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Ceccon C, Borga C, Angerilli V, Bergamo F, Munari G, Sabbadin M, Gasparello J, Schiavi F, Zovato S, Scarpa M, Urso EDL, Dei Tos AP, Luchini C, Grillo F, Lonardi S, Parente P, Fassan M. MLH1 gene promoter methylation status partially overlaps with CpG methylator phenotype (CIMP) in colorectal adenocarcinoma. Pathol Res Pract 2024; 266:155786. [PMID: 39724851 DOI: 10.1016/j.prp.2024.155786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/18/2024] [Accepted: 12/18/2024] [Indexed: 12/28/2024]
Abstract
BACKGROUND RAS/BRAF mutations, mismatch DNA repair complex deficiency (MMRd)/microsatellite instability (MSI), and CpG methylator phenotype (CIMP) are key molecular actors in colorectal carcinogenesis. To date, conflicting evidence about the correlations between these molecular features has been reported. MATERIALS AND METHODS A retrospectively selected cohort of 123 CRCs was divided into 3 groups based on the molecular characteristics: MMR proficient (MMRp)/BRAF p.V600E mutated (BRAFmut), MMRd/BRAFmut, and MMRd/BRAF wild type (BRAFwt). MLH1 promoter (pMLH1) methylation status was assessed by pyrosequencing. For 82 samples the CIMP phenotype was evaluated using the EpiTect® MethyLight kit. RESULTS The MMRd/BRAFmut group showed a higher pMLH1 methylation rate compared to both the MMRd/BRAFwt and the MMRp/BRAFmut groups. Overall, the two MMRd groups had a higher methylation rate compared to the MMRp cases independently from the mutational status of BRAF (p-value <0.0001). The MMRd/BRAFmut group was characterized by a 90.0 % of CIMP high (CIMP-H) tumors of which 97.2 % were pMLH1 methylated. Instead, the MMRd/BRAFwt group presented 50.0 % of CIMP-H adenocarcinomas. CONCLUSIONS Our study demonstrates that pMLH1 hypermethylation, MMRd, BRAFmut and CIMP phenotype do not completely overlap in CRC. These findings further refine the knowledge on the molecular landscape of CRC and may have critical implications also for the clinical management of the disease.
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Affiliation(s)
- Carlotta Ceccon
- Department of Medicine - DIMED, University of Padova, Padova, Italy; Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | - Chiara Borga
- Department of Pathology, Azienda Ospedale-Università Padova, Padua, Italy
| | - Valentina Angerilli
- Department of Medicine - DIMED, University of Padova, Padova, Italy; Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | | | - Giada Munari
- Department of Pathology, Azienda Ospedale-Università Padova, Padua, Italy
| | - Marianna Sabbadin
- Department of Medicine - DIMED, University of Padova, Padova, Italy; Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy
| | | | | | | | - Marco Scarpa
- General Surgery 3, Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), Azienda Ospedale-Università Padova, Padua, Italy
| | - Emanuele Damiano Luca Urso
- General Surgery 3, Department of Surgical, Oncological and Gastroenterological Sciences (DiSCOG), Azienda Ospedale-Università Padova, Padua, Italy
| | - Angelo Paolo Dei Tos
- Department of Medicine - DIMED, University of Padova, Padova, Italy; Department of Pathology, Azienda Ospedale-Università Padova, Padua, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy
| | - Federica Grillo
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, Italy
| | - Sara Lonardi
- Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Paola Parente
- Unit of Pathology, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia, Italy
| | - Matteo Fassan
- Department of Medicine - DIMED, University of Padova, Padova, Italy; Department of Pathology, Azienda ULSS2 Marca Trevigiana, Treviso, Italy.
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Fusco W, Bricca L, Kaitsas F, Tartaglia MF, Venturini I, Rugge M, Gasbarrini A, Cammarota G, Ianiro G. Gut microbiota in colorectal cancer: From pathogenesis to clinic. Best Pract Res Clin Gastroenterol 2024; 72:101941. [PMID: 39645279 DOI: 10.1016/j.bpg.2024.101941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 06/04/2024] [Indexed: 12/09/2024]
Abstract
Colorectal cancer is the third most common type of cancer, with a significant burden on healthcare and social systems. Its incidence is constantly rising, due to the spread of unhealthy lifestyle, i.e. Western diet. Increasing evidence suggests that westernization-driven microbiome alterations may play a critical role in colorectal tumorigenesis. The current screening strategies for this neoplasm, mainly fecal immunochemical tests, are burdened by unsatisfactory accuracy. Novel, non-invasive biomarkers are rising as the new frontier of colorectal cancer screening, and the microbiome-based ones are showing positive and optimistic results. This Review describes our current knowledge on the role of gut microbiota in colorectal cancer, from its pathogenetic action to its clinical potential as diagnostic biomarker.
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Affiliation(s)
- William Fusco
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy.
| | - Ludovica Bricca
- Department of Medicine - DIMED, Surgical Pathology and Cytopathology Unit, Università degli Studi di Padova, Padova, Italy
| | - Francesco Kaitsas
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy
| | | | - Irene Venturini
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Massimo Rugge
- Department of Medicine - DIMED, Surgical Pathology and Cytopathology Unit, Università degli Studi di Padova, Padova, Italy
| | - Antonio Gasbarrini
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Giovanni Cammarota
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Gianluca Ianiro
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Medical and Surgical Sciences, UOC Gastroenterologia, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Medical and Surgical Sciences, UOC CEMAD Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
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Sugai T, Osakabe M, Uesugi N, Habano W, Yanagawa N, Suzuki H. Comprehensive Analyses of Somatic Copy Number Alterations and Mutations Based on the Adenoma-Carcinoma Sequence. Genes Chromosomes Cancer 2024; 63:e23267. [PMID: 39258844 DOI: 10.1002/gcc.23267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 07/31/2024] [Accepted: 08/20/2024] [Indexed: 09/12/2024] Open
Abstract
AIMS Identifying molecular alterations in the adenoma and carcinoma components within the same tumor would greatly contribute to understanding the neoplastic progression of early colorectal cancer. METHODS AND RESULTS We examined somatic copy number alterations (SCNAs) and mutations involved in the adenoma and carcinoma components obtained from the same tumor in 46 cases of microsatellite-stable carcinoma in adenoma, using a genome-wide SNP array and gene mutation panel. In addition, we also performed hierarchical clustering to determine the SCNA frequencies in the tumors, resulting in stratification of the samples into two subgroups according to SCNA frequency. Subgroup 1 was characterized by multiple SCNAs and carcinoma components exclusively, while Subgroup 2 was characterized by a low frequency of SCNAs and both the adenoma and carcinoma components. The numbers of total genes and genes with gains were higher in the carcinoma than adenoma components. The three most frequent gains in both components were located at 1p36.33-1q44, 2p25.3-2q37.3, and 3p26.3-3q29. However, no candidate genes mapped to these regions. APC and KRAS mutations were common in both components, whereas the frequency of TP53 mutations was statistically higher in the carcinoma than adenoma component. However, TP53 mutations were not correlated with SCNA frequency. CONCLUSIONS We suggest that considerable SCNAs and TP53 mutations are required for progression from adenoma to carcinoma within the same intramucosal neoplastic lesion.
