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1
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Madden-Hennessey K, Gupta D, Radecki AA, Guild C, Rath A, Heinen CD. Loss of mismatch repair promotes a direct selective advantage in human stem cells. Stem Cell Reports 2022; 17:2661-2673. [PMID: 36368329 PMCID: PMC9768573 DOI: 10.1016/j.stemcr.2022.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 11/11/2022] Open
Abstract
Lynch syndrome (LS) is the most common hereditary form of colon cancer, resulting from a germline mutation in a DNA mismatch repair (MMR) gene. Loss of MMR in cells establishes a mutator phenotype, which may underlie its link to cancer. Acquired downstream mutations that provide the cell a selective advantage would contribute to tumorigenesis. It is unclear, however, whether loss of MMR has other consequences that would directly result in a selective advantage. We found that knockout of the MMR gene MSH2 results in an immediate survival advantage in human stem cells grown under standard cell culture conditions. This advantage results, in part, from an MMR-dependent response to oxidative stress. We also found that loss of MMR gives rise to enhanced formation and growth of human colonic organoids. These results suggest that loss of MMR may affect cells in ways beyond just increasing mutation frequency that could influence tumorigenesis.
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Affiliation(s)
| | - Dipika Gupta
- Center for Molecular Oncology, UConn Health, Farmington, CT 06030-3101, USA
| | | | - Caroline Guild
- Center for Molecular Oncology, UConn Health, Farmington, CT 06030-3101, USA
| | - Abhijit Rath
- Center for Molecular Oncology, UConn Health, Farmington, CT 06030-3101, USA
| | - Christopher D. Heinen
- Center for Molecular Oncology, UConn Health, Farmington, CT 06030-3101, USA,Corresponding author
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Han T, Hu X, Li K, Zhang D, Zhang Y, Li J. Bifidobacterium infantis Maintains Genome Stability in Ulcerative Colitis via Regulating Anaphase-Promoting Complex Subunit 7. Front Microbiol 2021; 12:761113. [PMID: 34795654 PMCID: PMC8593188 DOI: 10.3389/fmicb.2021.761113] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/08/2021] [Indexed: 12/12/2022] Open
Abstract
Probiotics represents a promising intestinal microbiota-targeted therapeutic method for the treatment of ulcerative colitis (UC). Several lines of evidence implicate that Bifidobacterium infantis serves as a probiotic strain with proven efficacy in maintaining the remission of UC. However, the exact mechanisms underlying the beneficial effects of B. infantis on UC progression have yet to be elucidated. Herein, we provide evidence that B. infantis acts as a key predisposing factor for the maintenance of host genome stability. First, we showed that the fecal microbiota transplantation (FMT) of UC-derived feces contributes to more severely DNA damage in dextran sodium sulfate (DSS)-induced mice likely due to mucosa-associated microbiota alterations, as reflected by the rapid appearance of DNA double strand breaks (DSBs), a typical marker of genome instability. Genomic DNA damage analysis of colon tissues derived from healthy controls, patients with UC or dysplasia, and colitis associated cancer (CAC) patients, revealed an enhanced level of DSBs with aggravation in the degree of the intestinal mucosal lesions. To evaluate whether B. infantis modulates the host genome stability, we employed the DSS-induced colitis model and a TNFα-induced intestinal epithelial cell model. Following the administration of C57BL/6 mice with B. infantis via oral gavage, we found that the development of DSS-induced colitis in mice was significantly alleviated, in contrast to the colitis model group. Notably, B. infantis administration decreased DSB levels in both DSS-induced colitis and TNF-treated colonial cell model. Accordingly, our bioinformatic and functional studies demonstrated that B. infantis altered signal pathways involved in ubiquitin-mediated proteolysis, transcriptional misregulation in cancer, and the bacterial invasion of epithelial cells. Mechanistically, B. infantis upregulated anaphase-promoting complex subunit 7 (APC7), which was significantly suppressed in colitis condition, to activate the DNA repair pathway and alter the genome stability, while downregulation of APC7 abolished the efficiency of B. infantis treatment to induce a decrease in the level of DSBs in TNFα-induced colonial cells. Collectively, our results support that B. infantis orchestrates a molecular network involving in APC7 and genome stability, to control UC development at the clinical, biological, and mechanistic levels. Supplying B. infantis and targeting its associated pathway will yield valuable insight into the clinical management of UC patients.
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Affiliation(s)
- Taotao Han
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaomin Hu
- Key Laboratory of Gut Microbiota Translational Medicine Research, Chinese Academy of Medical Sciences, Beijing, China.,State Key Laboratory of Complex Severe and Rare Diseases, Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Kemin Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Di Zhang
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Chinese Academy of Medical Sciences, Beijing, China
| | - Yan Zhang
- Institute of Cardiovascular Sciences and Key Laboratory of Molecular Cardiovascular Sciences, School of Basic Medical Sciences, Ministry of Education, Peking University Health Science Center, Beijing, China
| | - Jingnan Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.,Key Laboratory of Gut Microbiota Translational Medicine Research, Chinese Academy of Medical Sciences, Beijing, China
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Wang Y, Ding Y, Deng Y, Zheng Y, Wang S. Role of myeloid-derived suppressor cells in the promotion and immunotherapy of colitis-associated cancer. J Immunother Cancer 2020; 8:jitc-2020-000609. [PMID: 33051339 PMCID: PMC7555106 DOI: 10.1136/jitc-2020-000609] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/26/2020] [Indexed: 12/11/2022] Open
Abstract
Colitis-associated cancer (CAC) is a specific type of colorectal cancer that develops from inflammatory bowel disease (IBD). Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are essential for the pathological processes of inflammation and cancer. Accumulating evidence indicates that MDSCs play different but vital roles during IBD and CAC development and impede CAC immunotherapy. New insights into the regulatory network of MDSCs in the CAC pathogenesis are opening new avenues for developing strategies to enhance the effectiveness of CAC treatment. In this review, we explore the role of MDSCs in chronic inflammation, dysplasia and CAC and summarize the potential CAC therapeutic strategies based on MDSC blockade.
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Affiliation(s)
- Yungang Wang
- Department of Laboratory Medicine, The First People's Hospital of Yancheng, Nanjing University Medical School, Yancheng, China
| | - Yanxia Ding
- Department of Dermatology, The First People's Hospital of Yancheng, Nanjing University Medical School, Yancheng, China
| | - Yijun Deng
- Department of Critical Care Medicine, The First People's Hospital of Yancheng, Nanjing University Medical School, Yancheng, China
| | - Yu Zheng
- Department of Laboratory Medicine, The First People's Hospital of Yancheng, Nanjing University Medical School, Yancheng, China
| | - Shengjun Wang
- Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China
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Inflammation-Associated Microsatellite Alterations Caused by MSH3 Dysfunction Are Prevalent in Ulcerative Colitis and Increase With Neoplastic Advancement. Clin Transl Gastroenterol 2020; 10:e00105. [PMID: 31789935 PMCID: PMC6970556 DOI: 10.14309/ctg.0000000000000105] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVES: Inflammation-associated microsatellite alterations (also known as elevated microsatellite alterations at selected tetranucleotide repeats [EMAST]) result from IL-6–induced nuclear-to-cytosolic displacement of the DNA mismatch repair (MMR) protein MSH3, allowing frameshifts of dinucleotide or longer microsatellites within DNA. MSH3 also engages homologous recombination to repair double-strand breaks (DSBs), making MSH3 deficiency contributory to both EMAST and DSBs. EMAST is observed in cancers, but given its genesis by cytokines, it may be present in non-neoplastic inflammatory conditions. We examined ulcerative colitis (UC), a preneoplastic condition from prolonged inflammatory duration. METHODS: We assessed 70 UC colons without neoplasia, 5 UC specimens with dysplasia, 14 UC-derived colorectal cancers (CRCs), and 19 early-stage sporadic CRCs for microsatellite instability (MSI) via multiplexed polymerase chain reaction capable of simultaneous detection of MSI-H, MSI-L, and EMAST. We evaluated UC specimens for MSH3 expression via immunohistochemistry. RESULTS: UC, UC with dysplasia, and UC-derived CRCs demonstrated dinucleotide or longer microsatellite frameshifts, with UC showing coincident reduction of nuclear MSH3 expression. No UC specimen, with or without neoplasia, demonstrated mononucleotide frameshifts. EMAST frequency was higher in UC-derived CRCs than UC (71.4% vs 31.4%, P = 0.0045) and higher than early-stage sporadic CRCs (66.7% vs 26.3%, P = 0.0426). EMAST frequency was higher with UC duration >8 years compared with ≤8 years (40% vs 16%, P = 0.0459). DISCUSSION: Inflammation-associated microsatellite alterations/EMAST are prevalent in UC and signify genomic mutations in the absence of neoplasia. Duration of disease and advancement to neoplasia increases frequency of EMAST. MSH3 dysfunction is a potential contributory pathway toward neoplasia in UC that could be targeted by therapeutic intervention.
