this study was to elucidate gene expression patterns in EOCC and show its uniqueness compared to late-onset (LO) disease. METHODS Two cohorts of patients with sporadic CC were identified. Tumors and matching noninvolved tissues from six EOCC patients (<50) and six late-onset colon cancers (LOCC) patients (>65) were obtained from pathology archives. De-paraffinized tissues were macrodissected from FFPE sections, RNA isolated, and used for expression profiling of 770 cancer-related genes representing 13 canonical pathways. RESULTS Among 770 genes assayed, changes in expression levels of 93 genes were statistically significant between EOCC and matching noninvolved tissues. There were also significant differences in expression levels of 118 genes between LOCC and matching noninvolved tissues. Detailed comparative gene expression analysis between EOCC and LOCC normalized to their matching noninvolved tissues revealed that changes in expression of 88 genes were unique to EOCC using the cutoff criteria of expression levels difference >2 fold and P value <0.01. From these differentially expressed genes specific to EOCC, 28 genes were upregulated and 60 genes downregulated. At the pathway level, RAS, MAPK, WNT, and DNARepair pathways were similarly deregulated in both age groups, whereas PI3K-AKT signaling was more specific to EOCC and cell cycle pathway to LOCC. CONCLUSIONS These results suggest that sporadic EOCC is characterized by distinct molecular events compared to LOCC.
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Affiliation(s)
- Jana Jandova
- UA Cancer Center, Tucson, Arizona; Division of Surgical Oncology, UA Department of Surgery, Tucson, Arizona.
| | - Wenjie Xu
- NanoString Technologies, Seattle, Washington
| | - Valentine Nfonsam
- UA Cancer Center, Tucson, Arizona; Division of Surgical Oncology, UA Department of Surgery, Tucson, Arizona
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Quantitative Image Analysis of Epithelial and Stromal Area in Histological Sections of Colorectal Cancer: An Emerging Diagnostic Tool. BIOMED RESEARCH INTERNATIONAL 2015; 2015:569071. [PMID: 26579535 PMCID: PMC4633538 DOI: 10.1155/2015/569071] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 09/28/2015] [Accepted: 09/30/2015] [Indexed: 01/30/2023]
Abstract
In colorectal cancer (CRC), an increase in the stromal (S) area with the reduction of the epithelial (E) parts has been suggested as an indication of tumor progression. Therefore, an automated image method capable of discriminating E and S areas would allow an improved diagnosis. Immunofluorescence staining was performed on paraffin-embedded sections from colorectal tumors (16 samples from patients with liver metastasis and 18 without). Noncancerous tumor adjacent mucosa (n = 5) and normal mucosa (n = 4) were taken as controls. Epithelial cells were identified by an anti-keratin 8 (K8) antibody. Large tissue areas (5–63 mm2/slide) including tumor center, tumor front, and adjacent mucosa were scanned using an automated microscopy system (TissueFAXS). With our newly developed algorithms, we showed that there is more K8-immunoreactive E in the tumor center than in tumor adjacent and normal mucosa. Comparing patients with and without metastasis, the E/S ratio decreased by 20% in the tumor center and by 40% at tumor front in metastatic samples. The reduction of E might be due to a more aggressive phenotype in metastasis patients. The novel software allowed a detailed morphometric analysis of cancer tissue compartments as tools for objective quantitative measurements, reduced analysis time, and increased reproducibility of the data.
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28
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Pfütze K, Benner A, Hoffmeister M, Jansen L, Yang R, Bläker H, Herpel E, Ulrich A, Ulrich CM, Chang-Claude J, Brenner H, Burwinkel B. Methylation status at HYAL2 predicts overall and progression-free survival of colon cancer patients under 5-FU chemotherapy. Genomics 2015; 106:348-54. [PMID: 26453961 DOI: 10.1016/j.ygeno.2015.10.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Revised: 10/05/2015] [Accepted: 10/06/2015] [Indexed: 12/31/2022]
Abstract
DNA methylation variations in gene promoter regions are well documented tumor-specific alterations in human malignancies including colon cancer, which may influence tumor behavior and clinical outcome. As a subset of colon cancer patients does not benefit from adjuvant chemotherapy, predictive biomarkers are desirable. Here, we describe that DNA methylation levels at CpG loci of hyaluronoglucosaminidase 2 (HYLA2) could be used to identify stage II and III colon cancer patients who are most likely to benefit from 5-flourouracil (5-FU) chemotherapy with respect to overall survival and progression-free survival.
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Affiliation(s)
- Katrin Pfütze
- Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center (DKFZ), Germany; Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Germany.
| | - Axel Benner
- Division of Biostatistics, German Cancer Research Center (DKFZ), Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Germany
| | - Lina Jansen
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Germany
| | - Rongxi Yang
- Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center (DKFZ), Germany; Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Germany
| | - Hendrik Bläker
- Department of General Pathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany
| | - Esther Herpel
- Department of General Pathology, Institute of Pathology, University of Heidelberg, Heidelberg, Germany; NCT Tissue Bank, National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Alexis Ulrich
- Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany; Division of Molecular oncology, National Center for Tumor Diseases (NCT), Germany
| | - Cornelia M Ulrich
- Division of Preventive Oncology, National Center for Tumor Diseases (NCT)/German Cancer Research Center (DKFZ), Germany
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, Unit of Genetic Epidemiology, German Cancer Research Center (DKFZ), Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Germany; German Cancer Research Center (DKTk)Germany
| | - Barbara Burwinkel
- Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center (DKFZ), Germany; Molecular Biology of Breast Cancer, Department of Obstetrics and Gynecology, University of Heidelberg, Germany
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29
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Hardikar S, Newcomb PA, Campbell PT, Win AK, Lindor NM, Buchanan DD, Makar KW, Jenkins MA, Potter JD, Phipps AI. Prediagnostic Physical Activity and Colorectal Cancer Survival: Overall and Stratified by Tumor Characteristics. Cancer Epidemiol Biomarkers Prev 2015; 24:1130-7. [PMID: 25976417 DOI: 10.1158/1055-9965.epi-15-0039] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Accepted: 05/06/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Physical activity is associated with a lower incidence of colorectal cancer; however, the relationship of physical activity with colorectal cancer survival is not yet clear. We evaluated the association between prediagnostic physical activity and colorectal cancer survival, overall and accounting for tumor markers associated with colorectal cancer survival: BRAF and KRAS mutation status and microsatellite instability (MSI) status. METHODS Participants were 20- to 74-year-old colorectal cancer patients diagnosed between 1998 and 2007 from the population-based Seattle Colon Cancer Family Registry (S-CCFR). Self-reported physical activity in the years preceding colorectal cancer diagnosis was summarized as average metabolic equivalent task hours per week (MET-h/wk; n = 1,309). Somatic BRAF and KRAS mutations and MSI status were evaluated on a subset of patients (n = 1043). Cox regression was used to estimate HRs and 95% confidence intervals (CI) for overall and disease-specific survival after adjusting for relevant confounders. Stratified analyses were conducted across categories of BRAF, KRAS, and MSI, as well as tumor stage and site. RESULTS Higher prediagnostic recreational physical activity was associated with significantly more favorable overall survival (HR for highest vs. lowest category, 0.70; 95% CI, 0.52-0.96); associations were similar for colorectal cancer-specific survival. Results consistently indicated a favorable association with physical activity across strata defined by tumor characteristics. CONCLUSION Individuals who were physically active before colorectal cancer diagnosis experienced better survival than those who were inactive or minimally active. IMPACT Our results support existing physical activity recommendations for colorectal cancer patients and suggest that the beneficial effect of activity is not specific to a particular molecular phenotype of colorectal cancer.