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Affiliation(s)
- Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwa-gun, Japan
- Diagnostic Pathology Center, Southern Tohoku General Hospital, Fukushima, Japan
| | - Mitsumasa Osakabe
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwa-gun, Japan
| | - Noriyuki Uesugi
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwa-gun, Japan
- Diagnostic Pathology Center, Southern Tohoku General Hospital, Fukushima, Japan
| | - Wataru Habano
- Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Morioka, Japan
| | - Naoki Yanagawa
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwa-gun, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University, School of Medicine, Sapporo, Japan
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Korekawa K, Shimoyama Y, Fujishima F, Nagai H, Naito T, Moroi R, Shiga H, Kakuta Y, Kinouchi Y, Masamune A. White spots around colorectal tumors are cancer-related findings and may aid endoscopic diagnosis: a prospective study in Japan. Clin Endosc 2024; 57:637-646. [PMID: 38902852 PMCID: PMC11474470 DOI: 10.5946/ce.2024.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/14/2024] [Accepted: 04/28/2024] [Indexed: 06/22/2024] Open
Abstract
BACKGROUND/AIMS During endoscopy, white spots (WS) are sometimes observed around benign or malignant colorectal tumors; however, few reports have investigated WS, and their significance remains unknown. Therefore, we investigated the significance of WS from clinical and pathological viewpoints and evaluated its usefulness in endoscopic diagnosis. METHODS Clinical data of patients with lesions diagnosed as epithelial tumors from January 1, 2019, to December 31, 2020, were analyzed (n=3,869). We also performed a clinicopathological analysis of adenomas or carcinomas treated with endoscopic resection (n=759). Subsequently, detailed pathological observations of the WS were performed. RESULTS The positivity rates for WS were 9.3% (3,869 lesions including advanced cancer and non-adenoma/carcinoma) and 25% (759 lesions limited to adenoma and early carcinoma). Analysis of 759 lesions showed that the WS-positive lesion group had a higher proportion of cancer cases and larger tumor diameters than the WS-negative group. Multiple logistic analysis revealed the following three statistically significant risk factors for carcinogenesis: positive WS, flat lesions, and tumor diameter ≥5 mm. Pathological analysis revealed that WS were macrophages that phagocytosed fat and mucus and were white primarily because of fat. CONCLUSIONS WS are cancer-related findings and can become a new criterion for endoscopic resection in the future.
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Affiliation(s)
- Kai Korekawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yusuke Shimoyama
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Fumiyoshi Fujishima
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroshi Nagai
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takeo Naito
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Rintaro Moroi
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hisashi Shiga
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoichi Kakuta
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshitaka Kinouchi
- Student Healthcare Center, Institute for Excellence in Higher Education, Tohoku University, Sendai, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Yan L, Shi J, Zhu J. Cellular and molecular events in colorectal cancer: biological mechanisms, cell death pathways, drug resistance and signalling network interactions. Discov Oncol 2024; 15:294. [PMID: 39031216 PMCID: PMC11265098 DOI: 10.1007/s12672-024-01163-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 07/15/2024] [Indexed: 07/22/2024] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, affecting millions each year. It emerges from the colon or rectum, parts of the digestive system, and is closely linked to both genetic and environmental factors. In CRC, genetic mutations such as APC, KRAS, and TP53, along with epigenetic changes like DNA methylation and histone modifications, play crucial roles in tumor development and treatment responses. This paper delves into the complex biological underpinnings of CRC, highlighting the pivotal roles of genetic alterations, cell death pathways, and the intricate network of signaling interactions that contribute to the disease's progression. It explores the dysregulation of apoptosis, autophagy, and other cell death mechanisms, underscoring the aberrant activation of these pathways in CRC. Additionally, the paper examines how mutations in key molecular pathways, including Wnt, EGFR/MAPK, and PI3K, fuel CRC development, and how these alterations can serve as both diagnostic and prognostic markers. The dual function of autophagy in CRC, acting as a tumor suppressor or promoter depending on the context, is also scrutinized. Through a comprehensive analysis of cellular and molecular events, this research aims to deepen our understanding of CRC and pave the way for more effective diagnostics, prognostics, and therapeutic strategies.
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Affiliation(s)
- Lei Yan
- Medical Department, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jia Shi
- Department of Obstetrics and Gynecology, The Central Hospital of Shaoyang Affiliated to University of South China, Shaoyang, China
| | - Jiazuo Zhu
- Department of Oncology, Xuancheng City Central Hospital, No. 117 Tong Road, Xuancheng, Anhui, China.
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Kobayashi R, Yoshida N, Morinaga Y, Hashimoto H, Tomita Y, Sugino S, Inoue K, Hirose R, Dohi O, Murakami T, Inada Y, Morimoto Y, Itoh Y. The Comparison of Diagnostic Ability between Blue Laser/Light Imaging and Narrowband Imaging for Sessile Serrated Lesions with or without Dysplasia. Gastroenterol Res Pract 2024; 2024:2672289. [PMID: 38882393 PMCID: PMC11178415 DOI: 10.1155/2024/2672289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 03/14/2024] [Accepted: 05/06/2024] [Indexed: 06/18/2024] Open
Abstract
Objectives Diagnostic ability of sessile serrated lesions (SSL) and SSL with dysplasia (SSLD) using blue laser/light imaging (BLI) has not been well examined. We analyzed the diagnostic accuracy of BLI for SSL and SSLD using several endoscopic findings compared to those of narrow band imaging (NBI). Materials and Methods This was a subgroup analysis of prospective studies. 476 suspiciously serrated lesions of ≥2 mm on the proximal colon showing serrated change with magnified NBI or BLI in our institution between 2014 and 2021 were examined histopathologically. After propensity score matching, we evaluated the diagnostic ability of SSL and SSLD of the NBI and BLI groups regarding various endoscopic findings. For WLI findings, granule, depression, and reddish were examined for diagnosing SSLD. For NBI/BLI findings, expanded crypt opening (ECO) or thick and branched vessels (TBV) were examined for diagnosing SSL. Network vessels (NV) and white dendritic change (WDC) defined originally were examined for diagnosing SSLD. Results Among matched 176 lesions, the sensitivity of lesions with either ECO or TBV for SSL in the NBI/BLI group was 97.5%/98.5% (p = 0.668). Those with either WDC or NV for diagnosing SSLD in the groups were 81.0%/88.9% (p = 0.667). Regarding the rates of endoscopic findings among 30 SSLD and 290 SSL, there were significant differences in WDC (66.4% vs. 8.6%, p < 0.001), NV (55.3% vs. 1.4%, p < 0.001), and either WDC or NV (86.8% vs. 9.0%, p < 0.001). Conclusions The diagnostic ability of BLI for SSL and SSLD was not different from NBI. NV and WDC were useful for diagnosing SSLD.
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Affiliation(s)
- Reo Kobayashi
- Department of Molecular Gastroenterology and Hepatology Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Naohisa Yoshida
- Department of Molecular Gastroenterology and Hepatology Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Yukiko Morinaga
- Department of Surgical Pathology Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Hikaru Hashimoto
- Department of Molecular Gastroenterology and Hepatology Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Yuri Tomita
- Department of Molecular Gastroenterology and Hepatology Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Satoshi Sugino
- Department of Molecular Gastroenterology and Hepatology Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Ken Inoue
- Department of Molecular Gastroenterology and Hepatology Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Ryohei Hirose
- Department of Molecular Gastroenterology and Hepatology Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Osamu Dohi
- Department of Molecular Gastroenterology and Hepatology Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
| | - Takaaki Murakami
- Department of Gastroenterology Aiseikai Yamashina Hospital, Kyoto, Japan
| | - Yutaka Inada
- Department of Gastroenterology Kyoto First Red Cross Hospital, Kyoto, Japan
| | - Yasutaka Morimoto
- Department of Gastroenterology Saiseikai Kyoto Hospital, Kyoto, Japan
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology Kyoto Prefectural University of Medicine Graduate School of Medical Science, Kyoto, Japan
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Ogurchenok NE, Khalin KD, Bryukhovetskiy IS. Chemoprophylaxis of precancerous lesions in patients who are at a high risk of developing colorectal cancer (Review). MEDICINE INTERNATIONAL 2024; 4:25. [PMID: 38628384 PMCID: PMC11019464 DOI: 10.3892/mi.2024.149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Accepted: 03/07/2024] [Indexed: 04/19/2024]
Abstract
The diagnostics of colorectal cancer (CRC) and precancerous lesions in the colon is one of the most urgent matters to be considered for the modern protocols of complex examination, recommended for use from the age of 45 years, and including both instrumental and laboratory methods of research: Colonoscopy, CT colonography, flexible sigmoidoscopy, fecal occult blood test, fecal immunohistochemistry test and stool DNA test Nevertheless, the removal of those precancerous lesions does not solve the issue, and, apart from the regular endoscopic monitoring of patients who are at a high risk of developing CRC, the pharmacological treatment of certain key pathogenic mechanisms leading to the development of CRC is required. The present review to discusses the function of β-catenin in the transformation of precancerous colorectal lesions into CRC, when collaborating with PI3K/AKT/mTOR signaling pathway and other mechanisms. The existing methods for the early diagnostics and prevention of discovered anomalies are described and categorized. The analysis of the approaches to chemoprophylaxis of CRC, depending on the results of endoscopic, morphological and molecular-genetic tests, is presented.