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Vasavi M, Ponnala S, Gujjari K, Boddu P, Bharatula RS, Prasad R, Ahuja YR, Hasan Q. Dna Methylation in Esophageal Diseases Including Cancer: Special Reference to hMLH1 Gene Promoter Status. TUMORI JOURNAL 2019; 92:155-62. [PMID: 16724696 DOI: 10.1177/030089160609200212] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Aims and Background Chronic inflammation leading to malignancy in the esophagus may be due to errors in mismatch repair (MMR) genes such as hMLH1. Promoter hypermethylation has been suggested as the main cause of hMLH1 silencing. In this study we assessed hMLH1 promoter hypermethylation in a range of esophageal diseases. Further, we evaluated the role of factors affecting the methylation cycle: (1) methyt-enetetrahydrofolate reductase (MTHFR) C677T mutation and (2) serum homocysteine levels. Methods We endoscopically and histologically categorized 124 paired tissue and blood samples from patients into cancer, precancer, reflux esophagitis, other inflammatory esophagitis and controls (endoscopically normal). Restriction enzyme-based methylation analysis was carried out to assess hMLH1 promoter hypermethylation. Results and Conclusions hMLH1 promoter hypermethylation in tissue was seen in 63.5% of patients with cancer and 53.8% of those with precancer, which was significantly increased when compared with controls (P <0.001). There appears to be an increasing degree of hMLH1 hypermethylation with disease progression. Patients with gastroesophageal reflux disease (GERD) showed a high degree of hMLH1 hypermethylation (88.8%), indicating that local environment due to reflux may be promoting hypermethylation. We suggest that GERD is a progressive condition with an increased risk for developing into cancer. Only 14.5% of cases exhibited hypermethylation both in tissue and blood. Hence, we conclude that hMLH1 promoter hypermethylation is a tissue-specific change in the esophagus and blood testing cannot be used as a noninvasive tool to assess it. DNA methylation is dependent on the methylation cycle; MTHFR is a major enzyme in this pathway. MTHFR mutations did not correlate with hypermethylation or clinical pathology (P >0.5). Elevated homocysteine levels, independent of MTHFR mutation, correlated significantly with hMLH1 hypermethylation in tissue (P <0.005). Our study shows that hMLH1 hypermethylation in tissue may be the primary event caused by endogenous/exogenous factors in esophageal diseases, aiding disease progression.
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Affiliation(s)
- Mohan Vasavi
- Department of Genetics and Molecular Medicine, Gastroenterology and Biochemistry, Kamineni Hospitals, Hyderabad, India
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Lu X, Yu Y, Tan S. p53 expression in patients with ulcerative colitis - associated with dysplasia and carcinoma: a systematic meta-analysis. BMC Gastroenterol 2017; 17:111. [PMID: 29070013 PMCID: PMC5655860 DOI: 10.1186/s12876-017-0665-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 10/03/2017] [Indexed: 02/08/2023] Open
Abstract
Background Tumor suppressor gene p53 expression has been reported in patients with ulcerative colitis (UC). However, the correlation between p53 expression and UC remains controversial. The aim of this meta-analysis was to investigate the association between p53 expression and different pathological types of UC. Methods Publications were searched in the PubMed, Embase, EBSCO, Wangfang, and CNKI databases. The overall odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were summarized in this study. Results Final 19 papers were identified in this meta-analysis, including 1068 patients with UC and 130 normal tissue samples. Immunohistochemical p53 expression was significantly higher in UC without dysplasia and carcinoma (UC group) compared to normal tissue samples (OR = 3.14, P = 0.001), higher in UC with dysplasia than in UC group (OR = 10.76, P < 0.001), and higher in UC with colorectal cancer (CRC) than in UC with dysplasia (OR = 1.69, P = 0.035). Subgroup analysis of ethnicity (UC group vs. normal tissues) showed that p53 expression was correlated with UC in Asians, but not in Caucasians. When UC with dysplasia was compared to UC group, p53 expression was linked to UC with dysplasia among both Asians and Caucasians. When UC-CRC was compared to UC with dysplasia, p53 expression was not associated with UC-CRC in both Caucasians and Asians. Conclusions p53 expression was closely associated with UC-CRC development. p53 expression showed different ethnic characteristics among different pathological types of UC. Electronic supplementary material The online version of this article (10.1186/s12876-017-0665-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaohong Lu
- Departmemt of gastroenterology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China.
| | - Yuanjie Yu
- Departmemt of gastroenterology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
| | - Shiyun Tan
- Departmemt of gastroenterology, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
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7
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Namani A, Li J, Wang XJ, Tang X. A Review of Compounds for Prevention of Colorectal Cancer. ACTA ACUST UNITED AC 2017. [DOI: 10.1007/s40495-017-0101-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Khalili H, Gong J, Brenner H, Austin TR, Hutter CM, Baba Y, Baron JA, Berndt SI, Bézieau S, Caan B, Campbell PT, Chang-Claude J, Chanock SJ, Chen C, Hsu L, Jiao S, Conti DV, Duggan D, Fuchs CS, Gala M, Gallinger S, Haile RW, Harrison TA, Hayes R, Hazra A, Henderson B, Haiman C, Hoffmeister M, Hopper JL, Jenkins MA, Kolonel LN, Küry S, LaCroix A, Marchand LL, Lemire M, Lindor NM, Ma J, Manson JE, Morikawa T, Nan H, Ng K, Newcomb PA, Nishihara R, Potter JD, Qu C, Schoen RE, Schumacher FR, Seminara D, Taverna D, Thibodeau S, Wactawski-Wende J, White E, Wu K, Zanke BW, Casey G, Hudson TJ, Kraft P, Peters U, Slattery ML, Ogino S, Chan AT. Identification of a common variant with potential pleiotropic effect on risk of inflammatory bowel disease and colorectal cancer. Carcinogenesis 2015; 36:999-1007. [PMID: 26071399 DOI: 10.1093/carcin/bgv086] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Accepted: 06/06/2015] [Indexed: 12/12/2022] Open
Abstract
Although genome-wide association studies (GWAS) have separately identified many genetic susceptibility loci for ulcerative colitis (UC), Crohn's disease (CD) and colorectal cancer (CRC), there has been no large-scale examination for pleiotropy, or shared genetic susceptibility, for these conditions. We used logistic regression modeling to examine the associations of 181 UC and CD susceptibility variants previously identified by GWAS with risk of CRC using data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We also examined associations of significant variants with clinical and molecular characteristics in a subset of the studies. Among 11794 CRC cases and 14190 controls, rs11676348, the susceptibility single nucleotide polymorphism (SNP) for UC, was significantly associated with reduced risk of CRC (P = 7E-05). The multivariate-adjusted odds ratio of CRC with each copy of the T allele was 0.93 (95% CI 0.89-0.96). The association of the SNP with risk of CRC differed according to mucinous histological features (P heterogeneity = 0.008). In addition, the (T) allele was associated with lower risk of tumors with Crohn's-like reaction but not tumors without such immune infiltrate (P heterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (P heterogeneity = 0.03). The minor allele (T) in SNP rs11676348, located downstream from CXCR2 that has been implicated in CRC progression, is associated with a lower risk of CRC, particularly tumors with a mucinous component, Crohn's-like reaction and MSI-high. Our findings offer the promise of risk stratification of inflammatory bowel disease patients for complications such as CRC.
