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Muta Y, Nakanishi Y. Mouse colorectal cancer organoids: Lessons from syngeneic and orthotopic transplantation systems. Eur J Cell Biol 2025; 104:151478. [PMID: 39919450 DOI: 10.1016/j.ejcb.2025.151478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 01/01/2025] [Accepted: 02/04/2025] [Indexed: 02/09/2025] Open
Abstract
Colorectal cancer (CRC) organoids provide more accurate and tissue-relevant models compared to conventional two-dimensional cultured cell cultures. Mouse CRC organoids, in particular, offer unique advantages over their human counterparts, as they can be transplanted into immunocompetent mice. These syngeneic transplantation models create a robust system for studying cancer biology in the immunocompetent tumor microenvironment (TME). This article discusses the development and applications of these organoid systems, emphasizing their capacity to faithfully recapitulate in vivo tumor progression, metastasis, and the immune landscape.
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Affiliation(s)
- Yu Muta
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Yuki Nakanishi
- Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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Weng YY, Huang MY. The CpG Island Methylator Phenotype Status in Synchronous and Solitary Primary Colorectal Cancers: Prognosis and Effective Therapeutic Drug Prediction. Int J Mol Sci 2024; 25:5243. [PMID: 38791280 PMCID: PMC11121449 DOI: 10.3390/ijms25105243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Revised: 05/08/2024] [Accepted: 05/09/2024] [Indexed: 05/26/2024] Open
Abstract
Synchronous colorectal cancer (sCRC) is characterized by the occurrence of more than one tumor within six months of detecting the first tumor. Evidence suggests that sCRC might be more common in the serrated neoplasia pathway, marked by the CpG island methylator phenotype (CIMP), than in the chromosomal instability pathway (CIN). An increasing number of studies propose that CIMP could serve as a potential epigenetic predictor or prognostic biomarker of sCRC. Therapeutic drugs already used for treating CIMP-positive colorectal cancers (CRCs) are reviewed and drug selections for sCRC patients are discussed.
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Affiliation(s)
- Yun-Yun Weng
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
| | - Ming-Yii Huang
- Department of Radiation Oncology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan;
- Department of Radiation Oncology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
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Aloysius MM, Nikumbh T, Yadukumar L, Asija U, Shah NJ, Aswath G, John S, Goyal H. National Trends in the Incidence of Sporadic Malignant Colorectal Polyps in Young Patients (20-49 Years): An 18-Year SEER Database Analysis. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:673. [PMID: 38674319 PMCID: PMC11052004 DOI: 10.3390/medicina60040673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 04/14/2024] [Accepted: 04/19/2024] [Indexed: 04/28/2024]
Abstract
Background and Objectives: Conflicting guidelines exist for initiating average-risk colorectal cancer screening at the age of 45 years. The United States Preventive Services Task Force (USPSTF) changed its guidelines in 2021 to recommend initiating screening at 45 years due to an increasing incidence of young-onset colorectal cancer. However, the American College of Physicians (ACP) recently recommended not screening average-risk individuals between 45 and 49 years old. We aim to study the national trends in the incidence of sporadic malignant polyps (SMP) in patients from 20 to 49 years old. Materials and Methods: We analyzed the Surveillance, Epidemiology, and End Results database (2000-2017) on patients aged 20-49 years who underwent diagnostic colonoscopy with at least a single malignant sporadic colorectal polyp. Results: Of the 10,742 patients diagnosed with SMP, 42.9% were female. The mean age of incidence was 43.07 years (42.91-43.23, 95% CI). Approximately 50% of malignant polyps were diagnosed between 45 and 49 years of age, followed by 25-30% between 40 and 45. There was an upward trend in malignant polyps, with a decreased incidence of malignant villous adenomas and a rise in malignant adenomas and tubulovillous adenomas. Conclusions: Our findings suggest that almost half of the SMPs under 50 years occurred in individuals under age 45, younger than the current screening threshold recommended by the ACP. There has been an upward trend in malignant polyps in the last two decades. This reflects changes in tumor biology, and necessitates further research and support in the USPSTF guidelines to start screening at the age of 45 years.
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Affiliation(s)
- Mark M. Aloysius
- Division of Gastroenterology, Department of Medicine, State University of New York Upstate Syracuse, New York, NY 13210, USA; (M.M.A.)
| | - Tejas Nikumbh
- Department of Internal Medicine, The Wright Center for Graduate Medical Education, Scranton, PA 18505, USA; (L.Y.); (U.A.)
| | - Lekha Yadukumar
- Department of Internal Medicine, The Wright Center for Graduate Medical Education, Scranton, PA 18505, USA; (L.Y.); (U.A.)
| | - Udit Asija
- Department of Internal Medicine, The Wright Center for Graduate Medical Education, Scranton, PA 18505, USA; (L.Y.); (U.A.)
| | - Niraj J. Shah
- Division of Gastroenterology, University of Mississippi Medical Center, Jackson, MS 39216, USA
| | - Ganesh Aswath
- Division of Gastroenterology, Department of Medicine, State University of New York Upstate Syracuse, New York, NY 13210, USA; (M.M.A.)
| | - Savio John
- Division of Gastroenterology, Department of Medicine, State University of New York Upstate Syracuse, New York, NY 13210, USA; (M.M.A.)
| | - Hemant Goyal
- Advanced Endoscopy, Borland Groover Owntown Office, Jacksonville, FL 32207, USA
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Aiderus A, Barker N, Tergaonkar V. Serrated colorectal cancer: preclinical models and molecular pathways. Trends Cancer 2024; 10:76-91. [PMID: 37880007 DOI: 10.1016/j.trecan.2023.09.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 10/27/2023]
Abstract
Serrated lesions are histologically heterogeneous, and detection can be challenging as these lesions have subtle features that may be missed by endoscopy. Furthermore, while approximately 30% of colorectal cancers (CRCs) arise from serrated lesions, only 8-10% of invasive serrated CRCs exhibit serrated morphology at presentation, suggesting potential loss of apparent characteristics with increased malignancy. Thus, understanding the genetic basis driving serrated CRC initiation and progression is critical to improve diagnosis and identify therapeutic biomarkers and targets to guide disease management. This review discusses the preclinical models of serrated CRCs reported to date and how these systems have been used to provide mechanistic insights into tumor initiation, progression, and novel treatment targets.
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Affiliation(s)
- Aziz Aiderus
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore.
| | - Nick Barker
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), 2 Medical Drive, MD9, Singapore 117593, Republic of Singapore; Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore
| | - Vinay Tergaonkar
- Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore (NUS), 8 Medical Drive, MD7, Singapore 117596, Republic of Singapore
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Aberrant HMGA2 Expression Sustains Genome Instability That Promotes Metastasis and Therapeutic Resistance in Colorectal Cancer. Cancers (Basel) 2023; 15:cancers15061735. [PMID: 36980621 PMCID: PMC10046046 DOI: 10.3390/cancers15061735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/06/2023] [Accepted: 03/11/2023] [Indexed: 03/16/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most lethal cancers worldwide, accounting for nearly ~10% of all cancer diagnoses and deaths. Current therapeutic approaches have considerably increased survival for patients diagnosed at early stages; however, ~20% of CRC patients are diagnosed with late-stage, metastatic CRC, where 5-year survival rates drop to 6–13% and treatment options are limited. Genome instability is an enabling hallmark of cancer that confers increased acquisition of genetic alterations, mutations, copy number variations and chromosomal rearrangements. In that regard, research has shown a clear association between genome instability and CRC, as the accumulation of aberrations in cancer-related genes provides subpopulations of cells with several advantages, such as increased proliferation rates, metastatic potential and therapeutic resistance. Although numerous genes have been associated with CRC, few have been validated as predictive biomarkers of metastasis or therapeutic resistance. A growing body of evidence suggests a member of the High-Mobility Group A (HMGA) gene family, HMGA2, is a potential biomarker of metastatic spread and therapeutic resistance. HMGA2 is expressed in embryonic tissues and is frequently upregulated in aggressively growing cancers, including CRC. As an architectural, non-histone chromatin binding factor, it initiates chromatin decompaction to facilitate transcriptional regulation. HMGA2 maintains the capacity for stem cell renewal in embryonic and cancer tissues and is a known promoter of epithelial-to-mesenchymal transition in tumor cells. This review will focus on the known molecular mechanisms by which HMGA2 exerts genome protective functions that contribute to cancer cell survival and chemoresistance in CRC.
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Hidaka M, Iwaizumi M, Taniguchi T, Baba S, Osawa S, Sugimoto K, Maekawa M. Pure somatic pathogenic variation profiles for patients with serrated polyposis syndrome: a case series. BMC Res Notes 2022; 15:350. [PMID: 36419139 PMCID: PMC9682711 DOI: 10.1186/s13104-022-06245-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 11/08/2022] [Indexed: 11/24/2022] Open
Abstract
OBJECTIVE The serrated pathway is a distinct genetic/epigenetic mechanism of the adenoma-carcinoma sequence in colorectal carcinogenesis. Although many groups have reported the genetic-phenotypic correlation of serrated lesions (SLs), previous studies regarding the serrated pathway were conducted on patients with SLs that have different germline and environmental genetic backgrounds. We aimed to compare pure somatic genetic profiles among SLs within identical patient with SPS. RESULTS We analyzed SLs from one patient with SPS (Case #1) and compared DNA variant profiles using targeted DNA multigene panels via NGS among the patient's hyperplastic polyp (HP), three sessile serrated lesions (SSLs), and one traditional serrated adenoma (TSA), and separately analyzed three SSLs and one tubular adenoma (TA) within another patient with SPS (Case #2). In two patients, known pathogenic variant of BRAF (c.1799 T > A, p.Val600Glu) was observed in one TSA and one SSL in Case #1, and in three SSLs within Case #2. The pure somatic pathogenic variant BRAF (c.1799 T > A, p.Val600Glu) among SLs with identical germline genetic background supports its importance as a strong contributor for SLs.