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Affiliation(s)
- Sheetal Hardikar
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Epidemiology, University of Washington, Seattle, Washington.
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Epidemiology, University of Washington, Seattle, Washington
| | - Peter T Campbell
- Epidemiology Research Program, American Cancer Society, Atlanta, Georgia
| | - Aung Ko Win
- Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - Noralane M Lindor
- Department of Health Science Research, Mayo Clinic, Scottsdale, Arizona
| | - Daniel D Buchanan
- Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia. Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia
| | - Karen W Makar
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Mark A Jenkins
- Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Australia
| | - John D Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Epidemiology, University of Washington, Seattle, Washington. Centre for Public Health Research, Massey University, Wellington, New Zealand
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Department of Epidemiology, University of Washington, Seattle, Washington
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Maletzki C, Klier U, Marinkovic S, Klar E, Andrä J, Linnebacher M. Host defense peptides for treatment of colorectal carcinoma - a comparative in vitro and in vivo analysis. Oncotarget 2015; 5:4467-79. [PMID: 24962950 PMCID: PMC4147338 DOI: 10.18632/oncotarget.2039] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Host defense peptides (HDP) constitute effector molecules of the innate immune system. Besides acting against microbia and fungi, they exhibit broad and selective oncolytic activity. The underlying mechanism is at least partially attributable to elevated surface-exposed levels of phosphatidylserine (PS) on tumor targets. In this study, comprehensive analysis of NK-2-based derivatives (C7A, C7A-D21K, and C7A-Δ) was done on patient-derived ultra-low passage colorectal carcinoma (CRC) cell lines. Peptides were designed to improve antitumoral potential. Mellitin was used as positive control and a non-toxic peptide (NK11) served as negative control. Subsequently, effectiveness of local HDP application was determined in xenopatients. Generally, CRC lines displayed a heterogeneous pattern of surface-exposed PS, which was usually below standard CRC cells. Of note, five out of seven cell lines were susceptible towards HDP-mediated lysis (lytic activity of peptides: C7A-D21K > C7A-Δ= C7A). Oncolytic activity correlated mostly with surface-exposed PS levels. Apoptosis as well as necrosis were involved in killing. In an in vivo experiment, substantial growth inhibition of HROC24 xenografts was observed after HDP therapy and, surprisingly, also after NK11 treatment. These promising data underline the high potential of HDPs for oncolytic therapies and may provide a rationale for optimizing preclinical treatment schedules based on NK-2.
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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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Maletzki C, Gock M, Randow M, Klar E, Huehns M, Prall F, Linnebacher M. Establishment and characterization of cell lines from chromosomal instable colorectal cancer. World J Gastroenterol 2015; 21:164-176. [PMID: 25574089 PMCID: PMC4284332 DOI: 10.3748/wjg.v21.i1.164] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Revised: 06/26/2014] [Accepted: 07/24/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To generate novel tumor models for preclinical validation of biomarkers that allow drug response prediction and individual therapeutic decisions. METHODS Cell line establishment was conducted by both direct in vitro culturing and in vivo xenografting followed by in vitro culturing procedure. A comprehensive characterization was subsequently performed. This included quality control, consisting of the confirmation of human and colorectal cancer (CRC) origin by DNA fingerprint and epithelial cell adhesion molecule (EpCAM) staining, as well as mycoplasma and human virus testing. Phenotypic analysis was done by light microscopy and multicolor flow cytometry. Histopathological examination (β-catenin and cytokeratin staining) was conducted in direct comparison to parental tumor tissues. Extensive molecular-pathological profiling included mutation analysis for CRC-associated driver mutations, assessment of chromosomal and microsatellite instability, and the grade of CpG island methylation. Additionally, an array-based comparative genomic hybridization analysis was performed. Drug responsiveness was assessed for a panel of classical and novel substances in clinical use for the treatment of solid cancers. Finally, tumorigenicity of the cell lines was tested by xenografting into immunocompromised nude mice. RESULTS Herein we describe the establishment of three ultra-low passage cell lines from two individual patients suffering from sporadic CRC. One cell line was derived directly from an early stage case (HROC18), whereas two cell lines could be established both direct from patient material and after xenografting from a late stage tumor (HROC32). All cell lines were free of contaminating mycoplasma and viruses. Molecular-pathological analysis allowed all cell lines to be classified as chromosomal instable (CIN(+)). They were aneuploid, with CpG island promoter methylation and microsatellite instability being absent. The following mutational profile was observed both in the cell lines and the parental tumor tissue: HROC18: APC(mut), p53(mut), K-ras(wt); HROC32: APC(wt), p53(mut), K-ras(mut). All cell lines were characterized as epithelial (EpCAM(+)) cells, showing distinct morphology and migration speed, but comparable growth kinetics. The cell lines showed different patterns of response towards clinically approved and novel drugs, with HROC18 being more resistant than HROC32 cells. Finally, in vivo tumorigenicity was demonstrated. CONCLUSION We successfully established and characterized novel ultra-low passage patient-derived CRC models as useful instruments for analyzing biological characteristics associated with the CIN(+) phenotype.
