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Jarrar A, Lotti F, DeVecchio J, Ferrandon S, Gantt G, Mace A, Karagkounis G, Orloff M, Venere M, Hitomi M, Lathia J, Rich JN, Kalady MF. Poly(ADP-Ribose) Polymerase Inhibition Sensitizes Colorectal Cancer-Initiating Cells to Chemotherapy. Stem Cells 2018; 37:42-53. [PMID: 30353615 DOI: 10.1002/stem.2929] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 08/20/2018] [Accepted: 09/13/2018] [Indexed: 12/29/2022]
Abstract
Colorectal cancer (CRC) remains a leading killer in the U.S. with resistance to treatment as the largest hurdle to cure. Colorectal cancer-initiating cells (CICs) are a self-renewing tumor population that contribute to tumor relapse. Here, we report that patient-derived CICs display relative chemoresistance compared with differentiated progeny. In contrast, conventional cell lines failed model therapeutic resistance. CICs preferentially repaired chemotherapy-induced DNA breaks, prompting us to interrogate DNA damage pathways against which pharmacologic inhibitors have been developed. We found that CICs critically depended on the key single-strand break repair mediator, poly(ADP-ribose) polymerase (PARP), to survive treatment with standard-of-care chemotherapy. Small molecule PARP inhibitors (PARPi) sensitized CICs to chemotherapy and reduced chemotherapy-treated CIC viability, self-renewal, and DNA damage repair. Although PARPi monotherapy failed to kill CICs, combined PARPi therapy with chemotherapy attenuated tumor growth in vivo. Clinical significance of PARPi for CRC patients was supported by elevated PARP levels in colorectal tumors compared with normal colon, with further increases in metastases. Collectively, our results suggest that PARP inhibition serves as a point of fragility for CICs by augmenting therapeutic efficacy of chemotherapy. Stem Cells 2019;37:42-53.
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Affiliation(s)
- Awad Jarrar
- Department of Stem Cell and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Graduate Entry Medical School, University of Limerick, Limerick, Ireland
| | - Fiorenza Lotti
- Department of Stem Cell and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Jennifer DeVecchio
- Department of Stem Cell and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Sylvain Ferrandon
- Department of Stem Cell and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Gerald Gantt
- Department of Stem Cell and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Adam Mace
- Department of Stem Cell and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Georgios Karagkounis
- Department of Stem Cell and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Matthew Orloff
- Department of Stem Cell and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Monica Venere
- Department of Radiation Oncology, James Cancer Hospital and Comprehensive Cancer Center, The Ohio State University Wexner School of Medicine, Columbus, Ohio, USA
| | - Masahiro Hitomi
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Justin Lathia
- Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA
| | - Jeremy N Rich
- Department of Stem Cell and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
| | - Matthew F Kalady
- Department of Stem Cell and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, Ohio, USA.,Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio, USA.,Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
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Zhao P, Yu HZ, Cai JH. Clinical investigation of TROP-2 as an independent biomarker and potential therapeutic target in colon cancer. Mol Med Rep 2015; 12:4364-4369. [PMID: 26059528 DOI: 10.3892/mmr.2015.3900] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2014] [Accepted: 05/06/2015] [Indexed: 11/10/2022] Open
Abstract
Colon cancer is associated with a severe demographic and economic burden worldwide. The pathogenesis of colon cancer is highly complex and involves sequential genetic and epigenetic mechanisms. Despite extensive investigation, the pathogenesis of colon cancer remains to be elucidated. As the third most common type of cancer worldwide, the treatment options for colon cancer are currently limited. Human trophoblast cell‑surface marker (TROP‑2), is a cell‑surface transmembrane glycoprotein overexpressed by several types of epithelial carcinoma. In addition, TROP‑2 has been demonstrated to be associated with tumorigenesis and invasiveness in solid types of tumor. The aim of the present study was to investigate the protein expression of TROP‑2 in colon cancer tissues, and further explore the association between the expression of TROP‑2 and clinicopathological features of patients with colon cancer. The expression and localization of the TROP‑2 protein was examined using western blot analysis and immunofluorescence staining. Finally, the expression of TROP‑2 expression was correlated to conventional clinicopathological features of colon cancer using a χ2 test. The results revealed that TROP‑2 protein was expressed at high levels in the colon cancer tissues, which was associated with the development and pathological process of colon cancer. Therefore, TROP‑2 may be used as a biomarker to determine the clinical prognosis, and as a potential therapeutic target in colon cancer.