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Affiliation(s)
- Misaki Hidaka
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Moriya Iwaizumi
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan.
| | - Terumi Taniguchi
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
| | - Satoshi Baba
- Department of Diagnostic Pathology, Hamamatsu University Hospital, Hamamatsu, Japan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University of School of Medicine, Hamamatsu, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Masato Maekawa
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-Ku, Hamamatsu, 431-3192, Japan
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Al-Joufi FA, Setia A, Salem-Bekhit MM, Sahu RK, Alqahtani FY, Widyowati R, Aleanizy FS. Molecular Pathogenesis of Colorectal Cancer with an Emphasis on Recent Advances in Biomarkers, as Well as Nanotechnology-Based Diagnostic and Therapeutic Approaches. NANOMATERIALS (BASEL, SWITZERLAND) 2022; 12:169. [PMID: 35010119 PMCID: PMC8746463 DOI: 10.3390/nano12010169] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/22/2021] [Accepted: 12/24/2021] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is a serious disease that affects millions of people throughout the world, despite considerable advances in therapy. The formation of colorectal adenomas and invasive adenocarcinomas is the consequence of a succession of genetic and epigenetic changes in the normal colonic epithelium. Genetic and epigenetic processes associated with the onset, development, and metastasis of sporadic CRC have been studied in depth, resulting in identifying biomarkers that might be used to predict behaviour and prognosis beyond staging and influence therapeutic options. A novel biomarker, or a group of biomarkers, must be discovered in order to build an accurate and clinically useful test that may be used as an alternative to conventional methods for the early detection of CRC and to identify prospective new therapeutic intervention targets. To minimise the mortality burden of colorectal cancer, new screening methods with higher accuracy and nano-based diagnostic precision are needed. Cytotoxic medication has negative side effects and is restricted by medication resistance. One of the most promising cancer treatment techniques is the use of nano-based carrier system as a medication delivery mechanism. To deliver cytotoxic medicines, targeted nanoparticles might take advantage of differently expressed molecules on the surface of cancer cells. The use of different compounds as ligands on the surface of nanoparticles to interact with cancer cells, enabling the efficient delivery of antitumor medicines. Formulations based on nanoparticles might aid in early cancer diagnosis and help to overcome the limitations of traditional treatments, including low water solubility, nonspecific biodistribution, and restricted bioavailability. This article addresses about the molecular pathogenesis of CRC and highlights about biomarkers. It also provides conceptual knowledge of nanotechnology-based diagnostic techniques and therapeutic approaches for malignant colorectal cancer.
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Affiliation(s)
- Fakhria A. Al-Joufi
- Department of Pharmacology, College of Pharmacy, Jouf University, Aljouf 72341, Saudi Arabia;
| | - Aseem Setia
- Department of Pharmacy, Shri Rawatpura Sarkar University, Raipur 492015, India
| | - Mounir M. Salem-Bekhit
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (F.Y.A.); (F.S.A.)
- Department of Microbiology and Immunology, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
| | - Ram Kumar Sahu
- Department of Pharmaceutical Science, Assam University (A Central University), Silchar 788011, India
| | - Fulwah Y. Alqahtani
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (F.Y.A.); (F.S.A.)
| | - Retno Widyowati
- Department of Pharmaceutical Science, Faculty of Pharmacy, Universitas Airlangga, Surabaya 60115, Indonesia;
| | - Fadilah Sfouq Aleanizy
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; (F.Y.A.); (F.S.A.)
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Heckroth M, Eiswerth M, Elmasry M, Gala K, Cai W, Diamond S, Shine A, Liu D, Liu N, Tholkage S, Kong M, Parajuli D. Serrated polyp detection rate in colonoscopies performed by gastrointestinal fellows. Ther Adv Gastrointest Endosc 2022; 15:26317745221136775. [PMCID: PMC9749503 DOI: 10.1177/26317745221136775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 10/17/2022] [Indexed: 12/15/2022] Open
Abstract
Background: Clinically significant serrated polyp detection rate (CSSDR) and proximal serrated polyp detection rate (PSDR) have been suggested as the potential quality benchmarks for colonoscopy (CSSDR = 7% and PSDR = 11%) in comparison to the established benchmark adenoma detection rate (ADR). Another emerging milestone is the detection rate of lateral spreading lesions (LSLs). Objectives: This study aimed to evaluate CSSDR, PSDR, ADR, and LSL detection rates among gastrointestinal (GI) fellows performing a colonoscopy. A secondary aim was to evaluate patient factors associated with the detection rates of these lesions. Design and Methods: A retrospective review of 799 colonoscopy reports was performed. GI fellow details, demographic data, and pathology found on colonoscopy were collected. Multiple logistic regression analysis was performed to identify the factors associated with CSSDR, PSDR, ADR, and LSL detection rates. A p value < 0.05 was considered statistically significant. Results: For our patient population, the median age was 58 years; 396 (49.8%) were male and 386 (48.6%) were African American. The 15 GI fellows ranged from first (F1), second (F2), or third (F3) year of training. We found an overall CSSDR of 4.4%, PSDR of 10.5%, ADR of 42.1%, and LSL detection rate of 3.2%. Female gender was associated with CSSDR, while only age was associated with PSDR. GI fellow level of training was associated with LSL detection rate, with the odds of detecting them expected to be four times higher in F2/F3s than F1s. Conclusion: Although GI fellows demonstrated an above-recommended ADR and nearly reached target PSDR, they failed to achieve target CSSDR. Future studies investigating a benchmark for LSL detection rate are needed to quantify if GI fellows are detecting these lesions at adequate rates.
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Affiliation(s)
- Matthew Heckroth
- Department of Internal Medicine, University of Louisville, Louisville, KY, USA
| | - Michael Eiswerth
- Department of Internal Medicine, University of Louisville, Louisville, KY, USA
| | - Mohamed Elmasry
- Department of Internal Medicine, University of Louisville, Louisville, KY, USA
| | - Khushboo Gala
- Department of Internal Medicine, University of Louisville, Louisville, KY, USA
| | - Wenjing Cai
- Department of Internal Medicine, University of Louisville, Louisville, KY, USA
| | - Scott Diamond
- Department of Internal Medicine, University of Louisville, Louisville, KY, USA
| | - Amal Shine
- Department of Gastroenterology and Hepatology, University of Louisville, Louisville, KY, USA
| | - David Liu
- School of Medicine, University of Louisville, Louisville, KY, USA
| | - Nanlong Liu
- Department of Gastroenterology and Hepatology, University of Louisville, Louisville, KY, USA
| | - Sudaraka Tholkage
- Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY, USA
| | - Maiying Kong
- Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY, USA
| | - Dipendra Parajuli
- Department of Gastroenterology and Hepatology, University of Louisville, 550 S Jackson St, Louisville, KY 40202, USA
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Chiang SF, Huang HH, Tsai WS, Chin-Ming Tan B, Yang CY, Huang PJ, Yi-Feng Chang I, Lin J, Lu PS, Chin E, Liu YH, Yu JS, Chiang JM, Hung HY, You JF, Liu H. Comprehensive functional genomic analyses link APC somatic mutation and mRNA-miRNA networks to the clinical outcome of stage-III colorectal cancer patients. Biomed J 2021; 45:347-360. [PMID: 35550340 PMCID: PMC9250073 DOI: 10.1016/j.bj.2021.03.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 01/25/2021] [Accepted: 03/04/2021] [Indexed: 02/07/2023] Open
Abstract
Background Colorectal cancer (CRC) is a major health concern globally, but exhibits regional and/or environmental distinctions in terms of outcome especially for patients with stage III CRC. Methods From 2014 to 2016, matched pairs of tumor and adjacent normal tissue samples from 60 patients with stage I–IV CRC from Chang Gung Memorial Hospital in Taiwan were analyzed using next-generation sequencing. The DNA, mRNA, and miRNA sequences of paired tumor tissues were profiled. An observational study with survival analysis was done. Online datasets of The Cancer Genome Atlas (TCGA) and The International Cancer Genome Consortium (ICGC) were also integrated and compared. Results The gene that exhibited the highest mutation rate was adenomatous polyposis coli (APC) (75.0%), followed by TP53 (70.0%), KRAS (56.6%), and TTN (48.3%). APC was also the most frequently mutated gene in TCGA and ICGC datasets. Surprisingly, for non-metastatic cases (stages I-III), CRC patients with mutated APC had better outcome in terms of overall survival (p = 0.041) and recurrence free survival (p = 0.0048). Particularly for stage III CRC, the overall survival rate was 94.4% and 67.7%, respectively (p = 0.018), and the recurrence free survival rate was 94.4% and 16.7%, respectively (p = 0.00044). Further clinical and gene expression analyses revealed that the APC wt specimens to a greater extent exhibit poor differentiation state as well as EGFR upregulation, providing molecular basis for the poor prognosis of these patients. Finally, based on integrated transcriptome analysis, we constructed the mRNA-miRNA networks underlying disease recurrence of the stage III CRC and uncovered potential therapeutic targets for this clinical condition. Conclusion For stage III CRC, patients with mutated APC had better overall and recurrence free survival.