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Luo Y, Wong CJ, Kaz AM, Dzieciatkowski S, Carter KT, Morris SM, Wang J, Willis JE, Makar KW, Ulrich CM, Lutterbaugh JD, Shrubsole MJ, Zheng W, Markowitz SD, Grady WM. Differences in DNA methylation signatures reveal multiple pathways of progression from adenoma to colorectal cancer. Gastroenterology 2014; 147:418-29.e8. [PMID: 24793120 PMCID: PMC4107146 DOI: 10.1053/j.gastro.2014.04.039] [Citation(s) in RCA: 155] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Revised: 04/15/2014] [Accepted: 04/23/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Genetic and epigenetic alterations contribute to the pathogenesis of colorectal cancer (CRC). There is considerable molecular heterogeneity among colorectal tumors, which appears to arise as polyps progress to cancer. This heterogeneity results in different pathways to tumorigenesis. Although epigenetic and genetic alterations have been detected in conventional tubular adenomas, little is known about how these affect progression to CRC. We compared methylomes of normal colon mucosa, tubular adenomas, and colorectal cancers to determine how epigenetic alterations might contribute to cancer formation. METHODS We conducted genome-wide array-based studies and comprehensive data analyses of aberrantly methylated loci in 41 normal colon tissue, 42 colon adenomas, and 64 cancers using HumanMethylation450 arrays. RESULTS We found genome-wide alterations in DNA methylation in the nontumor colon mucosa and cancers. Three classes of cancers and 2 classes of adenomas were identified based on their DNA methylation patterns. The adenomas separated into classes of high-frequency methylation and low-frequency methylation. Within the high-frequency methylation adenoma class a subset of adenomas had mutant KRAS. Additionally, the high-frequency methylation adenoma class had DNA methylation signatures similar to those of cancers with low or intermediate levels of methylation, and the low-frequency methylation adenoma class had methylation signatures similar to that of nontumor colon tissue. The CpG sites that were differentially methylated in these signatures are located in intragenic and intergenic regions. CONCLUSIONS Genome-wide alterations in DNA methylation occur during early stages of progression of tubular adenomas to cancer. These findings reveal heterogeneity in the pathogenesis of colorectal cancer, even at the adenoma step of the process.
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Affiliation(s)
- Yanxin Luo
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
| | - Chao-Jen Wong
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Andrew M Kaz
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Research and Development Service, VA Puget Sound Health Care System, Seattle, Washington; Department of Medicine, University of Washington School of Medicine, Seattle, Washington
| | | | - Kelly T Carter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Shelli M Morris
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Jianping Wang
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, PR China
| | - Joseph E Willis
- Department of Pathology, Case Medical Center, Case Comprehensive Cancer Center and Case Western Reserve University, Cleveland, Ohio
| | - Karen W Makar
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Cornelia M Ulrich
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), University of Heidelberg, Heidelberg, Germany GDR
| | - James D Lutterbaugh
- Department of Medicine and Ireland Cancer Center, Case Western Reserve University School of Medicine and Case Medical Center, Cleveland, Ohio
| | - Martha J Shrubsole
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Sanford D Markowitz
- Department of Medicine and Ireland Cancer Center, Case Western Reserve University School of Medicine and Case Medical Center, Cleveland, Ohio
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
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Burnett-Hartman AN, Newcomb PA, Hutter CM, Peters U, Passarelli MN, Schwartz MR, Upton MP, Zhu LC, Potter JD, Makar KW. Variation in the association between colorectal cancer susceptibility loci and colorectal polyps by polyp type. Am J Epidemiol 2014; 180:223-32. [PMID: 24875374 PMCID: PMC4082340 DOI: 10.1093/aje/kwu114] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 04/11/2014] [Indexed: 12/14/2022] Open
Abstract
We conducted a case-control study of the association between subsets of colorectal polyps, including adenomas and serrated polyps, and single-nucleotide polymorphisms (SNPs) related to colorectal cancer through prior genome-wide association studies (GWAS). Participants were enrollees in the Group Health Cooperative (Seattle, Washington) aged 24-79 years who received a colonoscopy from 1998 to 2007, donated a buccal or blood sample, and completed a structured questionnaire. We performed genotyping of 13 colorectal cancer susceptibility SNPs. Polytomous logistic regression models were used to estimate odds ratios and 95% confidence intervals for associations between polyps and the colorectal cancer risk allele for each SNP under a log-additive model. Analyses included 781 controls, 489 cases with adenoma, 401 cases with serrated polyps, and 188 cases with both polyp types. The following SNPs were associated with advanced adenomas: rs10936599, rs10795668, rs16892766, and rs9929218 (P < 0.05). For nonadvanced adenomas and for serrated polyps overall, only rs961253 was statistically significant (P < 0.05). These associations were in the same directions as those in prior colorectal cancer GWAS. No SNP was significantly associated with hyperplastic polyps, and only rs6983267 was significantly associated with sessile serrated polyps, but this association was opposite of that found in colorectal cancer GWAS. Our results suggest that the association between colorectal cancer susceptibility SNPs and colorectal polyps varies by polyp type.