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Affiliation(s)
- Hamed Khalili
- Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Jian Gong
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany, German Cancer Cosortium (DKTK), Heidelberg, Germany
| | | | - Carolyn M Hutter
- Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA
| | - Yoshifumi Baba
- Department of Gastroenterological Surgery, Kumamoto University, Kumamoto, Japan
| | - John A Baron
- Department of Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | | | - Bette Caan
- Division of Hematology, Faculty of Medicine, The University of Ottawa, Ottawa, ON, Canada
| | - Peter T Campbell
- Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Stephen J Chanock
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Constance Chen
- Program in Molecular and Genetic Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Shuo Jiao
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - David V Conti
- Keck School of Medicine, University of Southern California, Los Angles, CA, USA
| | - David Duggan
- Systems Imagination, Computational Biology, Pheonix, AZ, USA
| | - Charles S Fuchs
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, Department of Epidemiology, Indiana University School of Public Health, Indianapolis, IN, USA
| | - Manish Gala
- Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA
| | - Steven Gallinger
- Department of Surgery, University Health Network Toronto General Hospital, Toronto, ON, Canada
| | | | - Tabitha A Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Richard Hayes
- Division of Epidemiology, New York University School of Medicine, New York, NY, USA
| | - Aditi Hazra
- Department of Epidemiology, Indiana University School of Public Health, Indianapolis, IN, USA
| | - Brian Henderson
- Keck School of Medicine, University of Southern California, Los Angles, CA, USA
| | - Chris Haiman
- Keck School of Medicine, University of Southern California, Los Angles, CA, USA
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany
| | - John L Hopper
- Melbourne School of Population Health, The University of Melbourne, Melbourne, Australia
| | - Mark A Jenkins
- Division of Epidemiology, New York University School of Medicine, New York, NY, USA
| | - Laurence N Kolonel
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Sébastien Küry
- CHU Nantes, Service de Génétique Médicale, Nantes, France
| | - Andrea LaCroix
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Loic Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Mathieu Lemire
- Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Noralane M Lindor
- Department of Health Science Services, Mayo Clinic, Scottsdale, AZ, USA
| | - Jing Ma
- Department of Epidemiology, Indiana University School of Public Health, Indianapolis, IN, USA
| | - JoAnn E Manson
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Teppei Morikawa
- Department of Pathology, The University of Tokyo Hospital, Tokyo, Japan
| | - Hongmei Nan
- Department of Epidemiology, Indiana University School of Public Health, Indianapolis, IN, USA
| | - Kimmie Ng
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Reiko Nishihara
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
| | - John D Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA, Department of Epidemiology, University of Washington, Seattle, WA, USA, Center for Public Health Research, Massey University, Wellington, New Zealand
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Robert E Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | | | - Daniela Seminara
- Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA
| | - Darin Taverna
- Systems Imagination, Computational Biology, Pheonix, AZ, USA
| | - Stephen Thibodeau
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Jean Wactawski-Wende
- Department of Social and Preventive Medicine, University of Buffalo, Buffalo, NY, USA
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Kana Wu
- Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
| | - Brent W Zanke
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, USA
| | - Graham Casey
- Keck School of Medicine, University of Southern California, Los Angles, CA, USA
| | - Thomas J Hudson
- Ontario Institute for Cancer Research, Toronto, ON, Canada, Department of Medical Biophysics, University of Toronto, Toronto, ON, USA
| | - Peter Kraft
- Program in Molecular and Genetic Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA, Department of Epidemiology, Indiana University School of Public Health, Indianapolis, IN, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA
| | - Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA, Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Andrew T Chan
- Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA, Department of Epidemiology, Indiana University School of Public Health, Indianapolis, IN, USA,
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Song M, Nishihara R, Wu K, Qian ZR, Kim SA, Sukawa Y, Mima K, Inamura K, Masuda A, Yang J, Fuchs CS, Giovannucci EL, Ogino S, Chan AT. Marine ω-3 polyunsaturated fatty acids and risk of colorectal cancer according to microsatellite instability. J Natl Cancer Inst 2015; 107:djv007. [PMID: 25810492 DOI: 10.1093/jnci/djv007] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Chronic inflammation is involved in the development of colorectal cancer (CRC) and microsatellite instability (MSI), a distinct phenotype of CRC. Experimental evidence indicates an anti-inflammatory and antineoplastic effect of marine ω-3 polyunsaturated fatty acids (PUFAs). However, epidemiologic data remain inconclusive. METHODS We investigated whether the association between marine ω-3 PUFAs and CRC varies by MSI-defined subtypes of tumors in the Nurses' Health Study and Health Professionals Follow-up Study. We documented and classified 1125 CRC cases into either MSI-high tumors, in which 30% or more of the 10 microsatellite markers demonstrated instability, or microsatellite-stable (MSS) tumors. Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of MSS tumors and MSI-high tumors in relation to marine ω-3 PUFA intake. All statistical tests were two-sided. RESULTS Marine ω-3 PUFA intake was not associated with overall incidence of CRC. However, a statistically significant difference was detected by MSI status (P heterogeneity = .02): High marine ω-3 PUFA intake was associated with a lower risk of MSI-high tumors (comparing ≥0.30g/d with <0.10g/d: multivariable HR = 0.54, 95% CI = 0.35 to 0.83, P linearity = .03) but not MSS tumors (HR = 0.97, 95% CI = 0.78 to 1.20, P linearity = .28). This differential association appeared to be independent of CpG island methylator phenotype and BRAF mutation status. CONCLUSIONS High marine ω-3 PUFA intake is associated with lower risk of MSI-high CRC but not MSS tumors, suggesting a potential role of ω-3 PUFAs in protection against CRC through DNA mismatch repair. Further research is needed to confirm our findings and elucidate potential underlying mechanisms.
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Affiliation(s)
- Mingyang Song
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Reiko Nishihara
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Kana Wu
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Zhi Rong Qian
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Sun A Kim
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Yasutaka Sukawa
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Kosuke Mima
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Kentaro Inamura
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Atsuhiro Masuda
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Juhong Yang
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Charles S Fuchs
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Edward L Giovannucci
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Shuji Ogino
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
| | - Andrew T Chan
- Department of Nutrition (MS, RN, KW, ELG) and Department of Epidemiology (MS, ELG, SO), Harvard School of Public Health, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (RN, ZRQ, SAK, YS, KM, AM, JY, CSF, SO); Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD (KI); Channing Division of Network Medicine, Department of Medicine (CSF, ELG, SO, ATC) and Department of Pathology (SO), Harvard Medical School, Brigham and Women's Hospital, Boston, MA; Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA (ATC)
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Kuehn F, Klar E, Bliemeister A, Linnebacher M. Reactivity against microsatellite instability-induced frameshift mutations in patients with inflammatory bowel disease. World J Gastroenterol 2015; 21:221-228. [PMID: 25574094 PMCID: PMC4284338 DOI: 10.3748/wjg.v21.i1.221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Revised: 07/20/2014] [Accepted: 08/13/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To analyze the cellular immune response towards microsatellite-instability (MSI)-induced frameshift-peptides (FSPs) in patients suffering from inflammatory bowel disease (IBD) with and without thiopurine-based immunosuppressive treatment. METHODS Frequencies of peripheral blood T cell responses of IBD patients (n = 75) against FSPs derived from 14 microsatellite-containing candidate genes were quantified by interferon-γ enzyme-linked immunospot. T cells derived from 20 healthy individuals served as controls. RESULTS Significant T cell reactivities against MSI-induced FSPs were observed in 59 of 75 IBD patients (78.7%). This was significantly more as we could observe in 20 healthy controls (P = 0.001). Overall, the reactivity was significantly influenced by thiopurine treatment (P = 0.032) and duration of disease (P = 0.002) but not by duration or cumulative amount of thiopurine therapy (P = 0.476). Unexpected, 15 of 24 (62.5%) IBD patients without prior thiopurine treatment also showed increased FSP-specific immune responses (P = 0.001). CONCLUSION These findings propose FSPs as potential novel class of inflammation-associated antigens and this in turn may have implications for screening, diagnosis as well as clinical management of patients suffering from IBD and other inflammatory conditions.
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Abstract
PURPOSE OF REVIEW Human colitis-associated cancers (CAC) represent a heterogeneous group of conditions in which multiple oncogenic pathways are involved. In this article, we review the latest studies using genetic, chemical, bacterial and innate immune-mediated experimental models of CAC. RECENT FINDINGS Using the azoxymethane-dextran sodium sulfate model, wound healing pathways seem to be required in the development of CAC. There is also an emerging understanding that commensal and/or pathogenic bacteria can promote tumorigenesis, through T cell and TLR-mediated inflammation. Using specific transgenic mice (villin-CD98, T cell SMAD7, villin-TLR4) or specific knockout mice, investigators have determined that derangements in epithelial or innate and adaptive immune pathways can result in CAC. Subtle perturbations in epithelial repair - both too little or too exuberant - can render mice susceptible to tumorigenesis. SUMMARY With the aid of animal models, we have witnessed a rapid expansion of our knowledge of the molecular and immunologic mechanisms underlying inflammatory cancers. Though animal models have contributed a discrete amount of information to our understanding of tumorigenesis in the setting of intestinal inflammation, it is clear that no single animal model will be able to adequately recapitulate the pathogenesis of complex colorectal cancers, but each model gets us one step closer to comprehending the nature of CAC.