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Affiliation(s)
- Sum-Fu Chiang
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Heng-Hsuan Huang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Wen-Sy Tsai
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Bertrand Chin-Ming Tan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Research Center for Emerging Viral Infections, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Chia-Yu Yang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Otolaryngology-Head & Neck Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Po-Jung Huang
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Genomic Medicine Research Core Laboratory, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Ian Yi-Feng Chang
- Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Jiarong Lin
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Pei-Shan Lu
- Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - En Chin
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yu-Hao Liu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Jau-Song Yu
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
| | - Jy-Ming Chiang
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Hsin-Yuan Hung
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Jeng-Fu You
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan
| | - Hsuan Liu
- Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan; Department of Cell and Molecular Biology, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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Sharma P, Burke CA, Johnson DA, Cash BD. The importance of colonoscopy bowel preparation for the detection of colorectal lesions and colorectal cancer prevention. Endosc Int Open 2020; 8:E673-E683. [PMID: 32355887 PMCID: PMC7165013 DOI: 10.1055/a-1127-3144] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 12/31/2019] [Indexed: 12/11/2022] Open
Abstract
Background and study aims Colonoscopy for colorectal cancer (CRC) screening has reduced CRC incidence and mortality and improved prognosis. Optimal bowel preparation and high-quality endoscopic technique facilitate early CRC detection. This review provides a narrative on the clinical importance of bowel preparation for colonoscopy and highlights available bowel preparations. Methods A PubMed search was conducted through June 2019 to identify studies evaluating clinical outcomes, efficacy, safety, and tolerability associated with bowel preparation for CRC screening-related colonoscopy. Results Selecting the optimal bowel preparation regimen is based on considerations of efficacy, safety, and tolerability, in conjunction with individual patient characteristics and preferences. Available bowel preparations include high-volume (4 L) and low-volume (2 L and 1 L), polyethylene glycol (PEG) solutions, sodium sulfate, sodium picosulfate/magnesium oxide plus anhydrous citric acid, sodium phosphate tablets, and the over-the-counter preparations magnesium citrate and PEG-3350. These preparations may be administered as a single dose on the same day or evening before, or as two doses administered the same day or evening before/morning of colonoscopy. Ingesting at least half the bowel preparation on the day of colonoscopy (split-dosing) is associated with higher adequate bowel preparation quality versus evening-before dosing (odds ratio [OR], 2.5; 95 % confidence interval [CI], 1.9-3.4). Conclusions High-quality bowel preparation is integral for optimal CRC screening/surveillance by colonoscopy. Over the last 30 years, patients and providers have gained more options for bowel preparation, including low-volume agents with enhanced tolerability and cleansing quality that are equivalent to 4 L preparations. Split-dosing is preferred for achieving a high-quality preparation.
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Affiliation(s)
- Prateek Sharma
- University of Kansas Medical Center, Kansas City, Kansas, United States
| | | | - David A. Johnson
- Eastern Virginia Medical School, Norfolk, Virginia, United States
| | - Brooks D. Cash
- University of Texas Health Science Center, Houston, Texas, United States
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11
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Zhou G, Xiao X, Tu M, Liu P, Yang D, Liu X, Zhang R, Li L, Lei S, Wang H, Song Y, Wang P. Computer aided detection for laterally spreading tumors and sessile serrated adenomas during colonoscopy. PLoS One 2020; 15:e0231880. [PMID: 32315365 PMCID: PMC7173785 DOI: 10.1371/journal.pone.0231880] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Accepted: 04/02/2020] [Indexed: 12/22/2022] Open
Abstract
Background Evidence has shown that deep learning computer aided detection (CADe) system achieved high overall detection accuracy for polyp detection during colonoscopy. Aim The detection performance of CADe system on non-polypoid laterally spreading tumors (LSTs) and sessile serrated adenomas/polyps (SSA/Ps), with higher risk for malignancy transformation and miss rate, has not been exclusively investigated. Methods A previously validated deep learning CADe system for polyp detection was tested exclusively on LSTs and SSA/Ps. 1451 LST images from 184 patients were collected between July 2015 and January 2019, 82 SSA/Ps videos from 26 patients were collected between September 2018 and January 2019. The per-frame sensitivity and per-lesion sensitivity were calculated. Results (1) For LSTs image dataset, the system achieved an overall per-image sensitivity and per-lesion sensitivity of 94.07% (1365/1451) and 98.99% (197/199) respectively. The per-frame sensitivity for LST-G(H), LST-G(M), LST-NG(F), LST-NG(PD) was 93.97% (343/365), 98.72% (692/701), 85.71% (324/378) and 85.71% (6/7) respectively. The per-lesion sensitivity of each subgroup was 100.00% (71/71), 100.00% (64/64), 98.31% (58/59) and 80.00% (4/5). (2) For SSA/Ps video dataset, the system achieved an overall per-frame sensitivity and per-lesion sensitivity of 84.10% (15883/18885) and 100.00% (42/42), respectively. Conclusions This study demonstrated that a local-feature-prioritized automatic CADe system could detect LSTs and SSA/Ps with high sensitivity. The per-frame sensitivity for non-granular LSTs and small SSA/Ps should be further improved.
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Affiliation(s)
- Guanyu Zhou
- Department of Gastroenterology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Xun Xiao
- Department of Gastroenterology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Mengtian Tu
- Department of Gastroenterology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Peixi Liu
- Department of Gastroenterology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Dan Yang
- Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Xiaogang Liu
- Department of Gastroenterology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Renyi Zhang
- Department of Gastroenterology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Liangping Li
- Department of Gastroenterology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Shan Lei
- Department of Gastroenterology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Han Wang
- Department of Gastroenterology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Yan Song
- Department of Gastroenterology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Pu Wang
- Department of Gastroenterology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
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12
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Chan AWH, Pan Y, Tong JHM, Lung RWM, Kwan JSH, Chow C, Tin EKY, Chung LY, Li H, Wong SSY, Chau SL, Chan YY, Mak TWC, Ng SSM, To KF. Receptor tyrosine kinase fusions act as a significant alternative driver of the serrated pathway in colorectal cancer development. J Pathol 2020; 251:74-86. [PMID: 32162306 DOI: 10.1002/path.5418] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 02/18/2020] [Accepted: 03/02/2020] [Indexed: 02/06/2023]
Abstract
Serrated polyps are a clinically and molecularly heterogeneous group of lesions that can contribute to the development of colorectal cancers (CRCs). However, the molecular mechanism underlying the development of serrated lesions is still not well understood. Here, we combined multiple approaches to analyze the genetic alterations in 86 colorectal adenomas (including 35 sessile serrated lesions, 15 traditional adenomas, and 36 conventional adenomatous polyps). We also investigated the in vitro and in vivo oncogenic properties of a novel variant of the NCOA4-RET fusion gene. Molecular profiling revealed that sessile serrated lesions and traditional serrated adenomas have distinct clinicopathological and molecular features. Moreover, we identified receptor tyrosine kinase translocations exclusively in sessile serrated lesions (17%), and the observation was validated in a separate cohort of 34 sessile serrated lesions (15%). The kinase fusions as well as the BRAF and KRAS mutations were mutually exclusive to each other. Ectopic expression of a novel variant of the NCOA4-RET fusion gene promoted cell proliferation in vitro and in vivo, and the proliferation was significantly suppressed by RET kinase inhibitors. All of these underscored the importance of mitogen-activated protein kinase (MAPK) pathway activation in the serrated pathway of colorectal tumorigenesis. In addition, we demonstrated that the kinase fusion may occur early in the precursor lesion and subsequent loss of TP53 may drives the transformation to carcinoma during serrated tumorigenesis. In conclusion, we identified kinase fusions as a significant alternative driver of the serrated pathway in colorectal cancer development, and detecting their presence may serve as a biomarker for the diagnosis of sessile serrated lesions. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Anthony W-H Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Yi Pan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Joanna H-M Tong
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Raymond W-M Lung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Johnny S-H Kwan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Chit Chow
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Edith K-Y Tin
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Lau-Ying Chung
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Hui Li
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Shela S-Y Wong
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Shuk-Ling Chau
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Yuk Yu Chan
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Tony W-C Mak
- Division of Colorectal Surgery, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Simon Siu-Man Ng
- Division of Colorectal Surgery, Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China
| | - Ka-Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Sir Y.K. Pao Cancer Center, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, PR China.,Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, PR China
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13
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Fanelli GN, Dal Pozzo CA, Depetris I, Schirripa M, Brignola S, Biason P, Balistreri M, Dal Santo L, Lonardi S, Munari G, Loupakis F, Fassan M. The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer. Cancer Cell Int 2020; 20:30. [PMID: 32015690 PMCID: PMC6990491 DOI: 10.1186/s12935-020-1117-2] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 01/20/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is a complex and molecularly heterogeneous disease representing one of the most frequent causes of cancer-related death worldwide. About 8-15% of CRCs harbor a mutation in BRAF gene, a proto-oncogene involved in cell proliferation, differentiation and survival through the MAPK signaling cascade. The acquisition of BRAF mutation is an early event in the "serrated" CRC carcinogenetic pathway and is associated with specific and aggressive clinico-pathological and molecular features. Despite that the presence of BRAF mutation is a well-recognized negative prognostic biomarker in metastatic CRC (mCRC), a great heterogeneity in survival outcome characterizes these patients, due to the complex, and still not completely fully elucidated, interactions between the clinical, genetic and epigenetic landscape of BRAF mutations. Because of the great aggressiveness of BRAF-mutated mCRCs, only 60% of patients can receive a second-line chemotherapy; so intensive combined and tailored first-line approach could be a potentially effective strategy, but to minimize the selective pressure of resistant clones and to reduce side effects, a better stratification of patients bearing BRAF mutations is needed.