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Affiliation(s)
- Andrea N. Burnett-Hartman
- Correspondence to Dr. Andrea N. Burnett-Hartman, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, M4-B402, Seattle, WA 98109 (e-mail: )
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Simons CCJM, van den Brandt PA, Stehouwer CDA, van Engeland M, Weijenberg MP. Body size, physical activity, early-life energy restriction, and associations with methylated insulin-like growth factor-binding protein genes in colorectal cancer. Cancer Epidemiol Biomarkers Prev 2014; 23:1852-62. [PMID: 24972776 DOI: 10.1158/1055-9965.epi-13-1285] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND We investigated body size, physical activity, and early-life energy restriction in relation to colorectal tumors with and without methylated insulin-like growth factor-binding protein (IGFBP) genes, which are putative tumor-suppressor genes. METHODS We determined IGFBP2, IGFBP3, and IGFBP7 promoter CpG island hypermethylation in tumors of 733 colorectal cancer cases from the Netherlands Cohort Study (N = 120,852). Participants self-reported lifestyle and dietary factors at baseline in 1986. Using a case-cohort approach (N subcohort = 5,000), we estimated hazard ratios (HR) for colorectal cancer by extent of IGFBP methylation. RESULTS Comparison of the highest versus lowest sex-specific tertiles of adult body mass index (BMI) gave multivariable-adjusted HRs [95% confidence intervals (CI)] for colorectal cancers with 0 (18.7%), 1 (29.5%), 2 (32.4%), and 3 (19.5%) methylated genes of 1.39 (0.88-2.19), 1.11 (0.77-1.62), 1.67 (1.17-2.38), and 2.07 (1.29-3.33), respectively. Other anthropometric measures and physical activity were not associated with colorectal cancer risk by extent of IGFBP methylation, except height in sex-specific analyses for women. Exposure to energy restriction during the Dutch Hunger Winter versus nonexposure gave HRs (95% CIs) for colorectal cancers with 0, 1, 2, and 3 methylated genes of 1.01 (0.67-1.53), 1.03 (0.74-1.44), 0.72 (0.52-0.99), and 0.50 (0.32-0.78), respectively. CONCLUSIONS Adult BMI, height (in women only), and early-life energy restriction were associated with the risk of having a colorectal tumor characterized by IGFBP methylation. IMPACT Body size may particularly increase the risk of IGFBP gene-methylated colorectal tumors; this finding might facilitate more targeted approaches to prevent obesity-related colorectal cancers.
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Affiliation(s)
- Colinda C J M Simons
- Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
| | - Piet A van den Brandt
- Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands
| | - Coen D A Stehouwer
- Department of Internal Medicine, CARIM - School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Manon van Engeland
- Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Matty P Weijenberg
- Department of Epidemiology, GROW - School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.
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Sanz-Pamplona R, Santos C, Grasselli J, Molleví DG, Dienstmann R, Paré-Brunet L, Sanjuán X, Biondo S, Capellà G, Tabernero J, Salazar R, Moreno V. Unsupervised analyses reveal molecular subtypes associated to prognosis and response to therapy in colorectal cancer. COLORECTAL CANCER 2014. [DOI: 10.2217/crc.14.15] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
SUMMARY Colorectal cancer (CRC) tumors are highly heterogeneous at a molecular level. Recent studies have proposed molecular classifications of intrinsic CRC molecular subtypes identified after applying unsupervised clustering methods to genome-wide data. Those subtypes, characterized by their distinct clinical and biological features, provide new insight about the complexity of CRC. A common finding shared by almost all analyses was the identification of microsatellite instable tumors as an independent cluster, which is associated to better prognosis. Clusters of tumors characterized by a high stromal component exhibited a poor outcome. Moreover, some of the clusters were associated with response to standard chemotherapy or targeted agents. Regarding biological functions underlying tumor subtypes, recurrent ones across different studies were WNT pathway activation, epithelial-to-mesenchymal transition or cancer stem cell-like phenotype. Now, the challenge is to translate these findings into a comprehensive CRC classification and characterization helpful for patients’ stratification and better clinical management.
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Affiliation(s)
- Rebeca Sanz-Pamplona
- Unit of Biomarkers & Susceptibility, Cancer Prevention & Control Program, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Epidemiology and Public Health Biomedical Research Consortium (CIBERESP), Spain
| | - Cristina Santos
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain
| | - Julieta Grasselli
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain
| | - David G Molleví
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Traslational Research Laboratory, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain
| | - Rodrigo Dienstmann
- Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Laia Paré-Brunet
- Unit of Biomarkers & Susceptibility, Cancer Prevention & Control Program, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Epidemiology and Public Health Biomedical Research Consortium (CIBERESP), Spain
| | - Xavier Sanjuán
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Pathology Service, Bellvitge University Hospital (HUB), L’Hospitalet de Llobregat, Barcelona, Spain
| | - Sebastiano Biondo
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- General & Digestive Surgery Service, University Hospital Bellvitge (HUB), L’Hospitalet de Llobregat, Barcelona, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Gabriel Capellà
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Traslational Research Laboratory, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain
- Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Hereditary Cancer Program, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain
| | - Josep Tabernero
- Medical Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain
- Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Ramón Salazar
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Department of Medical Oncology, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain
- Traslational Research Laboratory, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain
| | - Victor Moreno
- Unit of Biomarkers & Susceptibility, Cancer Prevention & Control Program, Catalan Institute of Oncology (ICO), L’Hospitalet de Llobregat, Barcelona, Spain
- Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
- Epidemiology and Public Health Biomedical Research Consortium (CIBERESP), Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
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Pierobon M, Silvestri A, Spira A, Reeder A, Pin E, Banks S, Parasido E, Edmiston K, Liotta L, Petricoin E. Pilot phase I/II personalized therapy trial for metastatic colorectal cancer: evaluating the feasibility of protein pathway activation mapping for stratifying patients to therapy with imatinib and panitumumab. J Proteome Res 2014; 13:2846-55. [PMID: 24787230 DOI: 10.1021/pr401267m] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
This nonrandomized phase I/II trial assessed the efficacy/tolerability of imatinib plus panitumumab in patients affected by metastatic colorectal cancer (mCRC) after stratification to treatment by selection of activated imatinib drug targets using reverse-phase protein array (RPPA). mCRC patients presenting with a biopsiable liver metastasis were enrolled. Allocation to the experimental and control arms was established using functional pathway activation mapping of c-Kit, PDGFR, and c-Abl phosphorylation by RPPA. The experimental arm received run-in escalation therapy with imatinib followed by panitumumab. The control arm received panitumumab alone. Seven patients were enrolled in the study. For three of the seven patients, sequential pre- and post-treatment biopsies were used to evaluate the effect of the therapeutic compounds on the drug targets and substrates. A decrease in the activation level of the drug targets and downstream substrates was observed in two of three patients. Combination therapy increased the activation of the AKT-mTOR pathway and several receptor tyrosine kinases. This study proposes a novel methodology for stratifying patients to personalized treatment based on the activation level of the drug targets. This workflow provides the ability to monitor changes in the signaling pathways after the administration of targeted therapies and to identify compensatory mechanisms.