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Affiliation(s)
- Nonna E. Ogurchenok
- Far Eastern Federal University, School of Medicine and Life Sciences, FEFU Medical Center, Russky Island, 690091 Vladivostok, Russian Federation
- Primorskiy Regional Clinical Hospital N1, Medical Center, Russky Island, 690091 Vladivostok, Russian Federation
| | - Konstantin D. Khalin
- Far Eastern Federal University, School of Medicine and Life Sciences, FEFU Medical Center, Russky Island, 690091 Vladivostok, Russian Federation
- Far Eastern Federal University, Medical Center, Russky Island, 690091 Vladivostok, Russian Federation
| | - Igor S. Bryukhovetskiy
- Far Eastern Federal University, Medical Center, Russky Island, 690091 Vladivostok, Russian Federation
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Yamamoto N, Yamashita K, Takehara Y, Morimoto S, Tanino F, Kamigaichi Y, Tanaka H, Arihiro K, Shimamoto F, Oka S. Characteristics and Prognosis of Sporadic Neoplasias Detected in Patients with Ulcerative Colitis. Digestion 2024; 105:213-223. [PMID: 38417416 DOI: 10.1159/000537756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 02/08/2024] [Indexed: 03/01/2024]
Abstract
INTRODUCTION Patients with ulcerative colitis (UC) develop not only UC-associated neoplasias but also sporadic neoplasias (SNs). However, few studies have described the characteristics of SNs in patients with UC. Therefore, this study aimed to evaluate the clinical features and prognosis of SNs in patients with UC. METHODS A total of 141 SNs in 59 patients with UC, detected by surveillance colonoscopy at Hiroshima University Hospital between January 1999 and December 2021, were included. SNs were diagnosed based on their location, endoscopic features, and histopathologic findings along with immunohistochemical staining for Ki67 and p53. RESULTS Of the SNs, 91.5% were diagnosed as adenoma and 8.5% were diagnosed as carcinoma (Tis carcinoma, 3.5%; T1 carcinoma, 5.0%). 61.0% of the SNs were located in the right colon, 31.2% were located in the left colon, and 7.8% were located in the rectum. When classified based on the site of the lesion, 70.9% of SNs occurred outside and 29.1% within the affected area. Of all SNs included, 95.7% were endoscopically resected and 4.3% were surgically resected. Among the 59 patients included, synchronous SNs occurred in 23.7% and metachronous multiple SNs occurred in 40.7% during surveillance. The 5-year cumulative incidence of metachronous multiple SNs was higher in patients with synchronous multiple SNs (54.2%) than in those without synchronous multiple SNs (46.4%). CONCLUSION Patients with UC with synchronous multiple SNs are at a higher risk of developing metachronous multiple SNs and may require a closer follow-up by total colonoscopy than patients without synchronous SNs.
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Affiliation(s)
- Noriko Yamamoto
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Ken Yamashita
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Yudai Takehara
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Shin Morimoto
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Fumiaki Tanino
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Yuki Kamigaichi
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Hidenori Tanaka
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
| | - Koji Arihiro
- Department of Anatomical Pathology, Hiroshima University Hospital, Hiroshima, Japan
| | - Fumio Shimamoto
- Faculty of Health Sciences, Hiroshima Cosmopolitan University, Hiroshima, Japan
| | - Shiro Oka
- Department of Gastroenterology, Hiroshima University Hospital, Hiroshima, Japan
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Kawaguchi T, Okamoto K, Fujimoto S, Bando M, Wada H, Miyamoto H, Sato Y, Muguruma N, Horimoto K, Takayama T. Lansoprazole inhibits the development of sessile serrated lesions by inducing G1 arrest via Skp2/p27 signaling pathway. J Gastroenterol 2024; 59:11-23. [PMID: 37989907 DOI: 10.1007/s00535-023-02052-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 10/07/2023] [Indexed: 11/23/2023]
Abstract
BACKGROUND Although the serrated-neoplasia pathway reportedly accounts for 15-30% of colorectal cancer (CRC), no studies on chemoprevention of sessile serrated lesions (SSLs) have been reported. We searched for effective compounds comprehensively from a large series of compounds by employing Connectivity Map (CMAP) analysis of SSL-specific gene expression profiles coupled with in vitro screening using SSL patient-derived organoids (PDOs), and validated their efficacy using a xenograft mouse model of SSL. METHODS We generated SSL-specific gene signatures based on DNA microarray data, and applied them to CMAP analysis with 1309 FDA-approved compounds to select candidate compounds. We evaluated their inhibitory effects on SSL-PDOs using a cell viability assay. SSL-PDOs were orthotopically transplanted into NOG mice for in vivo evaluation. The signal transduction pathway was evaluated by gene expression profile and protein expression analysis. RESULTS We identified 221 compounds by employing CMAP analysis of SSL-specific signatures, which should cancel the gene signatures, and narrowed them down to 17 compounds. Cell viability assay using SSL-PDOs identified lansoprazole as having the lowest IC50 value (47 µM) among 17 compounds. When SSL-PDO was orthotopically transplanted into murine intestinal tract, the tumor grew gradually. Administration of lansoprazole to mice inhibited the growth of SSL xenograft whereas the tumor in control mice treated with vehicle alone grew gradually over time. The Ki67 index in xenograft lesions from the lansoprazole group was significantly lower compared with the control group. Cell cycle analysis of SSL-PDOs treated with lansoprazole exhibited a significant increase in G1 phase cell population. Microarray and protein analysis revealed that lansoprazole downregulated Skp2 expression and upregulated p27 expression in SSL-PDOs. CONCLUSIONS Our data strongly suggest that lansoprazole is the most effective chemopreventive agent against SSL, and that lansoprazole induces G1 cell cycle arrest by downregulating Skp2 and upregulating p27 in SSL cells.
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Affiliation(s)
- Tomoyuki Kawaguchi
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Shota Fujimoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Masahiro Bando
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Hironori Wada
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Yasushi Sato
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Naoki Muguruma
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan
| | - Katsuhisa Horimoto
- Molecular Profiling Research Center for Drug Discovery (Molprof) National Institute of Advanced Industrial Science and Technology (AIST), 2-3-26 Aomi, Koto-ku, Tokyo, 135-0064, Japan
- SOCIUM Inc, 2-4-7 Aomi, Koto-ku, Tokyo, 135-0064, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
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10
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Boregowda U, Umapathy C, Echavarria J, Saligram S. Risk of Metachronous Neoplasia with High-Risk Adenoma and Synchronous Sessile Serrated Adenoma: A Systematic Review and Meta-Analysis. Diagnostics (Basel) 2023; 13:diagnostics13091569. [PMID: 37174960 PMCID: PMC10177994 DOI: 10.3390/diagnostics13091569] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/27/2023] [Accepted: 04/24/2023] [Indexed: 05/15/2023] Open
Abstract
Background: Sessile serrated adenomas are important precursors to colorectal cancers and account for 30% of colorectal cancers. The United States Multi-Society Task Force recommends that patients with sessile serrated adenomas undergo surveillance similar to tubular adenomas. However, the risk of metachronous neoplasia when the high-risk adenoma co-exists with sessile serrated adenomas is poorly defined. Objective: To examine the risk of metachronous neoplasia in the presence of high-risk adenoma and synchronous sessile serrated adenomas compared with isolated high-risk adenoma. Data sources: PubMed, Embase, Scopus, Cochrane Library. Study selection: A literature search for studies evaluating the risk of metachronous neoplasia in patients with high-risk adenoma alone and those with synchronous high-risk adenoma and sessile serrated adenomas during surveillance colonoscopy was conducted on online databases. Main outcome measures: The primary outcome of interest was the presence of metachronous neoplasia. Results: Of the 1164 records reviewed, six (four retrospective and two prospective) studies met inclusion criteria with 2490 patients (1607 males, mean age 59.98 ± 3.23 years). Average follow-up was 47.5 ± 12.5 months. There were 2068 patients with high-risk adenoma on index colonoscopy and 422 patients with high-risk adenoma and synchronous sessile serrated adenomas. Pooled estimates showed a significantly elevated risk for metachronous neoplasia in patients with high-risk adenoma and synchronous sessile serrated adenomas (pooled odds ratio 2.21; 95% confidence intervals 1.65-2.96; p < 0.01). There was low heterogeneity (I2 = 11%) among the studies. Sensitivity analysis of the prospective studies alone also showed elevated risk of metachronous neoplasm (pooled odds ratio 2.56; 95%, confidence intervals 1.05-6.23; p = 0.04). Limitations: Inclusion of a small number of retrospective studies. Conclusions: The presence of high-risk adenomas and synchronous sessile serrated adenomas is associated with an increased risk of metachronous neoplasia. Therefore, shorter surveillance intervals may be considered in patients with high-risk adenoma and synchronous sessile serrated adenomas compared to those with high-risk adenoma alone.