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12
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Samadder NJ, Mukherjee B, Huang SC, Ahn J, Rennert HS, Greenson JK, Rennert G, Gruber SB. Risk of colorectal cancer in self-reported inflammatory bowel disease and modification of risk by statin and NSAID use. Cancer 2011; 117:1640-8. [PMID: 21472711 PMCID: PMC3117060 DOI: 10.1002/cncr.25731] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2010] [Revised: 09/12/2010] [Accepted: 09/21/2010] [Indexed: 12/15/2022]
Abstract
BACKGROUND Statins and nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with reduced risk of colorectal cancer (CRC) in some studies. The objective of this study was to quantify the relative risk of inflammatory bowel disease (IBD) as a risk factor for CRC and to estimate whether this risk may be modified by long-term use of NSAIDs or statins. METHODS The Molecular Epidemiology of Colorectal Cancer study is a population-based, case-control study of incident colorectal cancer in northern Israel and controls matched by age, sex, clinic, and ethnicity. Personal histories of IBD and medication use were measured by structured, in-person interview. The relative risk of IBD and effect modification by statins and NSAIDs were quantified by conditional and unconditional logistic regression. RESULTS Among 1921 matched pairs of CRC cases and controls, a self-reported history of IBD was associated with a 1.9-fold increased risk of CRC (95% confidence interval [CI], 1.12-3.26). Long-term statin use was associated with a reduced risk of both IBD-associated CRC (odds ratio [OR] = 0.07; 95% CI, 0.01-0.78) and non-IBD CRC (OR = 0.49; 95% CI, 0.39-0.62). Stratified analysis suggested that statins may be more protective among those with IBD (ratio of OR = 0.14; 95% CI, 0.01-1.31; P = .51), although not statistically significant. NSAID use in patients with a history of IBD was suggestive of reduced risk of CRC but did not reach statistical significance (OR = 0.47; 95% CI, 0.12-1.86). CONCLUSIONS The risk of CRC was elevated 1.9-fold in patients with IBD. Long-term statin use was associated with reduced risk of CRC in patients with IBD.
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Affiliation(s)
- N Jewel Samadder
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48105, USA.
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Harpaz N, Polydorides AD. Colorectal dysplasia in chronic inflammatory bowel disease: pathology, clinical implications, and pathogenesis. Arch Pathol Lab Med 2010; 134:876-95. [PMID: 20524866 DOI: 10.5858/134.6.876] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
CONTEXT Colorectal cancer, the most lethal long-term complication of chronic inflammatory bowel disease (IBD), is the culmination of a complex sequence of molecular and histologic derangements of the intestinal epithelium that are initiated and at least partially sustained by chronic inflammation. Dysplasia, the earliest histologic manifestation of this process, plays an important role in cancer prevention by providing the first clinical alert that this sequence is underway and serving as an endpoint in colonoscopic surveillance of patients at high risk for colorectal cancer. OBJECTIVE To review the histology, nomenclature, clinical implications, and molecular pathogenesis of dysplasia in IBD. DATA SOURCE Literature review and illustrations from case material. CONCLUSIONS The diagnosis and grading of dysplasia in endoscopic surveillance biopsies play a decisive role in the management of patients with IBD. Although interpathologist variation, endoscopic sampling problems, and incomplete information regarding the natural history of dysplastic lesions are important limiting factors, indirect evidence that surveillance may be an effective means of reducing cancer-related mortality in the population with IBD has helped validate the histologic criteria, nomenclature, and clinical recommendations that are the basis of current practice among pathologists and clinicians. Emerging technologic advances in endoscopy may permit more effective surveillance, but ultimately the greatest promise for cancer prevention in IBD lies in expanding our thus far limited understanding of the molecular pathogenetic relationships between neoplasia and chronic inflammation.
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Affiliation(s)
- Noam Harpaz
- Department of Pathology, The Mount Sinai School of Medicine, New York, New York 10092, USA.
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Diosdado B, Buffart TE, Watkins R, Carvalho B, Ylstra B, Tijssen M, Bolijn AS, Lewis F, Maude K, Verbeke C, Nagtegaal ID, Grabsch H, Mulder CJJ, Quirke P, Howdle P, Meijer GA. High-resolution array comparative genomic hybridization in sporadic and celiac disease-related small bowel adenocarcinomas. Clin Cancer Res 2010; 16:1391-401. [PMID: 20179237 DOI: 10.1158/1078-0432.ccr-09-1773] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PURPOSE The molecular pathogenesis of small intestinal adenocarcinomas is not well understood. Understanding the molecular characteristics of small bowel adenocarcinoma may lead to more effective patient treatment. EXPERIMENTAL DESIGN Forty-eight small bowel adenocarcinomas (33 non-celiac disease related and 15 celiac disease related) were characterized for chromosomal aberrations by high-resolution array comparative hybridization, microsatellite instability, and APC promoter methylation and mutation status. Findings were compared with clinicopathologic and survival data. Furthermore, molecular alterations were compared between celiac disease-related and non-celiac disease-related small bowel adenocarcinomas. RESULTS DNA copy number changes were observed in 77% small bowel adenocarcinomas. The most frequent DNA copy number changes found were gains on 5p15.33-5p12, 7p22.3-7q11.21, 7q21.2-7q21.3, 7q22.1-7q34, 7q36.1, 7q36.3, 8q11.21-8q24.3, 9q34.11-9q34.3, 13q11-13q34, 16p13.3, 16p11.2, 19q13.2, and 20p13-20q13.33, and losses on 4p13-4q35.2, 5q15-5q21.1, and 21p11.2-21q22.11. Seven highly amplified regions were identified on 6p21.1, 7q21.1, 8p23.1, 11p13, 16p11.2, 17q12-q21.1, and 19q13.2. Celiac disease-related and non-celiac disease-related small bowel adenocarcinomas displayed similar chromosomal aberrations. Promoter hypermethylation of the APC gene was found in 48% non-celiac disease-related and 73% celiac disease-related small bowel adenocarcinomas. No nonsense mutations were found. Thirty-three percent of non-celiac disease-related small bowel adenocarcinomas showed microsatellite instability, whereas 67% of celiac disease-related small bowel adenocarcinomas were microsatellite unstable. CONCLUSIONS Our study characterized chromosomal aberrations and amplifications involved in small bowel adenocarcinoma. At the chromosomal level, celiac disease-related and non-celiac disease-related small bowel adenocarcinomas did not differ. A defect in the mismatch repair pathways seems to be more common in celiac disease-related than in non-celiac disease-related small bowel adenocarcinomas. In contrast to colon and gastric cancers, no APC nonsense mutations were found in small bowel adenocarcinoma. However, APC promoter methylation seems to be a common event in celiac disease-related small bowel adenocarcinoma. Clin Cancer Res; 16(5); 1391-401.
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Affiliation(s)
- Begoña Diosdado
- Departments of Pathology and Gastroenterology, VU University Medical Center, Amsterdam, The Netherlands.
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Alloreactive microenvironment after human hematopoietic cell transplantation induces genomic alterations in epithelium through an ROS-mediated mechanism: in vivo and in vitro study and implications to secondary neoplasia. Leukemia 2010; 24:536-43. [DOI: 10.1038/leu.2009.284] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Priya TP, Kapoor VK, Krishnani N, Agrawal V, Agarwal S. Fragile histidine triad (FHIT) gene and its association with p53 protein expression in the progression of gall bladder cancer. Cancer Invest 2009; 27:764-73. [PMID: 19452299 DOI: 10.1080/07357900802711304] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Present study deals with LOH and MSI in FHIT gene and p53 expression in GBC, CC, XGC, and normal GB to elucidate the role of FHIT gene in gall bladder cancer. METHODS Five microsatellite markers D3S1217, D3S1300, D3S1313, D3S1600, and D3S2757, were selected. RESULTS Among GBC cases the frequency of MSI-H and LOH was 17.5% and 27.5%, respectively. Significant difference was found between GBC and normal GB (p = .02), and GBC and CC groups (p= .002) when LOH was compared. CONCLUSIONS Our results suggested CC might act as a preinvasive stage in the pathogenesis of GBC.