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Affiliation(s)
- Peng Zhao
- Department of Surgery, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
| | - Hai-Zheng Yu
- Department of Social Sciences, Hebei United University, Tangshan, Hebei 063000, P.R. China
| | - Jian-Hui Cai
- Department of Surgery, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China
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Serrated polyps and the risk of synchronous colorectal advanced neoplasia: a systematic review and meta-analysis. Am J Gastroenterol 2015; 110:501-9; quiz 510. [PMID: 25756237 DOI: 10.1038/ajg.2015.49] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Accepted: 01/02/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Serrated polyps of the colon comprise a heterogeneous group of lesions with distinct histological and malignant features. The presence of serrated polyps has been associated with synchronous advanced neoplasia, although the magnitude of this relationship is unclear. METHODS Using studies identified from systematic literature search up to February 2014, we performed a systematic review and meta-analysis to estimate the pooled prevalence of serrated polyps and their association with synchronous advanced neoplasia. Random-effects models were used to combine estimates from heterogeneous studies, and odds ratios (ORs) with 95% confidence intervals (CIs) were presented. RESULTS Nine studies with 34,084 participants were included. The mean age of subjects was 59.9±6.6 years and 52.5% of the subjects were male. Pooled prevalence of serrated polyps was 15.6% (95% CI, 10.3-22.9%). The pooled OR of advanced neoplasia in individuals with serrated polyps was 2.05 (95% CI, 1.38-3.04). Pooled analysis showed that the presence of proximal serrated polyps (OR=2.77, 95% CI, 1.71-4.46) and large serrated polyps (OR=4.10, 95% CI, 2.69-6.26) was associated with an increased risk of synchronous advanced neoplasia. The pooled OR for advanced neoplasia in individuals with proximal and large serrated polyps was 3.35 (95% CI, 2.51-4.46). Considerable heterogeneity was observed in most analyses. CONCLUSIONS Our meta-analysis showed that serrated polyps are associated with a more than twofold increased risk of detection of synchronous advanced neoplasia. Individuals with proximal and large serrated polyps have the highest risk. These individuals deserve surveillance colonoscopy.
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Kang YK. Diminutive and Small Colorectal Polyps: The Pathologist's Perspective. Clin Endosc 2014; 47:404-8. [PMID: 25324998 PMCID: PMC4198555 DOI: 10.5946/ce.2014.47.5.404] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Accepted: 07/05/2014] [Indexed: 01/09/2023] Open
Abstract
Recent progress in advanced endoscopic imaging and electronic chromoendoscopy allows the real-time endoscopic estimation of the histologic type of polyps, mainly for the differentiation of adenomas from hyperplastic polyps. Accordingly, a "resect-and-discard" strategy applied to diminutive colorectal polyps is now one of the emerging issues among gastroenterologists. The strategy has a practical advantage in terms of the potential cost savings. However, it has a number of limitations in the medical, academic, and legal aspects. The major pitfalls include the endoscopic investigation of colorectal polyps with a wide variety of histogenetic origins, including serrated polyps, and the lack of a standardized method for polyp size measurement. Another issue is the importance of the pathologic diagnosis for legal purposes and medical research. Moreover, it is not certain whether the implementation of the strategy has economic benefit in countries with an undervalued reimbursement system for pathologic examination. There is no doubt that a highly confident optical diagnosis of polyp type is a novel valuable tool. It can provide a more steady symbiosis between gastroenterologists and pathologists to allow a more evident diagnosis and management of patients with colorectal polyps.