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Affiliation(s)
- M Pierobon
- Center for Applied Proteomics and Molecular Medicine, George Mason University , 10900 University Boulevard, Manassas, Virginia 20110, United States
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Kim B, Park SJ, Cheon JH, Kim TI, Kim WH, Hong SP. Clinical meaning of BRAF mutation in Korean patients with advanced colorectal cancer. World J Gastroenterol 2014; 20:4370-4376. [PMID: 24764675 PMCID: PMC3989973 DOI: 10.3748/wjg.v20.i15.4370] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2013] [Revised: 11/04/2013] [Accepted: 01/08/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the clinicopathological features of colorectal cancer (CRC) with a v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation and its molecular interaction with microsatellite instability (MSI) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) in patients with advanced CRCs.
METHODS: From October 2009 to December 2011, 141 patients with stage III (n = 51) or IV (n = 90) CRCs who were tested for the BRAF mutation at Severance Hospital were included. Among 141 patients, five were excluded due to follow-up loss. Therefore, 136 patients were included in the study. The clinicopathological data, MSI status, and KRAS/BRAF mutation status were reviewed retrospectively. In addition, to evaluating the value of BRAF mutation status, progression-free survival and overall survival in all patients were collected and compared between the BRAF wild-type group and BRAF mutation group.
RESULTS: Of 136 patients, 80 (58.8%) were male and the mean age was 59 years. BRAF and KRAS mutations were detected in 9.6% and 35.3% of patients, respectively. Only 4.3% of patients had MSI-high tumors and there were no MSI-high in tumors with a BRAF mutation. BRAF mutations tended to be more frequent in stage IV than in stage III (11.76% vs 5.88%, P = 0.370). Patients with a BRAF mutation had a lower incidence of KRAS mutation than those without (7.69% vs 38.21%, P = 0.033). Overall survival was significantly shorter in the BRAF mutation group than in the BRAF wild-type group both by univariate analysis (P = 0.041) and multivariate analysis (HR = 2.195; 95%CI: 1.039-4.640; P = 0.039), while progression-free survival was not different according to BRAF mutation status.
CONCLUSION: CRCs with a BRAF mutation have distinct molecular features and resulted in a poor prognosis in Korean patients with advanced CRC.
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Dawson H, Koelzer VH, Lukesch AC, Mallaev M, Inderbitzin D, Lugli A, Zlobec I. Loss of Cdx2 Expression in Primary Tumors and Lymph Node Metastases is Specific for Mismatch Repair-Deficiency in Colorectal Cancer. Front Oncol 2013; 3:265. [PMID: 24130965 PMCID: PMC3795344 DOI: 10.3389/fonc.2013.00265] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2013] [Accepted: 09/26/2013] [Indexed: 12/19/2022] Open
Abstract
Background: Approximately 20% of all colorectal cancers are hypothesized to arise from the “serrated pathway” characterized by mutation in BRAF, high-level CpG Island Methylator Phenotype, and microsatellite instability/mismatch repair (MMR)-deficiency. MMR-deficient cancers show frequent losses of Cdx2, a homeodomain transcription factor. Here, we determine the predictive value of Cdx2 expression for MMR-deficiency and investigate changes in expression between primary cancers and matched lymph node metastases. Methods: Immunohistochemistry for Cdx2, Mlh1, Msh2, Msh6, and Pms2 was performed on whole tissue sections from 201 patients with primary colorectal cancer and 59 cases of matched lymph node metastases. Receiver operating characteristic curve analysis and Area under the Curve (AUC) were investigated; association of Cdx2 with clinicopathological features and patient survival was carried out. Results: Loss of Cdx2 expression was associated with higher tumor grade (p = 0.0002), advanced pT (p = 0.0166), and perineural invasion (p = 0.0228). Cdx2 loss was an unfavorable prognostic factor in univariate (p = 0.0145) and multivariate [p = 0.0427; HR (95% CI): 0.58 (0.34–0.98)] analysis. The accuracy (AUC) for discriminating MMR-proficient and – deficient cancers was 87% [OR (95% CI): 0.96 (0.95–0.98); p < 0.0001]. Specificity and negative predictive value for MMR-deficiency was 99.1 and 96.3%. One hundred and seventy-four patients had MMR-proficient cancers, of which 60 (34.5%) showed Cdx2 loss. Cdx2 loss in metastases was related to MMR-deficiency (p < 0.0001). There was no difference in expression between primary tumors and matched metastases. Conclusion: Loss of Cdx2 is a sensitive and specific predictor of MMR-deficiency, but is not limited to these tumors, suggesting that events “upstream” of the development of microsatellite instability may impact Cdx2 expression.
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Affiliation(s)
- Heather Dawson
- Department of Clinical Pathology, Institute of Pathology, University of Bern , Bern , Switzerland ; Translational Research Unit, Institute of Pathology, University of Bern , Bern , Switzerland
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Bardhan K, Liu K. Epigenetics and colorectal cancer pathogenesis. Cancers (Basel) 2013; 5:676-713. [PMID: 24216997 PMCID: PMC3730326 DOI: 10.3390/cancers5020676] [Citation(s) in RCA: 186] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2013] [Revised: 05/22/2013] [Accepted: 05/24/2013] [Indexed: 12/13/2022] Open
Abstract
Colorectal cancer (CRC) develops through a multistage process that results from the progressive accumulation of genetic mutations, and frequently as a result of mutations in the Wnt signaling pathway. However, it has become evident over the past two decades that epigenetic alterations of the chromatin, particularly the chromatin components in the promoter regions of tumor suppressors and oncogenes, play key roles in CRC pathogenesis. Epigenetic regulation is organized at multiple levels, involving primarily DNA methylation and selective histone modifications in cancer cells. Assessment of the CRC epigenome has revealed that virtually all CRCs have aberrantly methylated genes and that the average CRC methylome has thousands of abnormally methylated genes. Although relatively less is known about the patterns of specific histone modifications in CRC, selective histone modifications and resultant chromatin conformation have been shown to act, in concert with DNA methylation, to regulate gene expression to mediate CRC pathogenesis. Moreover, it is now clear that not only DNA methylation but also histone modifications are reversible processes. The increased understanding of epigenetic regulation of gene expression in the context of CRC pathogenesis has led to development of epigenetic biomarkers for CRC diagnosis and epigenetic drugs for CRC therapy.
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Affiliation(s)
- Kankana Bardhan
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, and Cancer Center, Georgia Regents University, Augusta, GA 30912, USA.