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Affiliation(s)
- T Padma Priya
- Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, UP, India
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Vietri MT, Riegler G, De Paola M, Simeone S, Boggia M, Improta A, Parisi M, Molinari AM, Cioffi M. I219V polymorphism in hMLH1 gene in patients affected with ulcerative colitis. Genet Test Mol Biomarkers 2009; 13:193-7. [PMID: 19371218 DOI: 10.1089/gtmb.2008.0088] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
INTRODUCTION hMLH1 gene, lying on chromosome 3p21-23, is a key factor of the mismatch repair (MMR) complex, which amends DNA replication errors. MMR alterations are involved in the development of both hereditary and sporadic forms of colorectal carcinoma related to ulcerative colitis (UC). I219V Polymorphism is located on exon 8 of hMLH1 and provides an aminoacidic substitution of isoleucine to valine, on the protein codon 219. This may affect the speed and fidelity of protein synthesis because of a tRNA paucity or changes in the mRNA secondary structure. Most of the hereditary nonpolyposis colon cancer-associated missense mutations of hMLH1 cause structural changes of the amino- or carboxy-terminal regions, involving the domains that interact with ATP and hPMS2. AIMS AND METHODS In this study, we analyzed the hMLH1 I219V polymorphism frequency in colectomized patients with UC. Venous blood from 100 ulcerative patients and 97 apparently healthy subjects has been collected. Out of 100 patients affected with UC, 75 noncolectomized showed an alternating course of disease, while 25 did not respond to the common drugs, and underwent colectomy. Genotyping was performed by polymerase chain reaction and following enzymatic digestion by BccI. RESULTS No significant differences were found between patients with UC and controls both for genotype and allele frequencies. However, our data show a significant association when colectomized and noncolectomized patients are compared. The frequencies of G homozygosity were 28% in colectomized and 10.7% in noncolectomized patients (p < 0.05, chi(2) = 4.4, Odds ratio = 3.3). The allele frequencies of allele A were 52% in colectomized and 68% in noncolectomized patients; while those of allele G were 48% and 32%, respectively. CONCLUSIONS I219V polymorphism in hMLH1 could influence the clinical course of the disease and lead to resistance to therapy.
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Affiliation(s)
- Maria Teresa Vietri
- Dipartimento di Patologia generale, Cattedra di Patologia clinica, Seconda Università degli studi Napoli, Naples, Italy
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Fujiwara I, Yashiro M, Kubo N, Maeda K, Hirakawa K. Ulcerative colitis-associated colorectal cancer is frequently associated with the microsatellite instability pathway. Dis Colon Rectum 2008; 51:1387-94. [PMID: 18546042 DOI: 10.1007/s10350-008-9212-9] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2007] [Revised: 10/19/2007] [Accepted: 10/28/2007] [Indexed: 02/06/2023]
Abstract
PURPOSE Patients with ulcerative colitis have a high risk for the development of colorectal cancer. To understand the molecular mechanisms of the carcinogenesis process of ulcerative colitis-associated colorectal cancer, the genetic alterations in inflamed or neoplastic colon epithelium in ulcerative colitis were analyzed. METHODS Fifty-seven patients with ulcerative colitis were enrolled in this study. Specimens were obtained from the patients randomly at six colonic sites. Each patient was histologically classified according to the worst pathologic finding into cancer, dysplasia, indefinite, and normal cases. Microsatellite instability, mutations of target genes, hypermethylation of the hMLH1 promoter region, and mismatch repair protein expression were analyzed. RESULTS High-microsatellite instability was found in 4 of 11 cancer cases (36 percent), 5 of 15 dysplasia cases (33 percent), 5 of 11 indefinite cases (45 percent), and none of 20 normal cases (0 percent). A significant correlation was found between the malignant potential and high-microsatellite instability. A frameshift mutation of transforming growth factor beta receptor Type II (TGFbetaRII) was significantly correlated with worsening histologic grade. High-microsatellite instability was significantly associated with hMLH1 hypermethylation and loss of hMSH2 expression. CONCLUSION The carcinogenesis process in ulcerative colitis-associated colorectal cancer was closely associated with the microsatellite instability pathway through TGFbetaRII mutation by a dysfunction of the mismatch repair system.
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Affiliation(s)
- Ichiro Fujiwara
- Department of Surgical Oncology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan
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Edwards RA, Wang K, Davis JS, Birnbaumer L. Role for epithelial dysregulation in early-onset colitis-associated colon cancer in Gi2-alpha-/- mice. Inflamm Bowel Dis 2008; 14:898-907. [PMID: 18340649 PMCID: PMC2729494 DOI: 10.1002/ibd.20414] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a risk factor for developing colorectal cancer but the mechanisms are poorly characterized. Mice lacking the G-protein alpha subunit Gi2-alpha spontaneously develop colitis and colon cancer with high penetrance. Compared to canonical Wnt/APC signaling-based animal models of colon cancer, the tumors in Gi2-alpha-/- mice more closely recapitulate the features of IBD-associated cancers seen in humans. They are predominantly right-sided, multifocal, mucinous, and arise from areas of flat dysplasia. METHODS In evaluating the potential contribution of epithelial Gi2-alpha signaling to this phenotype, we found that Gi2-alpha-/- colonic epithelium is hyperproliferative even before the onset of colitis, and resistant to the induction of apoptosis. We generated colon cancer cell lines overexpressing dominant-negative Gi2-alpha. RESULTS Like other cells lacking Gi2-alpha, these cells release less arachidonic acid, an important antiinflammatory and epithelial growth regulator. They are also hyperproliferative and resistant to camptothecin-induced apoptosis and caspase-3 activation. CONCLUSIONS The colitis-associated cancers in Gi2-alpha-/- mice appear very similar to those seen in human IBD patients, and Gi2-alpha is a direct negative regulator of colonic epithelial cell growth.
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Affiliation(s)
- Robert A Edwards
- Department of Pathology, University of California, Irvine, Irvine, California 92697-4800, USA.
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Moriyama T, Matsumoto T, Nakamura S, Jo Y, Mibu R, Yao T, Iida M. Hypermethylation of p14 (ARF) may be predictive of colitic cancer in patients with ulcerative colitis. Dis Colon Rectum 2007; 50:1384-92. [PMID: 17665255 DOI: 10.1007/10350-007-0302-x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE The microsatellite instability and CpG island hypermethylation of p14 ( ARF ) and p16 ( INK4a ) are related to the pathogenesis of neoplasia in ulcerative colitis. This study was designed to assess the significance of those genetic or epigenetic alterations for cancer surveillance in ulcerative colitis. METHODS During surveillance colonoscopy in 39 patients with ulcerative colitis, biopsy specimens were obtained from the cecum and the rectum as well as from any other areas suspected of being neoplasia by chromoscopy. Using DNA extracts, the methylation status of p14 ( ARF ) and p16 ( INK4a ) and the microsatellite status were determined. RESULTS Microsatellite instability was positive in one of five dysplasias, but it was negative in the cecum and the rectum. The incidence of hypermethylation of p14 ( ARF ) was 0 percent in the cecum, 26 percent in the rectum, and 100 percent in dysplasia, whereas that of p16 ( INK4a ) was 10, 10, and 0 percent, respectively. Patients who were positive for the hypermethylation of p14 ( ARF )in the rectum had a longer duration of ulcerative colitis than those who were negative for such hypermethylation. Two of 10 patients who were positive for p14 ( ARF ) hypermethylation in the rectum and 1 of 29 patients who were negative for the hypermethylation had dysplasia. During the subsequent surveillance of 36 patients, dysplasia was detected in 2 of 8 patients with p14 ( ARF ) hypermethylation and in none of 28 patients without hypermethylation (P = 0.044). CONCLUSIONS In patients with ulcerative colitis, hypermethylation of p14 ( ARF ) seems to be associated with an early stage of dysplasia. The hypermethylation may be one of candidates for potential biomarker to identify patients at a high risk of dysplasia.
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Affiliation(s)
- Tomohiko Moriyama
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka, Japan.
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Løvig T, Andersen SN, Clausen OP, Rognum TO. Microsatellite instability in long-standing ulcerative colitis. Scand J Gastroenterol 2007; 42:586-91. [PMID: 17454879 DOI: 10.1080/00365520601013747] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Ulcerative colitis (UC) is a chronic inflammatory disease of the colon associated with a high risk of developing colorectal cancer. Several genetic alterations have been documented in dysplasia and cancer developing in UC. Concerning microsatellite instability (MSI), many contradictory results have been published. We therefore analysed a large, well-characterized UC material for MSI to elucidate its significance in long-standing UC. MATERIAL AND METHODS From 33 patients, a total of 159 microdissected lesions and 165 mucosa samples obtained adjacent to the tissue blocks were analysed for MSI using the five standard markers recommended by the National Cancer Institute; D2S123, D5S346, D17S250, BAT-25 and BAT-26. In addition, 12 of the patients were investigated by a mini-satellite marker at the D1S7 locus. RESULTS High-level MSI (MSI-H) was detected in one villous adenoma with high-grade dysplasia and right-sided location. This represents 3.6% (1/28) of dysplastic mucosa investigated. No other lesions showed MSI in the five standard markers or at the D1S7 locus. CONCLUSIONS This study suggests that MSI is rare in UC-related neoplasia as well as non-neoplastic lesions, and does not contribute to the development of dysplasia.
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Affiliation(s)
- Tone Løvig
- Institute of Forensic Medicine, Department of Pathology, Akershus University Hospital HF, Lørenskog, Norway.