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Affiliation(s)
- Giuseppe Nicolò Fanelli
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, via Gabelli 61, 35121 Padua, Italy
| | - Carlo Alberto Dal Pozzo
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, via Gabelli 61, 35121 Padua, Italy
| | - Ilaria Depetris
- Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy
| | - Marta Schirripa
- Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy
| | - Stefano Brignola
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, via Gabelli 61, 35121 Padua, Italy
| | - Paola Biason
- Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy
| | - Mariangela Balistreri
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, via Gabelli 61, 35121 Padua, Italy
| | - Luca Dal Santo
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, via Gabelli 61, 35121 Padua, Italy
| | - Sara Lonardi
- Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy
| | - Giada Munari
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, via Gabelli 61, 35121 Padua, Italy
- Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy
| | - Fotios Loupakis
- Department of Oncology, Veneto Institute of Oncology IOV–IRCCS, Padua, Italy
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, via Gabelli 61, 35121 Padua, Italy
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14
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Tapial S, Olmedillas-López S, Rueda D, Arriba M, García JL, Vivas A, Pérez J, Pena-Couso L, Olivera R, Rodríguez Y, García-Arranz M, García-Olmo D, González-Sarmiento R, Urioste M, Goel A, Perea J. Cimp-Positive Status is More Representative in Multiple Colorectal Cancers than in Unique Primary Colorectal Cancers. Sci Rep 2019; 9:10516. [PMID: 31324877 PMCID: PMC6642151 DOI: 10.1038/s41598-019-47014-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 07/09/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) with CpG island methylator phenotype (CIMP) is recognized as a subgroup of CRC that shows association with particular genetic defects and patient outcomes. We analyzed CIMP status of 229 individuals with CRC using an eight-marker panel (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1); CIMP-(+) tumors were defined as having ≥ 5 methylated markers. Patients were divided into individuals who developed a "unique" CRC, which were subclassified into early-onset CRC (EOCRC) and late-onset CRC (LOCRC), and patients with multiple primary CRCs subclassified into synchronous CRC (SCRC) and metachronous CRC (MCRC). We found 9 (15.2%) CIMP-(+) EOCRC patients related with the proximal colon (p = 0.008), and 19 (26.8%) CIMP-(+) LOCRC patients associated with tumor differentiation (p = 0.045), MSI status (p = 0.021) and BRAF mutation (p = 0.001). Thirty-five (64.8%) SCRC patients had at least one CIMP-(+) tumor and 20 (44.4%) MCRC patients presented their first tumor as CIMP-(+). Thirty-nine (72.2%) SCRC patients showed concordant CIMP status in their simultaneous tumors. The differences in CIMP-(+) frequency between groups may reflect the importance of taking into account several criteria for the development of multiple primary neoplasms. Additionally, the concordance between synchronous tumors suggests CIMP status is generally maintained in SCRC patients.
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Affiliation(s)
- Sandra Tapial
- Digestive Cancer Research Group, 12 de Octubre Research Institute, Madrid, Spain
- Hereditary Cancer Laboratory, 12 de Octubre University Hospital, Madrid, Spain
| | - Susana Olmedillas-López
- New Therapies Laboratory, Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | - Daniel Rueda
- Digestive Cancer Research Group, 12 de Octubre Research Institute, Madrid, Spain
- Hereditary Cancer Laboratory, 12 de Octubre University Hospital, Madrid, Spain
| | - María Arriba
- Department of Biochemistry, Gregorio Marañón University Hospital, Madrid, Spain
| | - Juan L García
- Biomedical Research Institute of Salamanca (IBSAL), University Hospital of Salamanca-USAL-CSIC, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | - Alfredo Vivas
- Surgery Department, University Hospital 12 de Octubre, Madrid, Spain
| | - Jessica Pérez
- Biomedical Research Institute of Salamanca (IBSAL), University Hospital of Salamanca-USAL-CSIC, Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain
| | - Laura Pena-Couso
- Familial Cancer Clinical Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Rocío Olivera
- New Therapies Laboratory, Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | - Yolanda Rodríguez
- Pathology Department, University Hospital 12 de Octubre, Madrid, Spain
| | - Mariano García-Arranz
- New Therapies Laboratory, Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | - Damián García-Olmo
- New Therapies Laboratory, Foundation Health Research Institute-Fundación Jiménez Díaz University Hospital, Madrid, Spain
- Surgery Department, Fundación Jiménez Díaz University Hospital, Madrid, Spain
| | - Rogelio González-Sarmiento
- Biomedical Research Institute of Salamanca (IBSAL), University Hospital of Salamanca-USAL-CSIC, Salamanca, Spain.
- Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-CSIC, Salamanca, Spain.
| | - Miguel Urioste
- Familial Cancer Clinical Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER). Institute of Health Carlos III, Madrid, Spain
| | - Ajay Goel
- Beckman Research Institute at City of Hope Comprehensive Cancer Center 1218S, Fifth Avenue, Monrovia, CA, 91016, USA.
| | - José Perea
- Surgery Department, Fundación Jiménez Díaz University Hospital, Madrid, Spain.
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15
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Cheah PL, Li J, Looi LM, Teoh KH, Ong DBL, Arends MJ. DNA mismatch repair and CD133-marked cancer stem cells in colorectal carcinoma. PeerJ 2018; 6:e5530. [PMID: 30221090 PMCID: PMC6138039 DOI: 10.7717/peerj.5530] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 08/07/2018] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Except for a few studies with contradictory observations, information is lacking on the possibility of association between DNA mismatch repair (MMR) status and the presence of cancer stem cells in colorectal carcinoma (CRC), two important aspects in colorectal carcinogenesis. METHODS Eighty (40 right-sided and 40 left-sided) formalin-fixed, paraffin-embedded primary CRC were immunohistochemically studied for CD133, a putative CRC stem cell marker, and MMR proteins MLH1, MSH2, MSH6 and PMS2. CD133 expression was semi-quantitated for proportion of tumor immunopositivity on a scale of 0-5 and staining intensity on a scale of 0-3 with a final score (units) being the product of proportion and intensity of tumor staining. The tumor was considered immunopositive only when the tumor demonstrated moderate to strong intensity of CD133 staining (a decision made after analysis of CD133 expression in normal colon). Deficient MMR (dMMR) was interpreted as unequivocal loss of tumor nuclear staining for any MMR protein despite immunoreactivity in the internal positive controls. RESULTS CD133 was expressed in 36 (90.0%) left-sided and 28 (70.0%) right-sided tumors (p < 0.05) and CD133 score was significantly higher in left- (mean ± SD = 9.6 ± 5.3 units) compared with right-sided tumors (mean ± SD = 6.8 ± 5.6 units) p < 0.05). dMMR was noted in 14 (35%) right-sided and no (0%) left-sided CRC. When stratified according to MMR status, dMMR cases showed a lower frequency of CD133 expression (42.9%) and CD133 score (mean ± SD = 2.5 ± 3.6 units) compared with pMMR tumors on the right (frequency = 84.6%; mean score ± SD = 9.2 ± 5.0 units) as well as pMMR tumors on the left (frequency = 90.0%; mean score ± SD = 9.6 ± 5.3 units) (p < 0.05). Interestingly, frequencies of CD133 immunoreactivity and CD133 scores did not differ between pMMR CRC on the right versus the left (p > 0.05). CONCLUSION Proficient MMR correlated with high levels of CD133-marked putative cancer stem cells in both right- and left-sided tumors, whereas significantly lower levels of CD133-marked putative cancer stem cells were associated with deficient MMR status in colorectal carcinomas found on the right.
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Affiliation(s)
- Phaik-Leng Cheah
- Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Jing Li
- Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Lai-Meng Looi
- Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Kean-Hooi Teoh
- Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Diana Bee-Lan Ong
- Division of Anatomical Pathology, Department of Pathology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Mark J. Arends
- Division of Pathology, Edinburgh Cancer Research Centre, University of Edinburgh, Edinburgh, United Kingdom
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16
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Lin SH, Raju GS, Huff C, Ye Y, Gu J, Chen JS, Hildebrandt MAT, Liang H, Menter DG, Morris J, Hawk E, Stroehlein JR, Futreal A, Kopetz S, Mishra L, Wu X. The somatic mutation landscape of premalignant colorectal adenoma. Gut 2018; 67:1299-1305. [PMID: 28607096 PMCID: PMC6031265 DOI: 10.1136/gutjnl-2016-313573] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 05/02/2017] [Accepted: 05/04/2017] [Indexed: 02/06/2023]
Abstract
OBJECTIVE There are few studies which characterised the molecular alterations in premalignant colorectal adenomas. Our major goal was to establish colorectal adenoma genome atlas and identify molecular markers of progression from colorectal adenoma to adenocarcinoma. DESIGN Whole-exome sequencing and targeted sequencing were carried out in 149 adenoma samples and paired blood from patients with conventional adenoma or sessile serrated adenoma to characterise the somatic mutation landscape for premalignant colorectal lesions. The identified somatic mutations were compared with those in colorectal cancer (CRC) samples from The Cancer Genome Atlas. A supervised random forest model was employed to identify gene panels differentiating adenoma from CRC. RESULTS Similar somatic mutation frequencies, but distinctive driver mutations, were observed in sessile serrated adenomas and conventional adenomas. The final model included 20 genes and was able to separate the somatic mutation profile of colorectal adenoma and adenocarcinoma with an area under the curve of 0.941. CONCLUSION The findings of this project hold potential to better identify patients with adenoma who may be candidates for targeted surveillance programmes and preventive interventions to reduce the incidence of CRC.