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Affiliation(s)
- Umesha Boregowda
- Division of Gastroenterology, Hepatology, and Nutrition, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Chandraprakash Umapathy
- Division of Gastroenterology, Hepatology, and Nutrition, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Juan Echavarria
- Division of Gastroenterology, Hepatology, and Nutrition, University of Texas Health San Antonio, San Antonio, TX 78229, USA
| | - Shreyas Saligram
- Division of Gastroenterology, Hepatology, and Nutrition, University of Texas Health San Antonio, San Antonio, TX 78229, USA
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11
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Yamada S, Osakabe M, Uesugi N, Yanagawa N, Matsumoto T, Suzuki H, Sugai T. Genome-wide analysis of colorectal cancer based on gene-based somatic copy number alterations during neoplastic progression within the same tumor. Cancer Med 2023; 12:4446-4454. [PMID: 35920319 PMCID: PMC9972084 DOI: 10.1002/cam4.5117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 07/25/2022] [Accepted: 07/26/2022] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND The objective of this study was to elucidate the association between neoplastic progression and somatic copy number alterations (SCNAs) occurring within the same colorectal cancer (CRC) tumor. METHODS We investigated SCNAs to identify the progression from a high-grade intramucosal lesion (HGIL) to an invasive front lesion (IFL), via an invasive submucosal lesion (ISL), within the same tumor using a crypt isolation method combined with a SNP array. Immunohistochemistry was also performed. RESULTS We identified 51 amplified genes that potentially promote progression from HGIL to ISL and 6 amplified genes involved in the progression from ISL to IFL. Of the 51 genes involved in HGIL to ISL progression, TORC1, MSLN, and STUB1, which are closely associated with CRC, were identified as candidate markers of submucosal invasion. However, no candidate genes were identified among the six genes associated with ISL to IFL progression. In addition, the number of total SCNAs and the number of gains were correlated with cancer progression (from HGIL to IFL). Finally, immunohistochemistry revealed higher expression of TORC1, MSLN, and STUB1 in ISL than in HGIL. CONCLUSIONS These results suggest that specific SCNAs are required for acquisition of invasive ability in CRC, and the affected genes are potential markers of invasion.
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Affiliation(s)
- Shun Yamada
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityYahabaJapan
- Division of Gastroenterology, Department of Internal MedicineIwate Medical UniversityYahabaJapan
| | - Mitsumasa Osakabe
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityYahabaJapan
| | - Noriyuki Uesugi
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityYahabaJapan
| | - Naoki Yanagawa
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityYahabaJapan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal MedicineIwate Medical UniversityYahabaJapan
| | - Hiromu Suzuki
- Department of Molecular BiologySapporo Medical UniversitySapporoJapan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityYahabaJapan
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12
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Gulubova MV, Chonov DC, Ivanova KV, Hristova MK, Krasimirova-Ignatova MM, Vlaykova TI. Intratumoural expression of IL-6/STAT3, IL-17 and FOXP3 immune cells in the immunosuppressive tumour microenvironment of colorectal cancer Immune cells-positive for IL-6, STAT3, IL-17 and FOXP3 and colorectal cancer development. BIOTECHNOL BIOTEC EQ 2022. [DOI: 10.1080/13102818.2022.2072765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
| | - Dimitur Chavdarov Chonov
- Department of General and Operative Surgery, Trakia University, Medical Faculty, Stara Zagora Bulgaria
- Ward of Operative Surgery, University Hospital “Prof. D-r Stoyan Kirkovich”, Stara Zagora, Bulgaria
| | - Koni Vancho Ivanova
- Department of Pathology, Trakia University, Medical Faculty, Stara Zagora, Bulgaria
| | | | | | - Tatyana Ivanova Vlaykova
- Department of Chemistry and Biochemistry, Medical Faculty, Trakia University, Stara Zagora, Bulgaria
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13
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Sugai T, Osakabe M, Eizuka M, Tanaka Y, Yamada S, Yanagawa N, Matsumoto T, Suzuki H. Genome-wide analysis of mRNA expression identified the involvement of trefoil factor 1 in the development of sessile serrated lesions. Pathol Res Pract 2022; 236:153987. [PMID: 35749918 DOI: 10.1016/j.prp.2022.153987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Revised: 06/13/2022] [Accepted: 06/15/2022] [Indexed: 11/30/2022]
Abstract
Precursor lesions that progress into colorectal cancer (CRC) could be largely classified into sessile serrated lesions (SSLs), traditional serrated adenoma (TSA), and tubular adenoma (TA). We aimed to determine whether high expression of trefoil factor 1 (TFF1) is closely associated with serrated lesions, particularly SSLs. The samples were divided into the first (12 SSLs, 5 TSAs, and 15 TAs) and second cohorts (15 SSLs, 9 TSAs, and 15 TAs). First, we investigated TFF1 expression in isolated gland samples using array-based and reverse-transcription PCR. Second, we performed immunohistochemical analysis of TFF1 expression in paraffin-embedded tissues obtained from SSL, TSA, TA, and hyperplastic polyp (HP) samples. In addition, we compared TFF1 mRNA levels between SSLs and HPs. TFF1 expression was significantly higher in SSLs than in TSA and TA in both cohorts. Additionally, immunohistochemical staining of TFF1 in the HP, SSL, TSA, and TA samples revealed significant differences in the immunohistochemical scores of TFF1 among the four types of lesions (higher expression in SSLs than in the other three lesions). Finally, there were significant differences in TFF1 mRNA expression levels between SSLs and HPs in paraffin-embedded tissues. However, there was considerable overlap in the immunohistochemical scores and expression levels of TFF1 transcripts between SSLs and HPs. The current findings may help elucidate the molecular mechanisms involved in serrated lesion development. In addition, we suggest that despite the limited practical application, upregulation of TFF1 transcripts may help differentiate SSLs from other lesions.
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Affiliation(s)
- Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou 028-3695, Japan.