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22
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Taniguchi K, Kakinuma S, Tokairin Y, Arai M, Kohno H, Wakabayashi K, Imaoka T, Ito E, Koike M, Uetake H, Nishimura M, Yamauchi K, Sugihara KI, Shimada Y. Mild inflammation accelerates colon carcinogenesis in Mlh1-deficient mice. Oncology 2007; 71:124-30. [PMID: 17347588 DOI: 10.1159/000100522] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2006] [Accepted: 11/19/2006] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Inflammatory bowel disease, which frequently accompanies silencing of Mlh1, plays a key role in the pathogenesis of colorectal cancer. The interaction between inflammation and mismatch repair deficiency, however, remains unclear. The aim of this study was to determine the effect of inflammation on colorectal carcinogenesis in Mlh1-deficient mice. METHOD Inflammatory colitis was induced by treatment with 1% dextran sodium sulfate (DSS) in drinking water for 1 week in Mlh1 knockout (Mlh1(-/-)), Mlh1 heterozygous (Mlh1(+/-)) and wild-type (Mlh1(+/+)) mice at 10 weeks of age. The development of colon tumors was followed for a subsequent 15 weeks and the tumors were analyzed immunohistochemically for the expression and localization of iNOS, beta-catenin and p53. RESULTS Male and female Mlh1(-/-) mice with DSS showed a 63 and 44% incidence of tumors, respectively, whereas no tumors were observed in Mlh1(+/-) and Mlh1(+/+) mice. The mice without DSS treatment did not develop any tumors regardless of the genotype. While aberrant expression of beta-catenin was not detected in colonic neoplasms, p53 and iNOS expression was increased in 100 and 77%, respectively. These immunohistochemical changes were consistent with those of human colon cancers associated with ulcerative colitis. CONCLUSION Our results indicate that Mlh1 deficiency strongly accelerates colon carcinogenesis when combined with inflammation. Thus the cells with Mlh1 deficiency, either inherently or colitis associated, may be at an increased risk of cancer under inflammatory conditions.
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Affiliation(s)
- Kazuki Taniguchi
- Surgical Oncology, Tokyo Medical and Dental University, Tokyo, Japan
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23
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Ozaki K, Nagasaka T, Notohara K, Kambara T, Takeda M, Sasamoto H, Jass JR, Tanaka N, Matsubara N. Heterogeneous microsatellite instability observed within epithelium of ulcerative colitis. Int J Cancer 2006; 119:2513-9. [PMID: 16929496 DOI: 10.1002/ijc.22095] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Microsatellite instability (MSI) has been associated with colitic cancer. However, reported frequency of MSI was varied and the association of MSI with mismatch repair (MMR) deficiency was unclear. In addition, the occurrence of genetic alterations in stromal cells within ulcerative colitis (UC) is still controversial. We therefore sampled 164 microareas in various pathological lesions of UC with or without colitic cancer and studied the MSI status in relation to the DNA repair protein expressions. A total of 129 microfoci from colorectal tissue of 5 colitic cancer patients and 35 microfoci of 7 UC patients (without neoplasm) were carefully sampled by laser-capture microdissection. MSI was analyzed in each microsamples. The protein expression of MMR genes (MLH1, MSH2, MSH6), O(6)-methylguanine-DNA methyltransferase and p53 were assessed by immunohistochemical analysis. Variety of di-nulcleotide microsatellite markers was altered in individual microfoci from different morphological epithelial lesions, in full range of nonneoplastic epithelium to colitic cancer. Interestingly, MSI was not observed in stromal cells at any sites, including those within colitic cancer/dysplasia lesions. Expression of the MMR proteins was not lost in any of the lesions examined. Microsatellite alterations rather seem to be related to the initiation than to the progression of colitic cancer.
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Affiliation(s)
- Kazuhide Ozaki
- Department of Gastroenterological Surgery and Surgical Oncology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
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24
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Xu CM, Qiao CH. Loss of fragile histidine triad protein expression in inflammatory bowel disease. World J Gastroenterol 2006; 12:7355-60. [PMID: 17143956 PMCID: PMC4087498 DOI: 10.3748/wjg.v12.i45.7355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression of fragile histidine triad (FHIT) protein in 64 patients with ulcerative colitis (UC) and Crohn’s disease (CD), and its relation with clinicopathological data.
METHODS: Rabbit-anti-FHIT antibody was used to detect FHIT protein expression in 64 formalin-fixed, paraffin-embedded tissue specimens of inflammatory bowel disease (IBD) by citrate-microwave-streptavidin (SP)-HRP immunohistochemical method.
RESULTS: The positive FHIT protein expression was 22.79% ± 16.16%, 42.14% ± 16.82% in active and remittent phases of UC, 36.07% ± 19.23% in CD, and 57.05% ± 8.86% in normal colon mucosa. Statistically significant differences in FHIT protein expression were observed between the active and remittent phases of UC, between the active phase of UC and normal colon mucosa, as well as between the remittent phase of UC and normal colon mucosa, and between CD and normal colon mucosa.
CONCLUSION: Our results show that FHIT protein expression is completely absent or reduced in IBD, suggesting that the FHIT gene might be associated with the oncogenesis and progression of IBD, an early event from inflammatory conditions to carcinoma in IBD.
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Affiliation(s)
- Chun-Mei Xu
- Department of Gastroenterology, Xiangfan No.1 Hospital, 75 Jiefang Road, Xiangfan 441000, Hubei Province, China.
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25
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van Dieren JM, Wink JC, Vissers KJ, van Marion R, Hoogmans MMCP, Dinjens WNM, Schouten WR, Tanke HJ, Szuhai K, Kuipers EJ, van der Woude CJ, van Dekken H. Chromosomal and Microsatellite Instability of Adenocarcinomas and Dysplastic Lesions (DALM) in Ulcerative Colitis. ACTA ACUST UNITED AC 2006; 15:216-22. [PMID: 17122649 DOI: 10.1097/01.pdm.0000213470.92925.18] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Longstanding ulcerative colitis (UC) is associated with a high risk of developing UC-related colonic adenocarcinoma (UCC). These carcinomas originate from nonadenomatous dysplastic regions referred to as dysplasia associated lesion or mass (DALM). We evaluated chromosomal and microsatellite instability (MSI) in 21 DALM/UCCs. Chromosomal instability was determined by high-resolution array comparative genomic hybridization with a 3500-element BAC-PAC array. MSI was assessed with markers BAT25 and BAT26 and by immunohistochemical analysis of mismatch repair genes. Comparative genomic hybridization revealed frequent losses of array clones (>20% of tumors) at chromosome arms 4p, 5q, and 18q, frequent gains of array clones (>20% of tumors) were found at 1q, 5p, 6p, 7p, 7q, 8p, 8q, 11p, 11q, 12q, 14q, 17q, 19q, 20p, and 20q. The pattern of alterations is dominated by gains on 5p and 20q with loss of 4p, all of which were already present in a patient with carcinoma in situ. Immunohistochemical analysis of mismatch repair genes MLH1, PMS2, MSH2, and MSH6 showed negative immunostaining in 1 neoplasm (5%). MSI of BAT25 and BAT26 was seen in 3 tumors (14%) including the neoplasm with aberrant immunostaining. In conclusion, we constructed a genomic profile of DALM/UCC including several novel genetic alterations. Further, we found a low percentage of MSI. Thus, DALM/UCCs display profound chromosomal instability, but this is not associated with concurrent MSI.
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Affiliation(s)
- Jolanda M van Dieren
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
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26
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Risques RA, Rabinovitch PS, Brentnall TA. Cancer surveillance in inflammatory bowel disease: new molecular approaches. Curr Opin Gastroenterol 2006; 22:382-90. [PMID: 16760754 DOI: 10.1097/01.mog.0000231812.95525.a7] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW Patients with chronic inflammatory bowel disease, such as ulcerative colitis and Crohn's disease, have an increased risk of colorectal cancer. Life-long colonoscopy surveillance is performed to detect the presence of dysplasia, but this approach is expensive and time-consuming. Thus, there is intensive research to identify molecular factors with prognostic value. This review summarizes recent research, with a special emphasis on the mechanisms underlying these molecular alterations. RECENT FINDINGS The role of chromosomal instability in the progression to inflammatory bowel disease-associated colorectal cancer is clear and likely relates to chronic cycles of injury, inflammation, repair and telomere shortening. The role of microsatellite instability has been a subject of discussion, and data suggest that microsatellite instability in inflammatory bowel disease might be different from microsatellite instability in sporadic colorectal cancer. Methylation, as a mechanism of gene silencing, also plays a role in ulcerative colitis tumorigenesis. Chronic inflammation has been linked to p53 activation and oxidative stress, contributing to the extensive genomic DNA damage observed in ulcerative colitis. SUMMARY Improved understanding of the molecular biology of cancer progression in inflammatory bowel disease will hopefully lead to the identification of useful prognostic biomarkers. Efforts are needed to prove the clinical utility of the most promising markers now identified.