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Affiliation(s)
- Shu-Hong Lin
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA,The University of Texas Graduate School of Biomedical Sciences at Houston and MD Anderson Cancer Center, Houston, Texas, USA
| | - Gottumukkala S Raju
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Chad Huff
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Yuanqing Ye
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jian Gu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jiun-Sheng Chen
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA,The University of Texas Graduate School of Biomedical Sciences at Houston and MD Anderson Cancer Center, Houston, Texas, USA
| | - Michelle A T Hildebrandt
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Han Liang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - David G Menter
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jeffery Morris
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Ernest Hawk
- Division of Cancer Prevention and Population Science, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - John R Stroehlein
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Andrew Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Lopa Mishra
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Xifeng Wu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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17
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Ogino S, Nowak JA, Hamada T, Phipps AI, Peters U, Milner DA, Giovannucci EL, Nishihara R, Giannakis M, Garrett WS, Song M. Integrative analysis of exogenous, endogenous, tumour and immune factors for precision medicine. Gut 2018; 67:1168-1180. [PMID: 29437869 PMCID: PMC5943183 DOI: 10.1136/gutjnl-2017-315537] [Citation(s) in RCA: 138] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 01/02/2018] [Accepted: 01/05/2018] [Indexed: 12/14/2022]
Abstract
Immunotherapy strategies targeting immune checkpoints such as the CTLA4 and CD274 (programmed cell death 1 ligand 1, PD-L1)/PDCD1 (programmed cell death 1, PD-1) T-cell coreceptor pathways are revolutionising oncology. The approval of pembrolizumab use for solid tumours with high-level microsatellite instability or mismatch repair deficiency by the US Food and Drug Administration highlights promise of precision immuno-oncology. However, despite evidence indicating influences of exogenous and endogenous factors such as diet, nutrients, alcohol, smoking, obesity, lifestyle, environmental exposures and microbiome on tumour-immune interactions, integrative analyses of those factors and immunity lag behind. Immune cell analyses in the tumour microenvironment have not adequately been integrated into large-scale studies. Addressing this gap, the transdisciplinary field of molecular pathological epidemiology (MPE) offers research frameworks to integrate tumour immunology into population health sciences, and link the exposures and germline genetics (eg, HLA genotypes) to tumour and immune characteristics. Multilevel research using bioinformatics, in vivo pathology and omics (genomics, epigenomics, transcriptomics, proteomics and metabolomics) technologies is possible with use of tissue, peripheral blood circulating cells, cell-free plasma, stool, sputum, urine and other body fluids. This immunology-MPE model can synergise with experimental immunology, microbiology and systems biology. GI neoplasms represent exemplary diseases for the immunology-MPE model, given rich microbiota and immune tissues of intestines, and the well-established carcinogenic role of intestinal inflammation. Proof-of-principle studies on colorectal cancer provided insights into immunomodulating effects of aspirin, vitamin D, inflammatory diets and omega-3 polyunsaturated fatty acids. The integrated immunology-MPE model can contribute to better understanding of environment-tumour-immune interactions, and effective immunoprevention and immunotherapy strategies for precision medicine.
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Affiliation(s)
- Shuji Ogino
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA,Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA,Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA
| | - Jonathan A Nowak
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Tsuyoshi Hamada
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA,Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA,Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Danny A Milner
- American Society for Clinical Pathology, Chicago, Illinois, USA
| | - Edward L Giovannucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA,Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Reiko Nishihara
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA,Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA,Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Marios Giannakis
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA,Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Wendy S Garrett
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA,Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Mingyang Song
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts, USA,Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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18
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Liu TY, Jin DC, Khan S, Chen X, Shi T, Dong WX, Qi YR, Guo ZX, Wang BM, Cao HL. Clinicopathological features of advanced colorectal serrated lesions: A single-center study in China. J Dig Dis 2018. [PMID: 29542866 DOI: 10.1111/1751-2980.12589] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE A growing body of evidence indicates that patients with colorectal serrated lesions, especially advanced serrated lesions (ASLs), are at risk of subsequent malignancy. This study aimed to analyze the clinicopathological features of ASLs and the association between ASLs and synchronous advanced colorectal neoplasia (sACN) in a single center of China. METHODS A retrospective cross-sectional study of consecutive symptomatic patients and healthy individuals who underwent colonoscopy between January 2010 and March 2016 was performed. Clinicopathological characteritics of the patients with ASLs were documented from the colonoscopy database. RESULTS Colorectal serrated lesions were pathologically confirmed in 277 (N = 38 981, 0.7%) cases. Among them, 156 (56.3%) were found to have ASLs, with a total of 161 lesions including 71 sessile serrated adenoma/polyps (SSA/P) and 90 traditional serrated adenomas (TSAs). There were no differences in age and gender between the ASL and non-ASL patients. Among the 161 ASLs, 29 (18.0%) were ≥10 mm in diameter. Compared with non-ASLs, ASLs appeared more in the proximal colon (P = 0.007). Flat and subpedunculated lesions were more commonly found in the ASL group compared with the non-ASL group. Nearly all ASLs (160/161) had dysplasia. Moreover, 16 sACN lesions were found in 156 ASL patients, and large diameter (≥10 mm) might be a significant risk factor for sACN (odds ratio 4.35, 95% confidence interval 1.467-12.894, P < 0.05). CONCLUSIONS ASLs are more likely to occur in the proximal colon, and mainly present as flat and sub-pedunculated types. Large ASLs are significantly associated with sACN.
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Affiliation(s)
- Tian Yu Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Duo Chen Jin
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Samiullah Khan
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Xue Chen
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Tao Shi
- Department of Pathology, Tianjin Medical University General Hospital, Tianjin, China
| | - Wen Xiao Dong
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Yan Rong Qi
- Department of Gastroenterology and Hepatology, Tianjin Haibin People's Hospital, Tianjin, China
| | - Zi Xuan Guo
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Bang Mao Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin, China
| | - Hai Long Cao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin, China
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19
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Tanaka T, Kobunai T, Yamamoto Y, Murono K, Otani K, Yasuda K, Nishikawa T, Kiyomatsu T, Kawai K, Hata K, Nozawa H, Ishihara S, Watanabe T. Increased Copy Number Variation of mtDNA in an Array-based Digital PCR Assay Predicts Ulcerative Colitis-associated Colorectal Cancer. ACTA ACUST UNITED AC 2018; 31:713-718. [PMID: 28652445 DOI: 10.21873/invivo.11119] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2017] [Revised: 05/27/2017] [Accepted: 05/29/2017] [Indexed: 01/14/2023]
Abstract
AIM Mitochondrial dysfunction plays a central role in carcinogenesis in numerous cancer-related diseases. We examined the copy number variation of mitochondrial DNA (mtDNA) and the expression of energy-producing genes in relation to ulcerative colitis (UC)-associated carcinogenesis. MATERIALS AND METHODS We studied 17 patients with UC-associated adenocarcinoma (UC-Ca) and 16 without UC-associated adenocarcinoma (UC-nonCa). The copy number of mtDNA in non-dysplastic mucosa in both groups was quantified by an array-based digital polymerase chain reaction (PCR) assay. Simultaneously, gene expression related to mitochondrial energy metabolism was determined by a PCR array. RESULTS We observed a higher copy number of mtDNA in non-dysplastic mucosa in the UC-Ca group compared to the UC-nonCa group (484.2 vs. 747.7 copies/cell, p=0.022). The sensitivity, specificity, positive predictive value, and negative predictive value for the detection of UC-associated adenocarcinoma by mtDNA copy number were 43.8%, 100%, 100%, and 60.9%, respectively. We observed an increased expression of mitochondrial genes related to energy metabolism together with an increased copy number of mtDNA. CONCLUSION Mitochondrial function and its metabolic process play essential roles in UC carcinogenesis and are possible risk markers for the development of colitic cancer.
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Affiliation(s)
- Toshiaki Tanaka
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Takashi Kobunai
- Translational Research Laboratory, Taiho Pharmaceutical Co., Ltd., Tokyo, Japan
| | - Yoko Yamamoto
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Koji Murono
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Kensuke Otani
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Koji Yasuda
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Takeshi Nishikawa
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | | | - Kazushige Kawai
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Keisuke Hata
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Hiroaki Nozawa
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Soichiro Ishihara
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
| | - Toshiaki Watanabe
- Department of Surgical Oncology, the University of Tokyo, Tokyo, Japan
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20
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Fan C, Younis A, Bookhout CE, Crockett SD. Management of Serrated Polyps of the Colon. CURRENT TREATMENT OPTIONS IN GASTROENTEROLOGY 2018; 16:182-202. [PMID: 29445907 PMCID: PMC6284520 DOI: 10.1007/s11938-018-0176-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
PURPOSE OF REVIEW The purpose of this review is to summarize the management of serrated colorectal polyps (SPs), with a particular focus on the most common premalignant SP, sessile serrated adenoma or polyp (SSA/P). These lesions present a challenge for endoscopists with respect to detection and resection, and are also susceptible to pathologic misdiagnosis. RECENT FINDINGS Patients with SSA/Ps are at an increased risk of future colorectal neoplasia, including advanced polyps and cancer. Reasonable benchmarks for SP detection rates are 5-7% for SSA/Ps and 10-12% for proximal SPs. Certain endoscopic techniques such as chromoendoscopy, narrow band imaging, water immersion, and wide-angle viewing may improve SSA/P detection. Emerging endoscopic techniques such as underwater polypectomy, suction pseudopolyp technique, and piecemeal cold snare polypectomy are helpful tools for the endoscopist's armamentarium for removing SSA/Ps. Proper orientation of SSA/P specimens can improve the accuracy of pathology readings. Patients with confirmed SSA/Ps and proximal HPs should undergo surveillance at intervals similar to what is recommended for patients with conventional adenomas. Patients with SSA/Ps may also be able to lower their risk of future polyps by targeting modifiable risk factors including tobacco and alcohol use and high-fat diets. NSAIDs and aspirin appear to be protective agents. SPs and SSA/Ps in particular are important colorectal cancer precursors that merit special attention to ensure adequate detection, resection, and surveillance.