| | - Mitsumasa Osakabe
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou 028-3695, Japan
| | - Makoto Eizuka
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou 028-3695, Japan
| | - Yoshihito Tanaka
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou 028-3695, Japan
| | - Shun Yamada
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou 028-3695, Japan; Division of Gastroenterology, Department of Internal Medicine, 2-1-1, Shiwagun,Yahabachou 028-3695, Japan
| | - Naoki Yanagawa
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 2-1-1, Shiwagun, Yahabachou 028-3695, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, 2-1-1, Shiwagun,Yahabachou 028-3695, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University, School of Medicine, Cyuuouku, Sapporo 060-0061, Japan
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14
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Rios-Valencia J, Cruz-Reyes C, Galindo-García TA, Rosas-Camargo V, Gamboa-Domínguez A. Mismatch repair system in colorectal cancer. Frequency, cancer phenotype, and follow-up. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2022; 87:432-438. [PMID: 35661637 DOI: 10.1016/j.rgmxen.2022.05.017] [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: 01/07/2021] [Accepted: 02/22/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION AND AIMS A frequent task in the study of colorectal carcinomas (CRC) is to identify tumors harboring deficient DNA mismatch repair systems (dMMR), which are associated with microsatellite instability. Given that there is scant information on those tumors in Mexican patients, our aim was to describe their frequency, clinical and pathologic characteristics, and results, which are necessary for future trials. MATERIALS AND METHODS A consecutive series of CRC patients, treated and followed at a tertiary care center was performed. The clinical and pathologic variables and the risk of hereditary or familial cancer syndrome were retrieved. The original slides and hMLH1, hPMS2, hMSH2, hMSH6 immunohistochemistry were evaluated. Tumors with an absence of at least one protein were considered dMMR. Differences were contrasted, utilizing non-parametric tests. RESULTS One hundred and forty-four patients were included, with a median age of 65 years. A total of 134/93% patients presented with sporadic CRC, 8/5.6% had a family history of CRC, and 2/1.4% met the diagnostic criteria for hereditary non-polyposis colon cancer, according to the Amsterdam and Bethesda criteria. dMMR tumors were found in 39 patients, distributed among the three groups. They were locally advanced (p<0.001), right-sided, had the mucinous phenotype, and harbored a Crohn's-like lymphoid reaction (all three features, p<0.04). Adjuvant or palliative chemotherapy was administered to 57 (39.6%), concomitant chemoradiotherapy to 24 (16.7%), but 63 (43.8%) patients received no additional treatment to surgery. Five-year follow-up was completed in 131 of the patients and the outcomes alive-with-disease or died-of-disease were more frequently observed in the proficient (pMMR) lesions. CONCLUSIONS In the present pre-FOLFOX case series, outcomes were better in dMMR CRC than in proficient lesions.
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Affiliation(s)
- J Rios-Valencia
- Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Mexico City, Mexico
| | - C Cruz-Reyes
- Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Mexico City, Mexico
| | - T A Galindo-García
- Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Mexico City, Mexico
| | - V Rosas-Camargo
- Departamento de Oncología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Mexico City, Mexico
| | - A Gamboa-Domínguez
- Departamento de Patología, Instituto Nacional de Ciencias Médicas y Nutrición «Salvador Zubirán», Mexico City, Mexico.
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15
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Chezar K, Minoo P. Appendiceal sessile serrated lesions are distinct from their right-sided colonic counterparts and may be precursors for appendiceal mucinous neoplasms. Hum Pathol 2022; 122:40-49. [PMID: 35121004 DOI: 10.1016/j.humpath.2022.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/23/2022] [Accepted: 01/25/2022] [Indexed: 11/30/2022]
Abstract
Low-grade appendiceal mucinous neoplasms (LAMNs) can occur concurrently with appendiceal sessile serrated lesions (SSLs). To interrogate relatedness, we performed multigene and immunohistochemical characterizations of paired and unpaired SSLs and LAMNs. We evaluated 62 serrated lesions from 50 appendectomy specimens for hotspot mutations in BRAF, KRAS and GNAS genes. Cases were subdivided into 3 groups: 20 unpaired SSLs, 18 unpaired LAMNs, and 12 with an SSL and concurrent LAMN. β-catenin and Annexin A10 immunostaining were performed on the SSL and LAMN components in the 12 paired cases, and fourteen colonic SSLs served as controls. There was no significant difference in KRAS hotspot mutation rates in appendiceal SSLs (17/26; 65.4%) and LAMNs (16/30; 53.3%) (p=0.42). BRAF V600E was identified in a single case (1/50; 2.0%) of SSL and concurrent LAMN (p=1.0). Mutations in GNAS were more common in LAMNs (6/30; 20.0%) compared to SSLs (1/31; 3.2%) (p=0.05). The molecular genotypes between paired SSLs and LAMNs were concordant in most cases (10/12; 83.3%). Annexin A10 immunostaining was significantly greater in colonic SSLs (14/14; 100%) compared to appendiceal SSLs (1/12; 8.3%) (p<0.0001). β-catenin immunostaining was significantly increased in LAMNs (10/12; 83.3%) compared to their paired appendiceal SSLs (2/12; 16.7%)(p=0.003). Overall, appendiceal sessile serrated lesions are predominantly driven by KRAS mutations and are not characterized by Annexin A10 immunostaining. Our data suggests that at least a subset of LAMNs may arise from a precursor SSL in which GNAS mutations and/or upregulation of the WNT-signaling pathway are likely key events modulating this progression.
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Affiliation(s)
- Ksenia Chezar
- Department of Pathology, Cumming School of Medicine and Alberta Precision Laboratories, University of Calgary, Calgary, Alberta, Canada
| | - Parham Minoo
- Department of Pathology, Cumming School of Medicine and Alberta Precision Laboratories, University of Calgary, Calgary, Alberta, Canada.
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16
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Kajiwara Saito M, Quaresma M, Fowler H, Benitez Majano S, Rachet B. Socioeconomic gaps over time in colorectal cancer survival in England: flexible parametric survival analysis. J Epidemiol Community Health 2021; 75:1155-1164. [PMID: 34049927 PMCID: PMC8588290 DOI: 10.1136/jech-2021-216754] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 05/15/2021] [Indexed: 11/17/2022]
Abstract
BACKGROUND Despite persistent reports of socioeconomic inequalities in colorectal cancer survival in England, the magnitude of survival differences has not been fully evaluated. METHODS Patients diagnosed with colon cancer (n=68 169) and rectal cancer (n=38 267) in England (diagnosed between January 2010 and March 2013) were analysed as a retrospective cohort study using the National Cancer Registry data linked with other population-based healthcare records. The flexible parametric model incorporating time-varying covariates was used to assess the difference in excess hazard of death and in net survival between the most affluent and the most deprived groups over time. RESULTS Survival analyses showed a clear pattern by deprivation. Hazard ratio of death was consistently higher in the most deprived group than the least deprived for both colon and rectal cancer, ranging from 1.08 to 1.17 depending on the model. On the net survival scale, the socioeconomic gap between the most and the least deprived groups reached approximately -4% at the maximum (-3.7%, 95% CI -1.6 to -5.7% in men, -3.6%, 95% CI -1.6 to -5.7% in women) in stages III for colon and approximately -2% (-2.3%, 95% CI -0.2 to -4.5% in men, -2.3%, 95% CI -0.2 to -4.3% in women) in stage II for rectal cancer at 3 years from diagnosis, after controlling for age, emergency presentation, receipt of resection and comorbidities. The gap was smaller in other stages and sites. For both cancers, patients with emergency presentation persistently had a higher excess hazard of death than those without emergency presentation. CONCLUSION Survival disparities were profound particularly among patients in the stages, which benefit from appropriate and timely treatment. For the patients with emergency presentation, excess hazard of death remained high throughout three years from the diagnosis. Public health measures should be taken to reduce access inequalities to improve survival disparities.
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Affiliation(s)
- Mari Kajiwara Saito
- Inequalities in Cancer Outcomes Network, Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
- Department of Gastroenterology, IMS Tokyo Katsushika General Hospital, Tokyo, Japan
| | - Manuela Quaresma
- Inequalities in Cancer Outcomes Network, Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
| | - Helen Fowler
- Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
| | - Sara Benitez Majano
- Inequalities in Cancer Outcomes Network, Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
| | - Bernard Rachet
- Inequalities in Cancer Outcomes Network, Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
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17
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Uesugi N, Ajioka Y, Arai T, Tanaka Y, Sugai T. Clinicopathological and molecular analyses of hyperplastic lesions including microvesicular variant and goblet cell rich variant hyperplastic polyps and hyperplastic nodules-Hyperplastic nodule is an independent histological entity. Pathol Int 2021; 72:128-137. [PMID: 34818448 PMCID: PMC9299182 DOI: 10.1111/pin.13187] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/03/2021] [Indexed: 01/23/2023]
Abstract
Hyperplastic nodules (HNs) have been considered to be hyperplastic lesions among Japanese pathologists, although they have not been recognized worldwide. Here, we examined clinicopathological and molecular differences between goblet cell-rich variant hyperplastic polyp (GCHPs), microvesicular variant HPs (MVHPs), and HNs. Patients with hyperplastic lesions including 61 GCHPs, 62 MVHPs, and 19 HNs were enrolled in the present study. The clinicopathological and molecular features examined included the mucin phenotype expression, p53 overexpression, annexin A10, genetic mutations (BRAF and KRAS), and DNA methylation status (low, intermediate, and high methylation epigenotype). In addition, hierarchical cluster analysis was also performed to identify patterns among the histological features. The lesions were stratified into three subgroups and each lesion was assigned into a subgroup. While GCHP was associated with KRAS mutation, MVHP was closely associated with BRAF mutation; no mutation was found in HN. We list specific histological findings that corresponded to each lesion. Finally, there were no significant differences in the methylation status among lesions. The current result shows that both MVHPs and GCHPs have a neoplastic nature whereas HN is non-neoplastic. We suggest that HNs should be distinguished from HPs, in particular GCHPs, in terms of pathological and genetic features.