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27
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Hanada T, Kobayashi T, Chinen T, Saeki K, Takaki H, Koga K, Minoda Y, Sanada T, Yoshioka T, Mimata H, Kato S, Yoshimura A. IFNgamma-dependent, spontaneous development of colorectal carcinomas in SOCS1-deficient mice. ACTA ACUST UNITED AC 2006; 203:1391-7. [PMID: 16717119 PMCID: PMC2118311 DOI: 10.1084/jem.20060436] [Citation(s) in RCA: 154] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Approximately 20% of human cancers are estimated to develop from chronic inflammation. Recently, the NF-kappaB pathway was shown to play an essential role in promoting inflammation-associated cancer, but the role of the JAK/STAT pathway, another important signaling pathway of proinflammatory cytokines, remains to be investigated. Suppressor of cytokine signaling-1 (SOCS1) acts as an important physiological regulator of cytokine responses, and silencing of the SOCS1 gene by DNA methylation has been found in several human cancers. Here, we demonstrated that SOCS1-deficient mice (SOCS1-/- Tg mice), in which SOCS1 expression was restored in T and B cells on a SOCS1-/- background, spontaneously developed colorectal carcinomas carrying nuclear beta-catenin accumulation and p53 mutations at 6 months of age. However, interferon (IFN)gamma-/- SOCS1-/- mice and SOCS1-/- Tg mice treated with anti-IFNgamma antibody did not develop such tumors. STAT3 and NF-kappaB activation was evident in SOCS1-/- Tg mice, but these were not sufficient for tumor development because these are also activated in IFNgamma-/- SOCS1-/- mice. However, colons of SOCS1-/- Tg mice, but not IFNgamma-/- SOCS1-/- mice, showed hyperactivation of STAT1, which resulted in the induction of carcinogenesis-related enzymes, cyclooxygenase-2 and inducible nitric oxide synthase. These data strongly suggest that SOCS1 is a unique antioncogene which prevents chronic inflammation-mediated carcinogenesis by regulation of the IFNgamma/STAT1 pathways.
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Affiliation(s)
- Toshikatsu Hanada
- Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
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28
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Michael-Robinson JM, Pandeya N, Walsh MD, Biemer-Huttmann AE, Eri RD, Buttenshaw RL, Lincoln D, Clouston AD, Jass JR, Radford-Smith GL. Characterization of tumour-infiltrating lymphocytes and apoptosis in colitis-associated neoplasia: comparison with sporadic colorectal cancer. J Pathol 2006; 208:381-7. [PMID: 16315333 DOI: 10.1002/path.1895] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The development of colorectal cancer is a major complication for patients with chronic idiopathic colitis. Colitis-associated tumours tend to occur at a younger age and be more aggressive than sporadic colorectal cancers. While we have previously associated the presence of tumour-infiltrating lymphocytes (TILs) and increased apoptosis in sporadic colorectal cancer with high-level microsatellite instability and improved prognosis, little is known of the relationship between these variables in colitis-associated colorectal cancer. The aim of this study was to correlate TILs and tumour cell apoptosis in colitis-associated neoplasms stratified according to microsatellite instability. Twenty tumour and 11 dysplastic samples resected from 21 patients with long-standing colitis were analysed for microsatellite instability at 10 microsatellite markers. TIL distribution (CD3, CD8) and function (granzyme B) were quantified by immunohistochemistry. Neoplastic cell apoptosis was assessed using the M30 CytoDEATH antibody. These findings were compared with 40 microsatellite stable (MSS) sporadic colorectal cancers previously evaluated for TILs and neoplastic apoptosis. Low-level microsatellite instability was found in 1/20 colitis-associated tumours. All other colitis-associated lesions were designated MSS. CD3(+) and CD8(+) TIL counts were significantly higher in colitis-associated lesions compared with MSS sporadic colorectal cancer (p < 0.0001, p = 0.001 respectively). Despite their higher TIL density, colitis-associated tumours were more likely to present late (Dukes' stage C or D) (p = 0.02). Functionally, colitis-associated TILs demonstrated significantly less granzyme B expression compared to sporadic cancers (p = 0.002). The level of tumour cell apoptosis was similar between the two groups (sporadic, 1.53%; colitis cancers, 1.45%). In conclusion, MSS colitis-associated tumours have a higher prevalence of CD3(+)/CD8(+) TILs but no associated increase in tumour cell killing by apoptosis. Unlike cytotoxic T cells in sporadic colorectal cancer, TILs do not appear to enhance the prognosis of colitis-associated colorectal cancer. This may be related to an impairment of granzyme B expression within these lesions.
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Affiliation(s)
- J M Michael-Robinson
- Crohn's and Colitis Laboratory, Clinical Research Centre, Royal Brisbane and Women's Hospital Research Foundation, Queensland Institute of Medical Research, Brisbane, Australia
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29
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Colliver DW, Crawford NPS, Eichenberger MR, Zacharius W, Petras RE, Stromberg AJ, Galandiuk S. Molecular profiling of ulcerative colitis-associated neoplastic progression. Exp Mol Pathol 2005; 80:1-10. [PMID: 16277983 DOI: 10.1016/j.yexmp.2005.09.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2005] [Accepted: 09/14/2005] [Indexed: 12/13/2022]
Abstract
Fundamental differences exist between ulcerative colitis (UC)-associated and sporadic forms of colorectal cancer, including preexisting inflammation, type of dysplasia, and timing of molecular events in carcinogenesis. Transcriptional alterations that occur in UC-associated neoplasia in the progression from normal mucosa through dysplastic epithelium to invasive cancer have not been described. We used Affymetrix U95Av2 microarrays to assess differential gene expression in the neoplastic progression of UC tissue from the colonic mucosa of individuals with benign UC, UC-dysplasia-associated lesions or masses, and UC adenocarcinoma. By correlating transcript alterations across tissue types using a mixed statistical model, we identified 699 genes exhibiting altered expression with dysplasia development. A different expression profile was observed in progression to adenocarcinoma with 392 transcripts exhibiting differential expression. There were 224 transcripts common to both dysplasia and adenocarcinoma. Most of the differentially expressed genes described herein were not previously known to play a role in neoplastic progression in UC, including transcripts affecting cell proliferation and apoptosis, signal transduction and signaling, and DNA repair. The altered expression of five transcripts was confirmed by quantitative real-time reverse-transcription polymerase chain reaction. Based on comparisons with previous studies on sporadic colorectal carcinoma, several similarities were found. There were, however, important differences that suggest that different molecular events may occur in the development of UC-associated neoplasia. Several of these genes demonstrated similar changes in dysplastic and cancerous tissue and may be involved in early cancer formation. Identification of these genes as potential clinical biomarkers may lead to improved early disease diagnosis.
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Affiliation(s)
- Daniel W Colliver
- Digestive Surgery Research Laboratory, Price Institute for Surgical Research, Department of Surgery, University of Louisville School of Medicine, Louisville, KY 40292, USA.
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30
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Schulmann K, Mori Y, Croog V, Yin J, Olaru A, Sterian A, Sato F, Wang S, Xu Y, Deacu E, Berki AT, Hamilton JP, Kan T, Abraham JM, Schmiegel W, Harpaz N, Meltzer SJ. Molecular phenotype of inflammatory bowel disease-associated neoplasms with microsatellite instability. Gastroenterology 2005; 129:74-85. [PMID: 16012936 DOI: 10.1053/j.gastro.2005.04.011] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Patients with inflammatory bowel disease (IBD) are at increased risk of developing colorectal cancer (CRC). We sought to determine the frequency of high-level microsatellite instability (MSI-H) and the mutational and methylation profile of MSI-H IBD-related neoplasms (IBDNs). METHODS A total of 124 IBDNs (81 cancers, 43 dysplasias) from 78 patients were studied for the frequency of MSI-H and hypermethylation of 3 target genes: MLH1 , HPP1 , and RAB-32 . Fifteen MSI-H IBDNs were characterized according to their profile of frameshift mutations in 28 mononucleotide repeats and compared with 46 sporadic MSI-H CRCs. RESULTS Nineteen of 124 IBDNs were MSI-H. The frequency of frameshift mutations in coding mononucleotide repeats was significantly lower in MSI-H IBDNs than in sporadic MSI-H CRCs for TGFBR2 (7 of 14 vs 34 of 43 samples; P = .047) and ACVR2 (3 of 14 vs 25 of 43 samples; P = .029). In contrast, ICA1 was mutated in 3 of 9 MSI-H IBDNs vs 2 of 54 sporadic MSI-H CRCs ( P = .028). HPP1 and RAB32 methylation was independent of MSI status and was observed in 4 of 59 and 0 of 64 nondysplastic mucosae, 20 of 38 and 1 of 25 dysplasias, and 28 of 61 and 20 of 60 carcinomas, respectively. CONCLUSIONS The profiles of coding microsatellite mutations (instabilotypes) differ significantly between MSI-H IBDNs and MSI-H sporadic CRCs. Specifically, TGFBR2 and ACVR2 mutations are significantly rarer in MSI-H IBDNs than in MSI-H sporadic CRCs. Furthermore, HPP1 methylation occurs early, in 7% of nondysplastic and approximately half of dysplastic mucosae, whereas RAB32 methylation occurs at the transition to invasive growth, being rarer in dysplasias.