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Affiliation(s)
- Claire Fan
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Adam Younis
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Christine E Bookhout
- Department of Pathology, University of North Carolina School of Medicine, Chapel Hill, NC, USA
| | - Seth D Crockett
- Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, CB#7080, 130 Mason Farm Road, Chapel Hill, NC, 27599, USA.
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21
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Review Article: The Role of Molecular Pathological Epidemiology in the Study of Neoplastic and Non-neoplastic Diseases in the Era of Precision Medicine. Epidemiology 2018; 27:602-11. [PMID: 26928707 DOI: 10.1097/ede.0000000000000471] [Citation(s) in RCA: 148] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Molecular pathology diagnostics to subclassify diseases based on pathogenesis are increasingly common in clinical translational medicine. Molecular pathological epidemiology (MPE) is an integrative transdisciplinary science based on the unique disease principle and the disease continuum theory. While it has been most commonly applied to research on breast, lung, and colorectal cancers, MPE can investigate etiologic heterogeneity in non-neoplastic diseases, such as cardiovascular diseases, obesity, diabetes mellitus, drug toxicity, and immunity-related and infectious diseases. This science can enhance causal inference by linking putative etiologic factors to specific molecular biomarkers as outcomes. Technological advances increasingly enable analyses of various -omics, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, microbiome, immunomics, interactomics, etc. Challenges in MPE include sample size limitations (depending on availability of biospecimens or biomedical/radiological imaging), need for rigorous validation of molecular assays and study findings, and paucities of interdisciplinary experts, education programs, international forums, and standardized guidelines. To address these challenges, there are ongoing efforts such as multidisciplinary consortium pooling projects, the International Molecular Pathological Epidemiology Meeting Series, and the Strengthening the Reporting of Observational Studies in Epidemiology-MPE guideline project. Efforts should be made to build biorepository and biobank networks, and worldwide population-based MPE databases. These activities match with the purposes of the Big Data to Knowledge (BD2K), Genetic Associations and Mechanisms in Oncology (GAME-ON), and Precision Medicine Initiatives of the United States National Institute of Health. Given advances in biotechnology, bioinformatics, and computational/systems biology, there are wide open opportunities in MPE to contribute to public health.
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22
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Abstract
AIM the evaluation of Ki-67 and CD44 expression in the 'serrated' polyps of the colon and comparison them with adenocarcinomas and tubular and tubule-villous adenomas of the colon. MATERIAL AND METHODS The study is including 49 'serrated' polyps, 34 tubular (AT) and tubulo-villous (ATV) adenomas and 32 adenocarcinomas of the colon. Antibodies CD44 and Ki-67 were used as immunohistochemical markers in this study. RESULTS A statistically significant difference (p<0.01) was observed between traditional serrated adenomas (TSA) from hyperplastic polyps (HP) and sessile serrated adenomas (SSA) in the Ki-67 level and the localization of the Ki-67 and CD44 reaction: surface areas of the crypts (upper third) in TSA and base of crypts (lower third) in HP and SSA. There was no difference between HP and SSA (p>0.05), neither by marker localization, nor by their level. In all 'serrated' polyps of the colon, the Ki-67 reaction was nuclear; CD44 - membrane (except for 1 TSA). CONCLUSION we are the first ones who suggested to evaluate not the overall level of reactions of CD44 and Ki-67, but particular level for each third part of crypts. The similarities of TSA, AT and ATV and between HP and SSA are shown as well as the principal statistical difference between these two groups. The cytoplasmic reaction of CD44 in adenocarcinomas and the membrane reaction of CD44 in 98% of the 'serrated' polyps of the colon are described. For the first time coexpression of CD44 and Ki-67 on particulate thirds of crypts in neoplasms of the colon is shown and the potential reasons for this phenomenon are discussed.
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Affiliation(s)
| | - O A Kharlova
- Lomonosov Moscow State University, Moscow, Russia
| | - P G Malkov
- Lomonosov Moscow State University, Moscow, Russia; Russian Medical Academy of Postgraduate Education Ministry of Health of Russia, Moscow, Russia
| | - N V Danilova
- Lomonosov Moscow State University, Moscow, Russia; Russian Medical Academy of Postgraduate Education Ministry of Health of Russia, Moscow, Russia
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23
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De Maio G, Zama E, Rengucci C, Calistri D. What influences preneoplastic colorectal lesion recurrence? Oncotarget 2017; 8:12406-12416. [PMID: 27902488 PMCID: PMC5355354 DOI: 10.18632/oncotarget.13628] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 11/15/2016] [Indexed: 12/16/2022] Open
Abstract
The hypothesis of the local recurrence of preneoplastic lesions was first put forward in the 1950s. Disease recurrence may result from an inherent imbalance in cell proliferation that promotes carcinogenesis in apparently normal mucosa. Our review sheds light on how early preneoplastic lesions could be used to diagnose relapsed preneoplastic and, developing neoplastic lesions. We focus in detail on the clinical-pathological and molecular features of adenoma subtypes and their role in relapsed adenoma and their development into colorectal carcinoma. Moreover, we include the data available on microbiota and its metabolites and their role in recurrence. We strongly believe that a significant improvement could be achieved in colorectal screening by introducing personalized endoscopic surveillance for polyp-bearing patients on the basis of the presence of molecular markers that are predictive of recurrence.
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Affiliation(s)
- Giulia De Maio
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy
| | - Elisa Zama
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy
| | - Claudia Rengucci
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy
| | - Daniele Calistri
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (FC), Italy
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24
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Herreros de Tejada A, González-Lois C, Santiago J. Serrated lesions and serrated polyposis syndrome. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2017; 109:516-526. [PMID: 28530106 DOI: 10.17235/reed.2017.4065/2015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The serrated pathway has been shown to be an alternative colorectal carcinogenetic route potentially accounting for up to one third of all CRCs. Serrated lesions, particularly SSPs, have been a focus of research during the past few years. They have well-established histological and molecular characteristics that account for their potential carcinogenetic risk through the accumulation BRAF, KRAS and methylator profile (CpG) mutations. Their endoscopic identification and resection represent a challenge because of their specific characteristics, and the need for an adequate specimen for histological diagnosis. Knowledge of these lesions is key, as is the adoption of established criteria for their endoscopic description and histological diagnosis. SPS is the maximum expression of involvement by serrated lesions, is associated with increased risk for CRC, and requires attentive endoscopic follow-up, as well as family screening. While the exact etiopathogenic mechanism remains unknown, current research will likely provide us with appropriate answers in the not too distant future.
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Affiliation(s)
| | - Carmen González-Lois
- Anatomía Patológica, Hospital Universitario Puerta de Hierro Majadahonda, España
| | - José Santiago
- Digestivo, Hospital Universitario Puerta de Hierro Majadahonda, España
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25
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Hamada T, Keum N, Nishihara R, Ogino S. Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis. J Gastroenterol 2017; 52:265-275. [PMID: 27738762 PMCID: PMC5325774 DOI: 10.1007/s00535-016-1272-3] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 09/22/2016] [Indexed: 02/07/2023]
Abstract
Molecular pathological epidemiology (MPE) is an integrative field that utilizes molecular pathology to incorporate interpersonal heterogeneity of a disease process into epidemiology. In each individual, the development and progression of a disease are determined by a unique combination of exogenous and endogenous factors, resulting in different molecular and pathological subtypes of the disease. Based on "the unique disease principle," the primary aim of MPE is to uncover an interactive relationship between a specific environmental exposure and disease subtypes in determining disease incidence and mortality. This MPE approach can provide etiologic and pathogenic insights, potentially contributing to precision medicine for personalized prevention and treatment. Although breast, prostate, lung, and colorectal cancers have been among the most commonly studied diseases, the MPE approach can be used to study any disease. In addition to molecular features, host immune status and microbiome profile likely affect a disease process, and thus serve as informative biomarkers. As such, further integration of several disciplines into MPE has been achieved (e.g., pharmaco-MPE, immuno-MPE, and microbial MPE), to provide novel insights into underlying etiologic mechanisms. With the advent of high-throughput sequencing technologies, available genomic and epigenomic data have expanded dramatically. The MPE approach can also provide a specific risk estimate for each disease subgroup, thereby enhancing the impact of genome-wide association studies on public health. In this article, we present recent progress of MPE, and discuss the importance of accounting for the disease heterogeneity in the era of big-data health science and precision medicine.
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Affiliation(s)
- Tsuyoshi Hamada
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Room SM1036, Boston, MA, 02215, USA
| | - NaNa Keum
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Reiko Nishihara
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Room SM1036, Boston, MA, 02215, USA.
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Room SM1036, Boston, MA, 02215, USA.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 450 Brookline Ave., Room SM1036, Boston, MA, 02215, USA.