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Affiliation(s)
- Noriyuki Uesugi
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun'yahabachou, Japan
| | - Yoichi Ajioka
- Division of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Tomio Arai
- Department of Diagnostic Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Itabashiku, Japan
| | - Yoshihito Tanaka
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun'yahabachou, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun'yahabachou, Japan
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18
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Chautard R, Corset L, Ibrahim S, Desvignes C, Paintaud G, Baroukh N, Guéguinou M, Lecomte T, Raoul W. Panitumumab and cetuximab affect differently miRNA expression in colorectal cancer cells. Biomark Med 2021; 15:685-696. [PMID: 34169732 DOI: 10.2217/bmm-2020-0520] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 03/12/2021] [Indexed: 12/20/2022] Open
Abstract
Background & aim: Resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (CRC) is frequent and prognostic biomarkers are lacking. MicroRNAs (miR) are good candidates in this context. We aimed to characterize cetuximab and panitumumab exposure influence on miR expression in colorectal cancer cells to identify those regulating the EGFR pathway and implicated in resistance to treatment. Finally, we aimed to identify miR expression in serum of patients with advanced CRC treated with cetuximab or panitumumab. Results: Cetuximab and panitumumab exposure induced significant expression variations of 17 miR out of a miRnome panel of 752. Six of those miR interacted with at least one downstream element of the EGFR pathway. Conclusion: After the bioinformatics two-phase process, five miR rarely described before could be potential actors of anti-EGFR monoclonal antibody resistance: miR-95-3p, miR-139-5p, miR-145-5p, miR-429 and miR-1247-5p. In vivo, we detected the expression of miR-139-5p and miR-145-5p in serum of patients with metastatic CRC.
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Affiliation(s)
- Romain Chautard
- Department of Hepato-Gastroenterology & Digestive Oncology, CHRU de Tours, France
- Université de Tours, EA 7501, GICC, France
| | - Laetitia Corset
- Université de Tours, EA 7501, GICC, France
- CNRS ERL 7001 LNOx, Université de Tours, France
| | | | - Céline Desvignes
- CHRU de Tours, Centre Pilote de suivi Biologique des traitements par Anticorps (CePiBAc), Tours, France
- Université de Tours, Tours, EA 4245 T2I, France
| | - Gilles Paintaud
- CHRU de Tours, Centre Pilote de suivi Biologique des traitements par Anticorps (CePiBAc), Tours, France
- Université de Tours, Tours, EA 4245 T2I, France
| | | | | | - Thierry Lecomte
- Department of Hepato-Gastroenterology & Digestive Oncology, CHRU de Tours, France
- Université de Tours, EA 7501, GICC, France
| | - William Raoul
- Université de Tours, EA 7501, GICC, France
- Inserm UMR 1069, Nutrition Croissance et Cancer (N2C), Université de Tours, France
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Immunohistochemical Examination is Highly Sensitive and Specific for Detection of the V600E BRAF Mutation in Colorectal Serrated Lesions. Appl Immunohistochem Mol Morphol 2020; 29:446-453. [PMID: 33306619 DOI: 10.1097/pai.0000000000000890] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 11/02/2020] [Indexed: 01/10/2023]
Abstract
Mutations in BRAF are important events in colorectal serrated lesions and specific genetic markers for the serrated pathway. However, examination of BRAF mutations is not easy in routine histopathologic analyses. Here, the authors examined 73 colorectal serrated lesions, including 21 hyperplastic polyps, 32 traditional serrated adenomas, and 30 sessile serrated lesions, for comparison of BRAF mutation status with immunopositive expression of the anti-BRAF V600E mutation-specific antibody VE1. Thirty-two tubular adenomas (TAs) were examined as controls. In addition, 5 examples of sessile serrated lesion with dysplasia were included. Mutations in BRAF (exon 15; V600E) and KRAS (exon 2) were analyzed in serrated lesions and TAs using pyrosequencing. Finally, the authors compared BRAF mutations with immunohistochemical expression of VE1 antibodies against the BRAF V600E mutation, which was examined based on quantitative analyses and correlations between semiquantitative (0, 1+, or 2+) and quantitative results in colorectal serrated lesions. The cut-off value of VE1 expression (32%) was set based on receiver operating characteristic curve analysis. In the current study, mutations in BRAF were well correlated with VE1 expression in serrated lesions, although no TAs without BRAF mutations were immunopositive. In contrast, serrated lesions and TAs with mutations in KRAS were not stained for VE1 expression. In serrated lesions, although the sensitivity was 96.2% to 100%, the specificity was 90.0% to 100%. In addition, there was also good correlation between semiquantitative and quantitative results. Analysis of BRAF V600E expression may be pathologically useful, particularly in routine histopathologic diagnosis.
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He K, Wang Y, Zhong Y, Pan X, Si L, Lu J. KRAS Codon 12 Mutation is Associated with More Aggressive Invasiveness in Synchronous Metastatic Colorectal Cancer (mCRC): Retrospective Research. Onco Targets Ther 2020; 13:12601-12613. [PMID: 33335401 PMCID: PMC7737549 DOI: 10.2147/ott.s279312] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 11/23/2020] [Indexed: 12/22/2022] Open
Abstract
Objective To investigate the connection between mutant KRAS/NRAS/BRAF and clinicopathological characteristics in therapy-naïve synchronous metastatic colorectal cancer (mCRC) in Chinese populations when compared with all wild type (KRAS/NRAS/BRAF wild type). Patients and Methods A total of 200 patients with therapy-naïve synchronous mCRC (TNM stage: TanyNanyM1) were retrospectively collected as study objects. Primary tumor tissues from 200 mCRC patients were analyzed through next-generation sequencing panel to assess the mutated regions of KRAS/NRAS/BRAF. Results The distribution frequency of gene mutation in our study was 41% KRAS, 4% NRAS, 11.5% BRAF, 0.5% both KRAS and BRAF. Tumors with any gene mutations (any gene mutations in KRAS/NRAS/BRAF), KRAS and KRAS codon 12 mutation were more likely to be located in right-sided colon (P=0.007, P=0.008, P=0.026, respectively). For metastasis, tumors with any gene mutations, KRAS and KRAS codon 12 mutation were significantly correlated with peritoneal metastasis (P=0.019, P=0.017, P=0.014, respectively), liver-peritoneum metastases (P=0.004, P=0.003, P=0.002, respectively) and multi-organ metastases (P=0.002, P=0.008, P=0.001, respectively). Tumors with all wild type were significantly correlated with distant lymph node-only metastasis. No statistically significant differences were found between clinicopathological characteristics and KRAS codon 13 and NRAS mutations. Conclusion Our study suggests that clinicopathological characteristics (specifically for metastasis) are related to KRAS/NRAS/BRAF mutations in therapy-naïve synchronous mCRC population in China. We demonstrated that distant lymph node-only metastasis is visibly linked to all wild-type tumors. We found that patients with any gene mutations, KRAS mutation are more likely to carry peritoneal metastasis, liver-peritoneum metastases and multi-organ metastases than those with all wild type. After stratification, KRAS codon 12 mutation, but not codon 13 mutation, was remarkably associated with peritoneal metastasis, liver-peritoneum metastases, and multi-organ metastases compared to all wild type. These results may be useful for aiding in the prediction of prognosis and choosing the appropriate regimens for therapy.