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Kumbhari V, Behary J, Hui JM. Prevalence of adenomas and sessile serrated adenomas in Chinese compared with Caucasians. J Gastroenterol Hepatol 2013; 28:608-12. [PMID: 23278321 DOI: 10.1111/jgh.12100] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/17/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Colonic adenomas and sessile serrated adenomas (SSA) are the most common premalignant polyps identified at colonoscopy. This study compares the prevalence of neoplastic polyps in Chinese and Caucasians in a general gastroenterology outpatient practice in Australia. METHODS This study included consecutive unselected colonoscopies performed for standard clinical indications by a single endoscopist (JMH). All polyps detected were measured, resected, and sent for histopathology. The prevalence of adenomas, advanced adenomas, SSA, and cancer in the Chinese and Caucasian cohorts were compared. Advanced adenomas were defined as adenomas > 10 mm, villous histology, or high-grade dysplasia. RESULTS The study included 346 Chinese and 654 Caucasians. There was no significant difference in the baseline characteristics including age, gender, and indications of colonoscopy, although Chinese were more likely to present with rectal bleeding (22.8% vs 15.9%, P = 0.01). The prevalence of adenomatous polyps was similar in both Caucasians (34.3%) and Chinese (35.3%). However, advanced adenomas were more significantly common in Caucasians (11.3%) compared with Chinese (4.6%) (P < 0.001). SSA was rare in Chinese (2%) but present more frequently in Caucasians (7%) (P = 0.001). Multivariate analysis showed that Caucasian ethnicity (odds ratio 2.4, 95% confidence interval 1.6-3.6) and the presence of SSA (odds ratio 4.4, 95% confidence interval 2.3-8.6) were independent predictors for the detection of an advanced adenoma. CONCLUSIONS The prevalence of significant colorectal lesions, including advanced adenomas, large adenomas, and SSA, were lower in Chinese compared with Caucasians. These findings may influence the guidelines for colonic cancer screening in Chinese populations.
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Affiliation(s)
- Vivek Kumbhari
- Department of Gastroenterology, The Sutherland Hospital, Sydney, New South Wales, Australia
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Burnett-Hartman AN, Passarelli MN, Adams SV, Upton MP, Zhu LC, Potter JD, Newcomb PA. Differences in epidemiologic risk factors for colorectal adenomas and serrated polyps by lesion severity and anatomical site. Am J Epidemiol 2013; 177:625-37. [PMID: 23459948 DOI: 10.1093/aje/kws282] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Using a case-control design, we evaluated differences in risk factors for colorectal polyps according to histological type, anatomical site, and severity. Participants were enrollees in the Group Health Cooperative aged 20-79 years who underwent colonoscopy in Seattle, Washington, between 1998 and 2007 and comprised 628 adenoma cases, 594 serrated polyp cases, 247 cases with both types of polyps, and 1,037 polyp-free controls. Participants completed a structured interview, and polyps were evaluated via standardized pathology review. We used multivariable polytomous logistic regression to compare case groups with controls and with the other case groups. Factors for which the strength of the association varied significantly between adenomas and serrated polyps were sex (P < 0.001), use of estrogen-only postmenopausal hormone therapy (P = 0.01), and smoking status (P < 0.001). For lesion severity, prior endoscopy (P < 0.001) and age (P = 0.05) had significantly stronger associations with advanced adenomas than with nonadvanced adenomas; and higher education was positively correlated with sessile serrated polyps but not with other serrated polyps (P = 0.02). Statistically significant, site-specific associations were observed for current cigarette smoking (P = 0.05 among adenomas and P < 0.001 among serrated polyps), postmenopausal estrogen-only therapy (P = 0.01 among adenomas), and obesity (P = 0.01 among serrated polyps). These findings further illustrate the epidemiologic heterogeneity of colorectal neoplasia and may help elucidate carcinogenic mechanisms for distinct pathways.
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Affiliation(s)
- Andrea N Burnett-Hartman
- Department of Cancer Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
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Burnett-Hartman AN, Newcomb PA, Potter JD, Passarelli MN, Phipps AI, Wurscher MA, Grady WM, Zhu LC, Upton MP, Makar KW. Genomic aberrations occurring in subsets of serrated colorectal lesions but not conventional adenomas. Cancer Res 2013; 73:2863-72. [PMID: 23539450 DOI: 10.1158/0008-5472.can-12-3462] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
A subset of aggressive colorectal cancers exhibit BRAF mutation, MLH1 methylation, and a CpG island methylator phenotype (CIMP), but precursors are poorly established. In this study, we determined the status of these markers in colorectal polyps and evaluated associated risk factors. The study included 771 polyp cases and 1,027 controls who were ages 24 to 80 years, part of a group health program, received a colonoscopy from 1998 to 2007, and completed a structured questionnaire assessing risk factors. Following standard pathology review, polyps were assayed for BRAF mutation (V600E) and tested for MLH1 and CIMP methylation, the latter including the genes, CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1. Polytomous logistic regression was used to estimate ORs and 95% confidence intervals for the association between molecularly defined subsets of polyps and potential risk factors. There were 580 conventional adenomas and 419 serrated lesions successfully assayed. For adenomas, the prevalence of each marker was ≤1%. In contrast, 55% of serrated lesions harbored mutant BRAF, 26% were CIMP-high, and 5% had methylated MLH1. In these lesions, the highest prevalence of markers was in sessile-serrated polyps (SSP) of ≥10 mm that were in the right-side/cecal regions of the colon. Risk factors for CIMP-high-serrated lesions included Caucasian race, current smoking status, and a history of polyps, whereas for serrated lesions with mutant BRAF, the significant risk factors were male sex, current smoking status, obesity, and a history of polyps. Our results suggest that SSPs and other large, right-sided serrated lesions have a unique molecular profile that is similar to CIMP-high, BRAF-mutated colorectal cancers.