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
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26
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Bailie L, Loughrey MB, Coleman HG. Lifestyle Risk Factors for Serrated Colorectal Polyps: A Systematic Review and Meta-analysis. Gastroenterology 2017; 152:92-104. [PMID: 27639804 DOI: 10.1053/j.gastro.2016.09.003] [Citation(s) in RCA: 136] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Revised: 08/18/2016] [Accepted: 09/21/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Certain subsets of colorectal serrated polyps (SP) have malignant potential. We performed a systematic review and meta-analysis to investigate the association between modifiable lifestyle factors and risk for SPs. METHODS We conducted a systematic search of Medline, Embase, and Web of Science for observational or interventional studies that contained the terms risk or risk factor, and serrated or hyperplastic, and polyps or adenomas, and colorectal (or synonymous terms), published by March 2016. Titles and abstracts of identified articles were independently reviewed by at least 2 reviewers. Adjusted relative risk (RR) and 95% confidence interval (CI) were combined using random effects meta-analyses to assess the risk of SP, when possible. RESULTS We identified 43 studies of SP risk associated with 7 different lifestyle factors: smoking, alcohol, body fatness, diet, physical activity, medication, and hormone-replacement therapy. When we compared the highest and lowest categories of exposure, factors we found to significantly increase risk for SP included tobacco smoking (RR, 2.47; 95% CI, 2.12-2.87), alcohol intake (RR, 1.33; 95% CI, 1.17-1.52), body mass index (RR, 1.40; 95% CI, 1.22-1.61), and high intake of fat or meat. Direct associations for smoking and alcohol, but not body fat, tended to be stronger for sessile serrated adenomas/polyps than hyperplastic polyps. In contrast, factors we found to significantly decrease risks for SP included use of nonsteroidal anti-inflammatory drugs (RR, 0.77; 95% CI, 0.65-0.92) or aspirin (RR, 0.81; 95% CI, 0.67-0.99), as well as high intake of folate, calcium, or fiber. No significant associations were detected between SP risk and physical activity or hormone replacement therapy. CONCLUSIONS Several lifestyle factors, most notably smoking and alcohol, are associated with SP risk. These findings enhance our understanding of mechanisms of SP development and indicate that risk of serrated pathway colorectal neoplasms could be reduced with lifestyle changes.
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Affiliation(s)
- Lesley Bailie
- Cancer Epidemiology and Health Services Research Group, Centre for Public Health, Queens University Belfast, Belfast, Northern Ireland
| | - Maurice B Loughrey
- Department of Pathology, Royal Victoria Hospital, Belfast Health and Social Care Trust, Belfast, Northern Ireland
| | - Helen G Coleman
- Cancer Epidemiology and Health Services Research Group, Centre for Public Health, Queens University Belfast, Belfast, Northern Ireland.
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Cao HL, Dong WX, Xu MQ, Zhang YJ, Wang SN, Piao MY, Cao XC, Wang BM. Clinical features of upper gastrointestinal serrated lesions: An endoscopy database analysis of 98746 patients. World J Gastroenterol 2016; 22:10038-10044. [PMID: 28018111 PMCID: PMC5143750 DOI: 10.3748/wjg.v22.i45.10038] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 11/03/2016] [Accepted: 11/16/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To analyse the clinical features of patients with the serrated lesions in the upper gastrointestinal tract (UPGI) tract.
METHODS Patients who underwent routine esophagogastroduodenoscopy (EGD) at the Digestive Endoscopy Centre of General Hospital, Tianjin Medical University between January 2011 and December 2015 were consecutively recruited. Patients with UPGI serrated lesions were consecutively identified. The patients’ demographics and histopathology were recorded. The colorectal findings for patients who underwent colonoscopy simultaneously or within six months were also extracted from the colonoscopy database. In addition, we analysed differences in colorectal neoplasia detection between the study patients and randomly selected patients matched for age and gender who did not exhibit serrated lesions and who also underwent colonoscopy in the same period.
RESULTS A total of 21 patients out of 98746 patients (0.02%) who underwent EGD were confirmed to have serrated lesions with predominantly crenated, sawtooth-like configurations. The mean age of the 21 patients was (55.3 ± 17.2) years, and 11 patients were male (52.4%). In terms of the locations of the serrated lesions, 17 were found in the stomach (including 3 in the cardia, 9 in the corpus and 5 in the antrum), 3 were found in the duodenum, and 1 was found in the esophagus. Serrated lesions were found in different mucosal lesions, with 14 lesions were detected in polyps (8 hyperplastic polyps and 6 serrated adenomas with low grade dysplasia), 3 detected in Ménétrier gastropathy, 3 detected in an area of inflammation or ulcer, and 1 detected in the intramucosal carcinoma of the duodenum. In addition, colonoscopy data were available for 18 patients, and a significantly higher colorectal adenoma detection rate was observed in the UPGI serrated lesions group than in the randomly selected age- and gender-matched group without serrated lesions who also underwent colonoscopy in the same period (38.9% vs 11.1%, OR = 5.091, 95%CI: 1.534-16.890, P = 0.010). The detection rate of advanced adenoma was also higher in the UPGI serrated lesions group (22.2% vs 4.2%, OR = 6.571, 95%CI: 1.322-32.660, P = 0.028).
CONCLUSION Serrated lesions in the UPGI were detected in various mucosal lesions with different pathological morphologies. Moreover colonoscopy is recommended for the detection of concurrent colorectal adenoma for these patients.
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Kin C. Management of malignant polyps. SEMINARS IN COLON AND RECTAL SURGERY 2016. [DOI: 10.1053/j.scrs.2016.04.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Abstract
The genetic events involved in the transformation of normal colonic epithelium to neoplastic polyps to invasive carcinoma, as initially proposed by Fearon and Vogelstein, form the foundation of our understanding of colorectal cancer. The identification of the polyp as the precursor lesion to colorectal cancer is the basis of many of our current practices for screening, surveillance, and prevention. The last three decades have seen a veritable explosion in our understanding of the molecular events involved in the pathogenesis of colorectal cancer. It is now clear that there are multiple genetic pathways in the polyp to carcinoma sequence. Some polyps previously thought to be nonneoplastic have now been shown to have malignant potential. Finally, increased understanding of the sequence of genetic events has led to the development of targeted therapeutics. The clinical translation of these scientific advances has made a significant impact on the management of patients with colorectal cancer. Accordingly, it is imperative that all clinicians caring for these patients have an understanding of the genetics of colorectal polyps and cancer. In this article, we review the etiology and genetic pathways to carcinoma associated with a range of polyps of the colon and rectum.
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Affiliation(s)
- Coen Laurens Klos
- Section of Colon and Rectal Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Sekhar Dharmarajan
- Section of Colon and Rectal Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
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Tsikitis VL, Potter A, Mori M, Buckmeier JA, Preece CR, Harrington CA, Bartley AN, Bhattacharyya AK, Hamilton SR, Lance MP, Thompson PA. MicroRNA Signatures of Colonic Polyps on Screening and Histology. Cancer Prev Res (Phila) 2016; 9:942-949. [PMID: 27658891 DOI: 10.1158/1940-6207.capr-16-0086] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 08/10/2016] [Accepted: 08/31/2016] [Indexed: 12/13/2022]
Abstract
Colorectal cancer and adenoma adjacent to cancer exhibit distinct microRNA (miRNA) alterations in an apparent mucosa-to-adenocarcinoma sequence. The pattern of microRNAs in screen-detected polyps in relation to histologic features and cancer risk has not been investigated. miRNA expression analysis was performed on normal mucosa (NM), hyperplastic polyps (HP), tubular adenomas (TA), tubulovillous adenomas or high-grade dysplasia (TVHG), and serrated polyps [sessile serrated adenoma/polyps (SSA/P) and traditional serrated adenomas (TSA)] in biopsy specimens from 109 patients undergoing screening/surveillance colonoscopy. Generalized linear models were used to identify differentially expressed miRNAs by histologic type and logistic regression to identify miRNA predictors of histopathology. False discovery rate (FDR) was used to control for multiple comparisons. We identified 99 miRNAs differing in at least one of five histopathologic groups (FDR ≤0.05). In a comparison of HPNM versus TVHG, the top most upregulated and downregulated miRNAs in HPNM included miR-145, -143, -107, -194, and -26a (upregulated), and miR-663, -1268, -320b, -1275, and -320b (downregulated; FDR P < 0.05). miR-145 and -619 showed high accuracy to discriminate low- from high-risk polyps without serrated histology (TVHG vs. HPNM + TA; CI, 95.6%), whereas miR-124, -143, and -30a showed high accuracy of separating high-risk polyps (TVHG + TSA) from low-risk polyps (HPNM + TA + SSA/P; CI, 96.0%). For TSAs, miR-125b and -199a were uniquely downregulated relative to HPNMs, and miR-335, -222, and -214 discriminated between non-serrated and serrated histology. Our data support the presence of colorectal cancer-associated miRNA alterations in screen-detected adenomas that may be useful for risk stratification for surveillance interval planning. Cancer Prev Res; 9(12); 942-9. ©2016 AACR.