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Affiliation(s)
- Karsten Schulmann
- Division of Gastroenterology, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
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Tahara T, Inoue N, Hisamatsu T, Kashiwagi K, Takaishi H, Kanai T, Watanabe M, Ishii H, Hibi T. Clinical significance of microsatellite instability in the inflamed mucosa for the prediction of colonic neoplasms in patients with ulcerative colitis. J Gastroenterol Hepatol 2005; 20:710-5. [PMID: 15853983 DOI: 10.1111/j.1440-1746.2005.03803.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Although molecular mechanisms underlying ulcerative colitis (UC)-associated neoplasms have been studied for years, understanding of these mechanisms remains incomplete and no good predictable marker for development of colonic neoplasms in patients with UC has been established. The aim of this study was to assess if microsatellite instability (MSI) contributes to the development of colonic neoplasms in patients with UC. METHODS We have examined MSI in chronic inflamed and neoplastic colonic mucosa of UC patients. We have also obtained serial biopsied colonic tissues retrospectively 2-12 years before the final diagnosis from patients with high level MSI (MSI-H+) UC-associated neoplasms, and analyzed MSI using them at different periods. RESULTS Eight of 12 UC-associated colon cancers (67%), four of six UC-associated high grade dysplasias (67%), and two of six UC-associated low grade dysplasias (33%) revealed MSI-H+ phenotypes. In contrast, 15 of 59 lesions (25%) in inflamed UC mucosa without colonic neoplasm revealed MSI-H +. Interestingly, all four patients with MSI-H+ phenotypes at the final diagnosis of UC-associated colon cancer or dysplasia had already had MSI-H+ at the stage of chronic colitis, 2-12 years before the final diagnosis. CONCLUSION These results support the notion that MSI contributes to the carcinogenesis of UC-associated neoplasms, and indicate that this analysis in inflamed colonic mucosa at surveillance colonoscopy is useful for identifying UC patients who have high risk for neoplastic progression.
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Affiliation(s)
- Toshiyuki Tahara
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan
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Bagnoli S, Putignano AL, Melean G, Baglioni S, Sestini R, Milla M, d'Albasio G, Genuardi M, Pacini F, Trallori G, Papi L. Susceptibility to refractory ulcerative colitis is associated with polymorphism in the hMLH1 mismatch repair gene. Inflamm Bowel Dis 2004; 10:705-8. [PMID: 15626886 DOI: 10.1097/00054725-200411000-00001] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The hMLH1 gene lies in the linkage susceptibility region to inflammatory bowel disease (IBD) on 3p21. A single nucleotide polymorphism, 655A>G, in exon 8 of the gene causes an I219V change in the MLH1 protein. To test whether hMLH1 may confer susceptibility to ulcerative colitis (UC), we investigated an association between the 655A>G polymorphism and the disease. DNA-based technologies were used to analyze the 655A>G polymorphism in 201 UC patients and 126 healthy ethnically matched controls. The comparison of the allelic frequencies of the 655A>G polymorphism in UC patients and healthy controls did not show significant differences. However, genotype frequencies at the hMLH1 655 position were found to be significantly different when patients with and without refractory UC were compared. This was mainly attributable to a higher level of homozygosity for the G allele in refractory UC patients. Almost 5 times as many (4.9 times) refractory UC patients carried the GG genotype compared with nonrefractory patients (P < 0.0001). The present study provides evidence that the hMLH1 gene is involved in genetic susceptibility to refractory UC. If confirmed by other studies, the GG genotype at position 655 of the hMLH1 gene may represent a useful predictive factor for the clinical management of UC patients.
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Affiliation(s)
- Siro Bagnoli
- Gastroenterology Unit, Careggi Hospital, Florence, Italy
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33
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Matsumura S, Oue N, Ito R, Nakayama H, Kitadai Y, Yokozaki H, Chayama K, Yasui W. The promoter methylation status of the DNA repair gene O6-methylguanine-DNA methyltransferase in ulcerative colitis. Virchows Arch 2003; 443:518-23. [PMID: 12920593 DOI: 10.1007/s00428-003-0877-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2003] [Accepted: 07/08/2003] [Indexed: 10/26/2022]
Abstract
Patients with long-standing and extensive ulcerative colitis (UC) have an increased incidence of colorectal cancer (CRC). It has been reported that a DNA repair gene, O6-methylguanine-DNA methyltransferase (MGMT) is inactivated by promoter hypermethylation in sporadic CRCs. Hence, we investigated the promoter methylation status of MGMT by methylation specific polymerase chain reaction (PCR) in a total of 67 tissue samples (61 non-cancerous tissues and 6 cancer tissues) from 24 patients with UC. Promoter hypermethylation of MGMT was detected in one well-differentiated adenocarcinoma (16.7%) of 6 cancer samples and not detected in any of adenomas and dysplasias. In non-dysplastic tissues, promoter hypermethylation of MGMT was detected in 2 (3.7%, mucosa with mild inflammation) of 54 samples. The frequency of MGMT promoter hypermethylation in UC-associated CRCs found in this study (16.7%) is obviously lower than previously reported in sporadic CRCs (39.0-42.0%). We also confirmed that 42.9% (6/14) of sporadic CRCs showed the promoter methylation. These findings indicated that promoter hypermethylation of the MGMT gene is infrequent in patients with UC, and may not closely contribute to UC-associated colorectal tumorigenesis. A different genetic pathway for tumor progression may exist between sporadic CRC and UC-associated CRC.
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Affiliation(s)
- Shunji Matsumura
- Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-ku, 734-8551 Hiroshima, Japan
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Fukushima N, Sato N, Ueki T, Rosty C, Walter KM, Wilentz RE, Yeo CJ, Hruban RH, Goggins M. Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2002; 160:1573-81. [PMID: 12000709 PMCID: PMC1850889 DOI: 10.1016/s0002-9440(10)61104-2] [Citation(s) in RCA: 167] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pancreatic intraductal neoplasia (PanIN) is thought to be the precursor to infiltrating pancreatic ductal adenocarcinoma. We have previously shown that the preproenkephalin (ppENK) and p16 genes are aberrantly methylated in pancreatic adenocarcinoma. In this study we define the methylation status of the ppENK and p16 genes in various grades of PanINs. One hundred seventy-four samples (28 nonneoplastic pancreatic epithelia, 7 reactive epithelia, 29 PanIN-1A, 48 PanIN-1B, 27 PanIN-2, 14 PanIN-3, 15 invasive ductal adenocarcinomas, and 6 miscellaneous pancreatic neoplasms) were microdissected from 29 formalin-fixed paraffin-embedded surgically resected pancreata, and were analyzed by methylation-specific polymerase chain reaction. Fourteen of 15 (93.3%) invasive pancreatic ductal adenocarcinomas showed methylation of the ppENK gene and 4 of 15 (26.7%) showed methylation of the p16 gene. Nonneoplastic pancreatic epithelia did not harbor methylation of either gene. The prevalence of methylation of the ppENK gene increased significantly with increasing PanIN grade. A similar nonsignificant trend was noted for p16 methylation. Aberrant methylation of the ppENK gene was found in 7.7% of PanIN-1A, 7.3% of PanIN-1B, 22.7% of PanIN-2, and 46.2% of PanIN-3. Aberrant methylation of the p16 gene was found in 12% of PanIN-1A, 2.6% of PanIN-1B, 4.5% of PanIN-2, and 21.4% of PanIN-3. All but one of the PanINs from the 14 pancreata without pancreatic carcinoma was unmethylated with respect to either the p16 or ppENK gene. Our results suggest that methylation-related inactivation of the ppENK and p16 genes is an intermediate or late event during pancreatic carcinogenesis. Because aberrant methylation of ppENK or p16 was more often detected in similar grade PanINs from patients with pancreatic carcinoma than in those with other pancreatic diseases, it may be a useful indicator of the potential malignancy of epithelial cells of the pancreas.
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Affiliation(s)
- Noriyoshi Fukushima
- Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2196, USA
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