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Bozzao C, Lastella P, Stella A. Anticipation in lynch syndrome: where we are where we go. Curr Genomics 2012; 12:451-65. [PMID: 22547953 PMCID: PMC3219841 DOI: 10.2174/138920211797904070] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2011] [Revised: 07/08/2011] [Accepted: 07/20/2011] [Indexed: 02/06/2023] Open
Abstract
Lynch syndrome (LS) is the most common form of inherited predisposition to develop cancer mainly in the colon and endometrium but also in other organ sites. Germline mutations in DNA mismatch repair (MMR) gene cause the transmission of the syndrome in an autosomal dominant manner. The management of LS patients is complicated by the large variation in age at cancer diagnosis which requires these patients to be enrolled in surveillance protocol starting as early as in their second decade of life. Several environmental and genetic factors have been proposed to explain this phenotypic heterogeneity, but the molecular mechanisms remain unknown. Although the presence of genetic anticipation in Lynch syndrome has been suspected since 15 years, only recently the phenomenon has been increasingly reported to be present in different cancer genetic syndromes including LS. While the biological basis of earlier cancer onset in successive generations remains poorly known, recent findings point to telomere dynamics as a mechanism significantly contributing to genetic anticipation in Lynch syndrome and in other familial cancers. In this review, we summarize the clinical and molecular features of Lynch syndrome, with a particular focus on the latest studies that have investigated the molecular mechanisms of genetic anticipation.
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Affiliation(s)
- Cristina Bozzao
- Medical Genetics Unit, Department of Biomedicine in Childhood, Università degli Studi di Bari "Aldo Moro", Bari, Italy
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Zheng W, Rutter CM. Estimated mean sojourn time associated with hemoccult SENSA for detection of proximal and distal colorectal cancer. Cancer Epidemiol Biomarkers Prev 2012; 21:1722-30. [PMID: 22911331 DOI: 10.1158/1055-9965.epi-12-0561] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Sojourn time is the length of the preclinical screen-detectable phase, a period when a test can detect asymptomatic disease. Mean sojourn time (MST) is an important factor in determining appropriate screening intervals. Available estimates of MST for colorectal cancer (CRC) are imprecise and are associated with the older Hemoccult II test. This article presents MST estimates associated with the newer Hemoccult SENSA test and describes differences in MST by the location of cancer in the colorectum and age at the time of screening. METHODS MST was estimated from a cohort of 42,079 patients who underwent Hemoccult SENSA between January 1, 1997 and December 31, 2010. The precision of MST estimates was improved by incorporating information from a meta-analysis of the sensitivity of Hemoccult SENSA into the analytic model. RESULTS Estimated MST for cancers in the proximal and distal colorectum, with 95% credible intervals (CrI) in years, were: 3.86 (1.55-6.91) and 3.35 (2.11-4.93) among 45- to 54-year olds; 3.78 (2.18-5.77) and 2.24 (1.48-3.17) among 55- to 64-year olds; and 2.70 (1.41-4.31) and 2.10 (1.34-3.04) among 65- to 74-year olds. CONCLUSIONS MST associated with Hemoccult SENSA was longer for CRC in the proximal versus distal colon. We found no evidence that MST increases with age and some evidence that it may decrease. IMPACT These results add new information about the natural history of CRC and information about the performance of Hemoccult SENSA.
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Affiliation(s)
- Wenying Zheng
- Department of Biostatistics, School of Public Health, University of Washington, Seattle, Washington, USA
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Gao Y, Killian K, Zhang H, Yu K, Li QZ, Weinstein S, Virtamo J, Tucker M, Taylor P, Albanes D, Meltzer P, Caporaso N. Leukocyte DNA methylation and colorectal cancer among male smokers. World J Gastrointest Oncol 2012; 4:193-201. [PMID: 22912915 PMCID: PMC3423510 DOI: 10.4251/wjgo.v4.i8.193] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2012] [Revised: 07/13/2012] [Accepted: 07/20/2012] [Indexed: 02/05/2023] Open
Abstract
AIM: To explore the association between methylation in leukocyte DNA and colorectal cancer (CRC) risk in male smokers using the α-tocopherol, β-carotene cancer prevention study.
METHODS: About 221 incident CRC cases, and 219 controls, frequency-matched on age and smoking intensity were included. DNA methylation of 1505 CpG sites selected from 807 genes were evaluated using Illumina GoldenGate Methylation Cancer Panel I in pre-diagnostic blood leukocytes of study subjects. Tertiles of methylation level classified according to the distribution in controls for each CpG site were used to analyze the association between methylation level and CRC risk with logistic regression. The time between blood draw to cancer diagnosis (classifying cases according to latency) was incorporated in further analyses using proportional odds regression.
RESULTS: We found that methylation changes of 31 CpG sites were associated with CRC risk at P < 0.01 level. Though none of these 31 sites remained statistically significant after Bonferroni correction, the most statistically significant CpG site associated with CRC risk achieved a P value of 1.0 × 10-4. The CpG site is located in DSP gene, and the risk estimate was 1.52 (95% CI: 0.91-2.53) and 2.62 (95% CI: 1.65-4.17) for the second and third tertile comparing with the lowest tertile respectively. Taking the latency information into account strengthened some associations, suggesting that the methylation levels of corresponding sites might change over time with tumor progression.
CONCLUSION: The results suggest that the methylation level of some genes were associated with cancer susceptibility and some were related to tumor development over time. Further studies are warranted to confirm and refine our results.
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Affiliation(s)
- Ying Gao
- Ying Gao, Kai Yu, Stephanie Weinstein, Margaret Tucker, Philip Taylor, Demetrius Albanes, Neil Caporaso, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20852, United States
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Colorectal endoscopy, advanced adenomas, and sessile serrated polyps: implications for proximal colon cancer. Am J Gastroenterol 2012; 107:1213-9. [PMID: 22688851 PMCID: PMC3418887 DOI: 10.1038/ajg.2012.167] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Colonoscopy is associated with a decreased risk of colorectal cancer but may be more effective in reducing the risk of distal than proximal malignancies. To gain insight into the differences between proximal and distal colon endoscopic performance, we conducted a case-control study of advanced adenomas, the primary targets of colorectal endoscopy screening, and sessile serrated polyps (SSPs), newly recognized precursor lesions for a colorectal cancer subset that occurs most often in the proximal colon. METHODS The Group Health-based study population included 213 advanced adenoma cases, 172 SSP cases, and 1,704 controls aged 50-79 years, who received an index colonoscopy from 1998-2007. All participants completed a structured questionnaire covering endoscopy history. Participants with polyps underwent a standard pathology review to confirm the diagnosis and reclassify a subset as advanced adenomas or SSPs. Logistic regression analyses were conducted to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between endoscopy and advanced adenomas and SSPs separately; site-specific analyses were completed. RESULTS Previous endoscopy was inversely associated with advanced adenomas in both the rectum/distal colon (OR=0.38; 95% CI: 0.26-0.56) and proximal colon (OR=0.31; 95% CI: 0.19-0.52), but there was no statistically significant association between previous endoscopy and SSPs (OR=0.80; 95%CI: 0.56-1.13). CONCLUSIONS Our results support the hypothesis that the effect of endoscopy differs between advanced adenomas and SSPs. This may have implications for proximal colon cancer prevention and be due to the failure of endoscopy to detect/remove SSPs, or the hypothesized rapid development of SSPs.