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Affiliation(s)
| | - Amiee Potter
- Oregon Health and Science University, Integrated Genomics Laboratory, Portland, Oregon
| | - Motomi Mori
- Oregon Health and Science University, Integrated Genomics Laboratory, Portland, Oregon.,Oregon Health and Science University, Knight Cancer Institute, Portland, Oregon
| | | | | | | | - Angela N Bartley
- Integrated Healthcare Associates, Dept of Anatomic and Clinical Pathology, Ann Arbor, Michigan
| | | | - Stanley R Hamilton
- Integrated Healthcare Associates, Dept of Anatomic and Clinical Pathology, Ann Arbor, Michigan
| | - M Peter Lance
- Department of Molecular and Cell Biology, University of Arizona Cancer Center, Tucson, Arizona
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Ruiz-Rebollo ML, Del Olmo-Martínez L, Velayos-Jiménez B, Muñoz MF, Álvarez-Quiñones-Sanz M, González-Hernández JM. Aetiology and prevalence of post-colonoscopy colorrectal cancer. GASTROENTEROLOGIA Y HEPATOLOGIA 2016; 39:647-655. [PMID: 26996465 DOI: 10.1016/j.gastrohep.2016.01.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2015] [Revised: 01/02/2016] [Accepted: 01/13/2016] [Indexed: 11/17/2022]
Abstract
BACKGROUND Colonoscopy is the gold standard for the detection and prevention of colorectal cancer (CRC). However, some individuals are diagnosed with CRC soon after a previous colonoscopy. AIMS To evaluate the rate of new onset or missed CRC after a previous colonoscopy and to study potential risk factors. METHODS Patients in our endoscopy database diagnosed with CRC from March 2004 to September 2011 were identified, selecting those with a colonoscopy performed within the previous 5years. Medical records included age, gender, comorbidities and colonoscopy indication. Tumour characteristics studied were localization, size, histological grade and TNM stage and possible cause. These patients were compared with those diagnosed with CRC at their first endoscopy (sporadic CRC-control group). RESULTS A total of 712 patients with CRC were included; 24 patients (3.6%) had undergone colonoscopy within the previous 5 years (50% male, 50% female, mean age 72). Post-colonoscopy CRCs were attributed to: 1 (4.2%) incomplete colonoscopy, 4 (16.6%) incomplete polyp removal, 1 (4.2%) failed biopsy, 8 (33.3%) 'missed lesions' and 10 (41.7%) new onset CRC. Post-colonoscopy CRCs were smaller in size than sporadic CRCs (3.2cm vs. 4.5cm, P<.001) and were mainly located in the proximal colon (63% vs. 35%, P=.006); no difference in histological grade was found (P=.125), although there was a tendency towards a lower TNM stage (P=.053). CONCLUSIONS There is a minor risk of CRC development after a previous colonoscopy (3.6%). Most of these (58.4%) are due to preventable factors. Post-colonoscopy CRCs were smaller and mainly right-sided, with a tendency towards an earlier TNM stage.
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Affiliation(s)
| | | | | | - Maria Fe Muñoz
- Unidad de Apoyo a la Investigación, Hospital Clínico Universitario, Valladolid, España
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Nishi A, Milner DA, Giovannucci EL, Nishihara R, Tan AS, Kawachi I, Ogino S. Integration of molecular pathology, epidemiology and social science for global precision medicine. Expert Rev Mol Diagn 2015; 16:11-23. [PMID: 26636627 PMCID: PMC4713314 DOI: 10.1586/14737159.2016.1115346] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The precision medicine concept and the unique disease principle imply that each patient has unique pathogenic processes resulting from heterogeneous cellular genetic and epigenetic alterations and interactions between cells (including immune cells) and exposures, including dietary, environmental, microbial and lifestyle factors. As a core method field in population health science and medicine, epidemiology is a growing scientific discipline that can analyze disease risk factors and develop statistical methodologies to maximize utilization of big data on populations and disease pathology. The evolving transdisciplinary field of molecular pathological epidemiology (MPE) can advance biomedical and health research by linking exposures to molecular pathologic signatures, enhancing causal inference and identifying potential biomarkers for clinical impact. The MPE approach can be applied to any diseases, although it has been most commonly used in neoplastic diseases (including breast, lung and colorectal cancers) because of availability of various molecular diagnostic tests. However, use of state-of-the-art genomic, epigenomic and other omic technologies and expensive drugs in modern healthcare systems increases racial, ethnic and socioeconomic disparities. To address this, we propose to integrate molecular pathology, epidemiology and social science. Social epidemiology integrates the latter two fields. The integrative social MPE model can embrace sociology, economics and precision medicine, address global health disparities and inequalities, and elucidate biological effects of social environments, behaviors and networks. We foresee advancements of molecular medicine, including molecular diagnostics, biomedical imaging and targeted therapeutics, which should benefit individuals in a global population, by means of an interdisciplinary approach of integrative MPE and social health science.
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Affiliation(s)
- Akihiro Nishi
- Yale Institute for Network Science, New Haven, CT, USA (AN); Department of Sociology, Yale University, New Haven, CT, USA (AN); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (DAM, SO); Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA (DAM); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN, SO); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (ELG); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA (RN); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA (RN, AST, SO); Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA (AST, IK)
| | - Danny A Milner
- Yale Institute for Network Science, New Haven, CT, USA (AN); Department of Sociology, Yale University, New Haven, CT, USA (AN); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (DAM, SO); Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA (DAM); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN, SO); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (ELG); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA (RN); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA (RN, AST, SO); Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA (AST, IK)
| | - Edward L. Giovannucci
- Yale Institute for Network Science, New Haven, CT, USA (AN); Department of Sociology, Yale University, New Haven, CT, USA (AN); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (DAM, SO); Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA (DAM); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN, SO); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (ELG); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA (RN); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA (RN, AST, SO); Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA (AST, IK)
| | - Reiko Nishihara
- Yale Institute for Network Science, New Haven, CT, USA (AN); Department of Sociology, Yale University, New Haven, CT, USA (AN); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (DAM, SO); Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA (DAM); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN, SO); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (ELG); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA (RN); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA (RN, AST, SO); Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA (AST, IK)
| | - Andy S. Tan
- Yale Institute for Network Science, New Haven, CT, USA (AN); Department of Sociology, Yale University, New Haven, CT, USA (AN); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (DAM, SO); Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA (DAM); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN, SO); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (ELG); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA (RN); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA (RN, AST, SO); Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA (AST, IK)
| | - Ichiro Kawachi
- Yale Institute for Network Science, New Haven, CT, USA (AN); Department of Sociology, Yale University, New Haven, CT, USA (AN); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (DAM, SO); Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA (DAM); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN, SO); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (ELG); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA (RN); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA (RN, AST, SO); Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA (AST, IK)
| | - Shuji Ogino
- Yale Institute for Network Science, New Haven, CT, USA (AN); Department of Sociology, Yale University, New Haven, CT, USA (AN); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (DAM, SO); Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA (DAM); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN, SO); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (ELG); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA (RN); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA (RN, AST, SO); Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA (AST, IK)
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Liu FT, Ou-Yang X, Zhang GP, Luo HL. Progress in research of colorectal intraepithelial neoplasia and adenoma. Shijie Huaren Xiaohua Zazhi 2015; 23:3413-3420. [DOI: 10.11569/wcjd.v23.i21.3413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is a common malignant tumor in the digestive system, and the early diagnosis of colorectal cancer has been the focus of its prevention and control. Colorectal intraepithelial neoplasia and adenoma are considered to be the most important precancerous lesions of colorectal cancer. In recent years, with the development of biological medicine, genetics,
and other disciplines, many studies have explored the relationship between intraepithelial neoplasia and adenoma and colorectal cancer, and some new research progress has been achieved to provide some guidance for the future clinical screening, regular follow-up and chemical prevention. However, it remains to be studied how colorectal intraepithelial neoplasia and adenoma form and evolve to colorectal cancer.
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Ogino S, Campbell PT, Nishihara R, Phipps AI, Beck AH, Sherman ME, Chan AT, Troester MA, Bass AJ, Fitzgerald KC, Irizarry RA, Kelsey KT, Nan H, Peters U, Poole EM, Qian ZR, Tamimi RM, Tchetgen Tchetgen EJ, Tworoger SS, Zhang X, Giovannucci EL, van den Brandt PA, Rosner BA, Wang M, Chatterjee N, Begg CB. Proceedings of the second international molecular pathological epidemiology (MPE) meeting. Cancer Causes Control 2015; 26:959-72. [PMID: 25956270 DOI: 10.1007/s10552-015-0596-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 04/27/2015] [Indexed: 02/07/2023]
Abstract
Disease classification system increasingly incorporates information on pathogenic mechanisms to predict clinical outcomes and response to therapy and intervention. Technological advancements to interrogate omics (genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, interactomics, etc.) provide widely open opportunities in population-based research. Molecular pathological epidemiology (MPE) represents integrative science of molecular pathology and epidemiology. This unified paradigm requires multidisciplinary collaboration between pathology, epidemiology, biostatistics, bioinformatics, and computational biology. Integration of these fields enables better understanding of etiologic heterogeneity, disease continuum, causal inference, and the impact of environment, diet, lifestyle, host factors (including genetics and immunity), and their interactions on disease evolution. Hence, the Second International MPE Meeting was held in Boston in December 2014, with aims to: (1) develop conceptual and practical frameworks; (2) cultivate and expand opportunities; (3) address challenges; and (4) initiate the effort of specifying guidelines for MPE. The meeting mainly consisted of presentations of method developments and recent data in various malignant neoplasms and tumors (breast, prostate, ovarian and colorectal cancers, renal cell carcinoma, lymphoma, and leukemia), followed by open discussion sessions on challenges and future plans. In particular, we recognized need for efforts to further develop statistical methodologies. This meeting provided an unprecedented opportunity for interdisciplinary collaboration, consistent with the purposes of the Big Data to Knowledge, Genetic Associations and Mechanisms in Oncology, and Precision Medicine Initiative of the US National Institute of Health. The MPE meeting series can help advance transdisciplinary population science and optimize training and education systems for twenty-first century medicine and public health.
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Affiliation(s)
- Shuji Ogino
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 450 Brookline Ave., Room M422, Boston, MA, 02215, USA,
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