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Affiliation(s)
- Kang He
- The Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, People's Republic of China
| | - Yajing Wang
- The Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, People's Republic of China
| | - Yuejiao Zhong
- The Department of Oncology, Jiangsu Cancer Hospital, and the Affiliated Cancer Hospital of Nanjing Medical University and Jiangsu Institute of Cancer Research, Nanjing, People's Republic of China
| | - Xiaohua Pan
- The Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, People's Republic of China
| | - Lixiang Si
- The Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, People's Republic of China
| | - Jianwei Lu
- The Department of Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, and Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research, Nanjing, People's Republic of China
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21
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Yamashiro Y, Saito T, Hayashi T, Murakami T, Yanai Y, Tsuyama S, Suehara Y, Takamochi K, Yao T. Molecular and clinicopathological features of colorectal adenocarcinoma with enteroblastic differentiation. Histopathology 2020; 77:492-502. [PMID: 32438490 DOI: 10.1111/his.14158] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 04/22/2020] [Accepted: 05/15/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND Colorectal adenocarcinoma with enteroblastic differentiation (CAED) is a rare subtype of colorectal malignancy with expression of enteroblastic markers (glypican 3, SALL4, AFP); however, the clinicopathological and epidemiological features are not fully elucidated. AIMS The aims of this study were to elucidate and establish the molecular and clinicopathological characteristics of CAED. MATERIALS AND METHODS In addition to three cases recently diagnosed as CAED, colorectal carcinoma (CRC) with expression of enteroblastic markers were selected by using immunohistochemistry (IHC) on tissue microarrays of 988 advanced CRC. We employed next-generation sequencing (NGS) and Sanger sequencing for the detection of genetic alterations. IHC for p53 and HER2, HER2-FISH and MSI status was also investigated. Survival analyses for clinicopathological parameters were performed using Kaplan-Meier methods. RESULTS Thirty-nine cases (4.0%) were positive for at least one enteroblastic marker. Histological evaluation of the total of 42 cases revealed that 10 contained tumour cells with clear cytoplasm. Enteroblastic marker-positive cases had aggressive behaviour and poor prognosis. NGS revealed TP53 as the most frequently mutated gene. The rate of HER2-positive cases and MSI-H cases was 9.5% (four of 42) and 12.2% (five of 41), respectively. Among these 42 cases, there were no molecular and clinicopathological differences according to the presence of tumour cells with clear cytoplasm. CONCLUSIONS Enteroblastic marker-positive CRC could be grouped together as CAED regardless of clear cell cytoplasm. Using this definition, the frequency of CAED is 4.0% and has a poorer prognosis than that for conventional CRCs. HER2 targeted therapy would be a meaningful treatment for CAED, and CAEDs contain both MSI-H and MSI-stable CRCs, although the MSS phenotype is dominant.
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Affiliation(s)
- Yuya Yamashiro
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Tsuyoshi Saito
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan.,Intractable Disease Research Center, Juntendo University, Graduate School of Medicine, Tokyo, Japan
| | - Takuo Hayashi
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Takashi Murakami
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Yuka Yanai
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Sho Tsuyama
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
| | - Yoshiyuki Suehara
- Intractable Disease Research Center, Juntendo University, Graduate School of Medicine, Tokyo, Japan.,Department of Orthopaedic Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Kazuya Takamochi
- Department of General Thoracic Surgery, Juntendo University School of Medicine, Tokyo, Japan
| | - Takashi Yao
- Department of Human Pathology, Juntendo University School of Medicine, Tokyo, Japan
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22
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Ouchi A, Toriyama K, Kinoshita T, Tanaka T, Shimizu Y, Niwa Y, Tajika M, Komori K. Variations in clinical features and oncologic behaviors of T1 colorectal cancer according to tumor location. Int J Clin Oncol 2020; 25:1130-1136. [PMID: 32124095 DOI: 10.1007/s10147-020-01642-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2019] [Accepted: 02/20/2020] [Indexed: 01/09/2023]
Abstract
BACKGROUND Different genetic characteristics according to tumor location result in variations in survival rates and treatment responses in advanced colorectal cancer (CRC). However, the effects of tumor location during early CRC are still unclear. METHODS Patients with T1 CRC treated between 2003 and 2019 were enrolled from a prospectively collected database. Patients were once divided into four groups, then combined into two groups (right- and left-sided CRC) according to the tumor location, and clinical features and oncologic behaviors were compared. RESULTS In total, 458 patients were analyzed. Right-sided CRC had a lower incidence of polypoid type tumor than left-sided CRC (36/126 (28.6%) vs 186/332 (56.0%), p < 0.001). There were no differences in tumor size, pathological grade, pT1 substage and lymphovascular invasion between right- and left-sided CRC. Overall, lymph nodal involvement was observed in 42/458 (9.1%) patients. Right-sided CRC had a lower rate of patients with lymph nodal involvement than left-sided CRC (6/126 (4.8%) vs 36/332 (10.8%), p = 0.04). CONCLUSION The present study revealed that there were significant differences in the macroscopic type and the incidence of lymph node involvement between right- and left-sided CRC. The clinical features and oncologic behaviors of T1 CRC are possible to vary according to tumor location.
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Affiliation(s)
- Akira Ouchi
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1, Kanokoden, Chikusa, Nagoya, Aichi, 464-8681, Japan
| | - Kazuhiro Toriyama
- Department of Gastroenterology, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Takashi Kinoshita
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1, Kanokoden, Chikusa, Nagoya, Aichi, 464-8681, Japan
| | - Tsutomu Tanaka
- Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Yasuhiro Shimizu
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1, Kanokoden, Chikusa, Nagoya, Aichi, 464-8681, Japan
| | - Yasumasa Niwa
- Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Masahiro Tajika
- Department of Endoscopy, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan
| | - Koji Komori
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, 1-1, Kanokoden, Chikusa, Nagoya, Aichi, 464-8681, Japan.
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23
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Jackstadt R, van Hooff SR, Leach JD, Cortes-Lavaud X, Lohuis JO, Ridgway RA, Wouters VM, Roper J, Kendall TJ, Roxburgh CS, Horgan PG, Nixon C, Nourse C, Gunzer M, Clark W, Hedley A, Yilmaz OH, Rashid M, Bailey P, Biankin AV, Campbell AD, Adams DJ, Barry ST, Steele CW, Medema JP, Sansom OJ. Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis. Cancer Cell 2019; 36:319-336.e7. [PMID: 31526760 PMCID: PMC6853173 DOI: 10.1016/j.ccell.2019.08.003] [Citation(s) in RCA: 289] [Impact Index Per Article: 48.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Revised: 05/31/2019] [Accepted: 08/06/2019] [Indexed: 12/14/2022]
Abstract
The metastatic process of colorectal cancer (CRC) is not fully understood and effective therapies are lacking. We show that activation of NOTCH1 signaling in the murine intestinal epithelium leads to highly penetrant metastasis (100% metastasis; with >80% liver metastases) in KrasG12D-driven serrated cancer. Transcriptional profiling reveals that epithelial NOTCH1 signaling creates a tumor microenvironment (TME) reminiscent of poorly prognostic human CRC subtypes (CMS4 and CRIS-B), and drives metastasis through transforming growth factor (TGF) β-dependent neutrophil recruitment. Importantly, inhibition of this recruitment with clinically relevant therapeutic agents blocks metastasis. We propose that NOTCH1 signaling is key to CRC progression and should be exploited clinically.
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Affiliation(s)
| | - Sander R van Hooff
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - Joshua D Leach
- Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
| | | | | | | | - Valérie M Wouters
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - Jatin Roper
- Department of Medicine, Division of Gastroenterology, Duke University, Durham, NC, USA
| | - Timothy J Kendall
- Division of Pathology/Centre for Inflammation Research, University of Edinburgh, UK
| | - Campbell S Roxburgh
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow, UK
| | - Paul G Horgan
- Academic Unit of Surgery, School of Medicine, University of Glasgow, Glasgow, UK
| | - Colin Nixon
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Craig Nourse
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Matthias Gunzer
- Institute for Experimental Immunology and Imaging, University Hospital, University Duisburg-Essen, Essen, Germany
| | | | - Ann Hedley
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Omer H Yilmaz
- Division of Gastroenterology, Tufts Medical Center, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Mamunur Rashid
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
| | - Peter Bailey
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
| | - Andrew V Biankin
- Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
| | | | - David J Adams
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
| | - Simon T Barry
- Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK
| | - Colin W Steele
- Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - Owen J Sansom
- Cancer Research UK Beatson Institute, Glasgow, UK; Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Glasgow, UK.