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Relative Expression of Vitamin D Hydroxylases, CYP27B1 and CYP24A1, and of Cyclooxygenase-2 and Heterogeneity of Human Colorectal Cancer in Relation to Age, Gender, Tumor Location, and Malignancy: Results from Factor and Cluster Analysis. Cancers (Basel) 2012; 4:763-76. [PMID: 24213465 PMCID: PMC3712714 DOI: 10.3390/cancers4030763] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Revised: 07/06/2012] [Accepted: 07/13/2012] [Indexed: 01/02/2023] Open
Abstract
Previous studies on the significance of vitamin D insufficiency and chronic inflammation in colorectal cancer development clearly indicated that maintenance of cellular homeostasis in the large intestinal epithelium requires balanced interaction of 1,25-(OH)2D3 and prostaglandin cellular signaling networks. The present study addresses the question how colorectal cancer pathogenesis depends on alterations of activities of vitamin D hydroxylases, i.e., CYP27B1-encoded 25-hydroxyvitamin D-1α-hydroxylase and CYP24A1-encoded 25-hydroxyvitamin D-24-hydroxylase, and inflammation-induced cyclooxygenase-2 (COX-2). Data from 105 cancer patients on CYP27B1, VDR, CYP24A1, and COX-2 mRNA expression in relation to tumor grade, anatomical location, gender and age were fit into a multivariate model of exploratory factor analysis. Nearly identical results were obtained by the principal factor and the maximum likelihood method, and these were confirmed by hierarchical cluster analysis: Within the eight mutually dependent variables studied four independent constellations were found that identify different features of colorectal cancer pathogenesis: (i) Escape of COX-2 activity from restraints by the CYP27B1/VDR system can initiate cancer growth anywhere in the colorectum regardless of age and gender; (ii) variations in COX-2 expression are mainly responsible for differences in cancer incidence in relation to tumor location; (iii) advancing age has a strong gender-specific influence on cancer incidence; (iv) progression from well differentiated to undifferentiated cancer is solely associated with a rise in CYP24A1 expression.
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Sweetser S, Smyrk TC, Sugumar A. Serrated polyps: critical precursors to colorectal cancer. Expert Rev Gastroenterol Hepatol 2011; 5:627-35. [PMID: 21910580 DOI: 10.1586/egh.11.67] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Colorectal polyps have been traditionally classified as either hyperplastic or adenomatous, with only the latter progressing to carcinoma. However, it is now recognized that certain subtypes of serrated polyps have a risk of malignant transformation via a serrated neoplasia pathway. Serrated polyps are a heterogeneous group of lesions with distinct morphologic, histologic and molecular genetics profiles. Based on available evidence, there are reasons to suspect that this pathway may contribute to interval or missed cancers because serrated lesions are more likely than conventional adenomas to be missed on colonoscopy, and the progression of serrated polyps to cancer may be more rapid. Therefore, it is paramount that physicians recognize the importance of serrated polyps and are aware of the latest surveillance guidelines.
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Affiliation(s)
- Seth Sweetser
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
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Gustafsson SB, Palmqvist R, Henriksson ML, Dahlin AM, Edin S, Jacobsson SOP, Öberg Å, Fowler CJ. High tumour cannabinoid CB1 receptor immunoreactivity negatively impacts disease-specific survival in stage II microsatellite stable colorectal cancer. PLoS One 2011; 6:e23003. [PMID: 21901119 PMCID: PMC3161987 DOI: 10.1371/journal.pone.0023003] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2010] [Accepted: 07/11/2011] [Indexed: 12/22/2022] Open
Abstract
Background There is good evidence in the literature that the cannabinoid system is disturbed in colorectal cancer. In the present study, we have investigated whether CB1 receptor immunoreactive intensity (CB1IR intensity) is associated with disease severity and outcome. Methodology/Principal Findings CB1IR was assessed in formalin-fixed, paraffin-embedded specimens collected with a consecutive intent during primary tumour surgical resection from a series of cases diagnosed with colorectal cancer. Tumour centre (n = 483) and invasive front (n = 486) CB1IR was scored from 0 (absent) to 3 (intense staining) and the data was analysed as a median split i.e. CB1IR <2 and ≥2. In microsatellite stable, but not microsatellite instable tumours (as adjudged on the basis of immunohistochemical determination of four mismatch repair proteins), there was a significant positive association of the tumour grade with the CB1IR intensity. The difference between the microsatellite stable and instable tumours for this association of CB1IR was related to the CpG island methylation status of the cases. Cox proportional hazards regression analyses indicated a significant contribution of CB1IR to disease-specific survival in the microsatellite stable tumours when adjusting for tumour stage. For the cases with stage II microsatellite stable tumours, there was a significant effect of both tumour centre and front CB1IR upon disease specific survival. The 5 year probabilities of event-free survival were: 85±5 and 66±8%; tumour interior, 86±4% and 63±8% for the CB1IR<2 and CB1IR≥2 groups, respectively. Conclusions/Significance The level of CB1 receptor expression in colorectal cancer is associated with the tumour grade in a manner dependent upon the degree of CpG hypermethylation. A high CB1IR is indicative of a poorer prognosis in stage II microsatellite stable tumour patients.
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Affiliation(s)
- Sofia B. Gustafsson
- Department of Pharmacology and Clinical Neuroscience, Pharmacology, Umeå University, Umeå, Sweden
| | - Richard Palmqvist
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | | | - Anna M. Dahlin
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Sofia Edin
- Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden
| | - Stig O. P. Jacobsson
- Department of Pharmacology and Clinical Neuroscience, Pharmacology, Umeå University, Umeå, Sweden
| | - Åke Öberg
- Department of Surgical and Perioperative Sciences, Surgery, Umeå University, Umeå, Sweden
| | - Christopher J. Fowler
- Department of Pharmacology and Clinical Neuroscience, Pharmacology, Umeå University, Umeå, Sweden
- * E-mail:
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