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Affiliation(s)
- Yun Kyung Kang
- Department of Pathology, Inje University Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea
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ALVARADO-BACHMANN RAUL, SMITH ADRIAN, GUNDARA JUSTINS, KUO SAMUELC, GILL ANTHONYJ, SAMRA JASWINDERS, HUGH THOMASJ. The incidence of mismatch repair gene defects in colorectal liver metastases. Mol Med Rep 2014; 10:1003-6. [DOI: 10.3892/mmr.2014.2257] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Accepted: 03/29/2014] [Indexed: 11/06/2022] Open
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You HX, Zhou YH, Tan SY, She TH. Effects of silencing RIP1 with siRNA on the biological behavior of the LoVo human colon cancer cell line. Oncol Lett 2014; 7:2065-2072. [PMID: 24932290 PMCID: PMC4049674 DOI: 10.3892/ol.2014.2040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Accepted: 02/26/2014] [Indexed: 01/05/2023] Open
Abstract
The present study aimed to investigate the effects of silencing RIP1 by small interfering RNA (siRNA) on the biological behavior of the LoVo human colorectal carcinoma cell line and to provide evidence for the feasibility of colorectal cancer gene therapy. LoVo cells were divided into the RIP1 siRNA group, the blank control group and the negative control group. Chemically synthesized siRNA targeting RIP1 (RIP1 siRNA) was transfected into LoVo cells. Following transfection of the RIP1-targeted siRNA into the LoVo cells, the expression of the RIP1 gene was effectively inhibited. The results demonstrated that RIP1 effectively regulated the malignant biological behavior of the LoVo colon cancer cell line. Furthermore, the proliferation, motility and invasiveness of LoVo cells were inhibited by siRNA knockdown of RIP1. The results revealed that the RIP1 gene has an important role in the regulation of proliferation and apoptosis in colorectal carcinoma cells.
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Affiliation(s)
- Hong-Xia You
- Department of Gastroenterology, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China ; Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yan-Hong Zhou
- Department of Gastroenterology, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China
| | - Shi-Yun Tan
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Tong-Hui She
- Department of Gastroenterology, Hubei University of Science and Technology, Xianning, Hubei 437100, P.R. China
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Metachronous serrated neoplasia is uncommon after right colectomy in patients with methylator colon cancers with a high degree of microsatellite instability. Dis Colon Rectum 2014; 57:39-46. [PMID: 24316944 DOI: 10.1097/01.dcr.0000437690.18709.76] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Right-sided serrated polyps are precursors to sporadic microsatellite unstable colon cancers via the methylator pathway and have a high rate of synchronous and metachronous lesions. Serrated polyps also occur in Lynch syndrome, where right-sided microsatellite unstable cancers arise from germline mutations in mismatch repair genes. OBJECTIVE The aim of this study was to compare serrated neoplasia in patients with sporadic and hereditary microsatellite unstable colon cancer and to examine the effect of right colectomy on the risk of metachronous polyps and cancers. DESIGN This is a retrospective, descriptive, cohort study from database and chart review. SETTING This study was conducted at a tertiary care hospital with a center for hereditary colorectal cancer. PATIENTS Patients who had colon cancers with a high degree of microsatellite instability, methylator cancers, and Lynch syndrome cancers, were included. INTERVENTIONS Interventions included colectomy, surveillance colonoscopy, and polypectomy. MAIN OUTCOME MEASURES The primary outcomes measured were the incidence and location of metachronous polyps and cancers. RESULTS Eighty-five patients were included: 47 with methylator cancers and 38 with Lynch syndrome. Median ages at surgery were 75 years (range, 41-90) and 48 years (range, 27-77), p < 0.0001. Forty-six (98%) patients with methylator cancers and 17 (45%) patients with Lynch syndrome underwent a right colectomy, p < 0.0001. Metachronous cancers occurred in 19/60 (32%) of patients with Lynch syndrome and no patients with methylator cancers, p < 0.0001. Thirty-four patients with methylator cancers had colonoscopic follow-up, with a median of 2 colonoscopies per patient over a 32-month follow-up (range, 1-136). Sixty-three percent of patients with Lynch syndrome had colonoscopic follow-up, median of 4 colonoscopies per patient over 102 months (range, 1-462), p < 0.0001. Four (9%) patients with methylator cancers each had 1 metachronous serrated polyp, compared with 10/37 (27%) patients with Lynch syndrome (p = 0.049), whose median number of polyps was 2 (range, 1-8). Characteristics of other associated polyps were similar between cohorts. LIMITATIONS This study is somewhat limited by potential inherent bias from its retrospective design. Also, a high number of deaths in the CIMP+ cohort could have contributed to the low number of serrated polyps detected on colonoscopy surveillance, but given current understanding of serrated polyp growth, this may truly represent the left colon's tendency not to develop serrated polyps. CONCLUSIONS Cancers with a high degree of microsatellite instability arise through 2 different molecular mechanisms. Metachronous serrated neoplasia, benign and malignant, following right colectomy in patients with the CpG-island methylator phenotype of colorectal cancer is uncommon. However, the colons of patients with Lynch syndrome are at high risk after segmental colectomy.
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Steele SR, Johnson EK, Champagne B, Davis B, Lee S, Rivadeneira D, Ross H, Hayden DA, Maykel JA. Endoscopy and polyps-diagnostic and therapeutic advances in management. World J Gastroenterol 2013; 19:4277-4288. [PMID: 23885138 PMCID: PMC3718895 DOI: 10.3748/wjg.v19.i27.4277] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2013] [Revised: 05/30/2013] [Accepted: 06/10/2013] [Indexed: 02/06/2023] Open
Abstract
Despite multiple efforts aimed at early detection through screening, colon cancer remains the third leading cause of cancer-related deaths in the United States, with an estimated 51000 deaths during 2013 alone. The goal remains to identify and remove benign neoplastic polyps prior to becoming invasive cancers. Polypoid lesions of the colon vary widely from hyperplastic, hamartomatous and inflammatory to neoplastic adenomatous growths. Although these lesions are all benign, they are common, with up to one-quarter of patients over 60 years old will develop pre-malignant adenomatous polyps. Colonoscopy is the most effective screening tool to detect polyps and colon cancer, although several studies have demonstrated missed polyp rates from 6%-29%, largely due to variations in polyp size. This number can be as high as 40%, even with advanced (> 1 cm) adenomas. Other factors including sub-optimal bowel preparation, experience of the endoscopist, and patient anatomical variations all affect the detection rate. Additional challenges in decision-making exist when dealing with more advanced, and typically larger, polyps that have traditionally required formal resection. In this brief review, we will explore the recent advances in polyp detection and therapeutic options.
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Rex DK, Ahnen DJ, Baron JA, Batts KP, Burke CA, Burt RW, Goldblum JR, Guillem JG, Kahi CJ, Kalady MF, O’Brien MJ, Odze RD, Ogino S, Parry S, Snover DC, Torlakovic EE, Wise PE, Young J, Church J. Serrated lesions of the colorectum: review and recommendations from an expert panel. Am J Gastroenterol 2012; 107:1315-29; quiz 1314, 1330. [PMID: 22710576 PMCID: PMC3629844 DOI: 10.1038/ajg.2012.161] [Citation(s) in RCA: 822] [Impact Index Per Article: 63.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Serrated lesions of the colorectum are the precursors of perhaps one-third of colorectal cancers (CRCs). Cancers arising in serrated lesions are usually in the proximal colon, and account for a disproportionate fraction of cancer identified after colonoscopy. We sought to provide guidance for the clinical management of serrated colorectal lesions based on current evidence and expert opinion regarding definitions, classification, and significance of serrated lesions. A consensus conference was held over 2 days reviewing the topic of serrated lesions from the perspectives of histology, molecular biology, epidemiology, clinical aspects, and serrated polyposis. Serrated lesions should be classified pathologically according to the World Health Organization criteria as hyperplastic polyp, sessile serrated adenoma/polyp (SSA/P) with or without cytological dysplasia, or traditional serrated adenoma (TSA). SSA/P and TSA are premalignant lesions, but SSA/P is the principal serrated precursor of CRCs. Serrated lesions have a distinct endoscopic appearance, and several lines of evidence suggest that on average they are more difficult to detect than conventional adenomatous polyps. Effective colonoscopy requires an endoscopist trained in the endoscopic appearance of serrated lesions. We recommend that all serrated lesions proximal to the sigmoid colon and all serrated lesions in the rectosigmoid > 5 mm in size, be completely removed. Recommendations are made for post-polypectomy surveillance of serrated lesions and for surveillance of serrated polyposis patients and their relatives.
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Affiliation(s)
| | - Dennis J. Ahnen
- Staff Physician Denver VA Medical Center and Professor of Medicine, University of Colorado School of Medicine
| | | | | | - Carol A. Burke
- Department of Gastroenterology and Hepatology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio
| | - Randall W. Burt
- Division of Gastroenterology, Department of Internal Medicine, University of Utah School of Medicine
| | | | | | - Charles J. Kahi
- Indiana University School of Medicine; Richard L. Roudebush VA Medical Center
| | | | | | - Robert D. Odze
- Brigham and Womens Hospital, Department of Pathology, Harvard Medical School, Boston MA
| | - Shuji Ogino
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Susan Parry
- New Zealand Familial GI Cancer Registry, Auckland City Hospital, New Zealand; Department of Gastroenterology, Middlemore Hospital, Auckland, New Zealand
| | - Dale C. Snover
- Department of Pathology, Fairview Southdale Hospital, Edina, MN
| | - Emina Emilia Torlakovic
- Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Paul E. Wise
- Department of Surgery, Vanderbilt University Medical Center
| | - Joanne Young
- Cancer Council Queensland Senior Research Fellow, Laboratory Head, Familial Cancer Laboratory, Australia
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Kang GH. Four molecular subtypes of colorectal cancer and their precursor lesions. Arch Pathol Lab Med 2011; 135:698-703. [PMID: 21631262 DOI: 10.5858/2010-0523-ra.1] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT In addition to chromosomal instability and microsatellite instability (MSI), a third pathway, epigenetic instability, has been implicated in progression to colorectal carcinogenesis. CpG island methylator phenotype (CIMP) refers to a subset of colorectal cancers (CRCs) that occur through the epigenetic instability pathway and that are characterized by widespread hypermethylation of promoter CpG island loci, resulting in the inactivation of several tumor suppressor genes or tumor-related genes. Colorectal cancers can be classified into 4 molecular subtypes according to their CIMP and MSI statuses: CIMP+/MSI+, CIMP+/MSI-, CIMP-/MSI+, and CIMP-/MSI-. There are differences between Western (United States and European Union) and Eastern (Korea and China) populations in the number of CRCs that are MSI+, and in the number of MSI+ CRCs that are CIMP+. OBJECTIVE To review the clinicopathologic and molecular features of the 4 molecular subtypes of CRCs and their precursor lesions, and to emphasize geographic differences in CRCs between Eastern and Western populations. DATA SOURCES This article is based on the author's own experimental data and a literature review of relevant articles indexed in PubMed (US National Library of Medicine). CONCLUSION The 4 molecular subtypes of CRC that are defined by their CIMP and MSI statuses are characterized by their own distinct clinicopathologic and molecular features and precursor lesions. In particular, the clinicopathologic features of MSI+ CRCs differ depending on the CIMP status. Further understanding of the heterogeneity in CRC molecular pathways may help to explain the diverse morphologic features of CRCs.
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Affiliation(s)
- Gyeong Hoon Kang
- Department of Pathology, Cancer Research Institute, Brain Korea 2nd Stage, Seoul National University College of Medicine, Korea.
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