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24
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Kuno T, Tsukui Y, Takano S, Maekawa S, Yamaguchi T, Yoshida T, Kobayashi S, Iwamoto F, Ishida Y, Kawakami S, Tanaka K, Fukasawa Y, Muraoka M, Fukasawa M, Shindo H, Inoue T, Nakayama Y, Mochizuki K, Sato T, Enomoto N. Genetic alterations related to endoscopic treatment of colorectal tumors. JGH OPEN 2019; 4:75-82. [PMID: 32055701 PMCID: PMC7008167 DOI: 10.1002/jgh3.12220] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 05/20/2019] [Accepted: 05/25/2019] [Indexed: 12/24/2022]
Abstract
Background and Aim Genetic indicators of endoscopic resection for colorectal carcinoma remain inconclusive. This study analyzed genetic changes in early colorectal tumors that could inform decisions for endoscopic procedures. Methods A total of 83 colorectal tumors from 81 patients, including adenoma (n = 7), Tis–T1a (n = 22), T1b (n = 14), and advanced carcinoma (n = 40), were analyzed. Tis tumors (n = 16) and some T1 carcinomas (n = 11) were analyzed as mixed adenomas and carcinomas. Lesions were laser‐capture microdissected for DNA extraction, and targeted sequencing of 50 cancer‐related genes was performed. Genetic data were then correlated with clinical records, including magnifying endoscopic findings. Results Numbers of gene alteration rates in TP53 and SMAD4 increased with tumor progression from adenoma to carcinoma. Frequencies of mutant variants in TP53 (P = 0.004) and rates of copy number loss in SMAD4 (P = 0.006) increased in carcinoma components of mixed tumors compared to adenoma components. Moreover, adenoma components of T1b carcinomas had higher TP53 mutation rates than Tis or T1a carcinomas (P = 0.011) and pure adenomas (P = 0.026). Gene alterations in TP53 (P = 0.0055) and SMAD4 (P = 0.0055) increased in cases with irregular surface patterns of magnifying endoscopic findings. Conclusions Numbers of copy number variations and TP53 and SMAD4 alterations were related to colorectal tumor progression. TP53 alteration rates in adenoma components were high in T1b carcinomas, warranting complete treatment with en bloc resection. Magnifying endoscopic findings might reflect the genetic status of colorectal tumors.
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Affiliation(s)
- Toru Kuno
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Yuya Tsukui
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan.,Department of Gastroenterology Koyo Hospital Hokuto Japan
| | - Shinichi Takano
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Shinya Maekawa
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Tatsuya Yamaguchi
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Takashi Yoshida
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Shoji Kobayashi
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Fumihiko Iwamoto
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Yasuaki Ishida
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Satoshi Kawakami
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Keisuke Tanaka
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Yoshimitsu Fukasawa
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Masaru Muraoka
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Mitsuharu Fukasawa
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Hiroko Shindo
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Taisuke Inoue
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Yasuhiro Nakayama
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Kunio Mochizuki
- Department of Pathology, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Tadashi Sato
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Nobuyuki Enomoto
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
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25
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Vleugels JLA, Hassan C, Senore C, Cassoni P, Baron JA, Rex DK, Ponugoti PL, Pellise M, Parejo S, Bessa X, Arnau-Collell C, Kaminski MF, Bugajski M, Wieszczy P, Kuipers EJ, Melson J, Ma KH, Holman R, Dekker E, Pohl H. Diminutive Polyps With Advanced Histologic Features Do Not Increase Risk for Metachronous Advanced Colon Neoplasia. Gastroenterology 2019; 156:623-634.e3. [PMID: 30395813 DOI: 10.1053/j.gastro.2018.10.050] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 10/19/2018] [Accepted: 10/30/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS With advances in endoscopic imaging, it is possible to differentiate adenomatous from hyperplastic diminutive (1-5 mm) polyps during endoscopy. With the optical Resect-and-Discard strategy, these polyps are then removed and discarded without histopathology assessment. However, failure to recognize adenomas (vs hyperplastic polyps), or discarding a polyp with advanced histologic features, could result in a patient being considered at low risk for metachronous advanced neoplasia, resulting in an inappropriately long surveillance interval. We collected data from international cohorts of patients undergoing colonoscopy to determine what proportion of patients are high risk because of diminutive polyps advanced histologic features and their risk for metachronous advanced neoplasia. METHODS We collected data from 12 cohorts (in the United States or Europe) of patients undergoing colonoscopy after a positive result from a fecal immunochemical test (FIT cohort, n = 34,221) or undergoing colonoscopies for screening, surveillance, or evaluation of symptoms (colonoscopy cohort, n = 30,123). Patients at high risk for metachronous advanced neoplasia were defined as patients with polyps that had advanced histologic features (cancer, high-grade dysplasia, ≥25% villous features), 3 or more diminutive or small (6-9 mm) nonadvanced adenomas, or an adenoma or sessile serrated lesion ≥10 mm. Using an inverse variance random effects model, we calculated the proportion of diminutive polyps with advanced histologic features; the proportion of patients classified as high risk because their diminutive polyps had advanced histologic features; and the risk of these patients for metachronous advanced neoplasia. RESULTS In 51,510 diminutive polyps, advanced histologic features were observed in 7.1% of polyps from the FIT cohort and 1.5% polyps from the colonoscopy cohort (P = .044); however, this difference in prevalence did not produce a significant difference in the proportions of patients assigned to high-risk status (0.8% of patients in the FIT cohort and 0.4% of patients in the colonoscopy cohort) (P = .25). The proportions of high-risk patients because of diminutive polyps with advanced histologic features who were found to have metachronous advanced neoplasia (17.6%) did not differ significantly from the proportion of low-risk patients with metachronous advanced neoplasia (14.6%) (relative risk for high-risk categorization, 1.13; 95% confidence interval 0.79-1.61). CONCLUSION In a pooled analysis of data from 12 international cohorts of patients undergoing colonoscopy for screening, surveillance, or evaluation of symptoms, we found that diminutive polyps with advanced histologic features do not increase risk for metachronous advanced neoplasia.
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Affiliation(s)
- Jasper L A Vleugels
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, location Academic Medical Center, University of Amsterdam, the Netherlands
| | - Cesare Hassan
- Department of Gastroenterology and Hepatology, Humanitas Research Hospital, Humanitas University, Milan, Italy
| | - Carlo Senore
- Epidemiology and screening Unit - CPO, University Hospital Città della Salute e della Scienza, Turin, Italy
| | - Paola Cassoni
- Department of Medical Science, Pathology unit, University of Turin, Turin, Italy
| | - John A Baron
- Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Douglas K Rex
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Prasanna L Ponugoti
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Maria Pellise
- Department of Gastroenterology, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Sofia Parejo
- Department of Gastroenterology, Hospital Ramón y Cajal, Madrid, Spain
| | - Xavier Bessa
- Gastroenterology Department, Hospital del Mar, Barcelona, Spain; IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
| | - Coral Arnau-Collell
- Department of Gastroenterology, Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Michal F Kaminski
- Department of Gastroenterological Oncology, Maria Sklodowska-Curie Memorial Cancer Centre, Warsaw, Poland; Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Centre for Postgraduate Education, Warsaw, Poland; Department of Cancer Prevention, Maria Sklodowska-Curie Memorial Cancer Centre, Warsaw, Poland
| | - Marek Bugajski
- Department of Gastroenterological Oncology, Maria Sklodowska-Curie Memorial Cancer Centre, Warsaw, Poland; Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Centre for Postgraduate Education, Warsaw, Poland
| | - Paulina Wieszczy
- Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Centre for Postgraduate Education, Warsaw, Poland; Department of Cancer Prevention, Maria Sklodowska-Curie Memorial Cancer Centre, Warsaw, Poland
| | - Ernst J Kuipers
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, the Netherlands
| | - Joshua Melson
- Department of Medicine, Division of Digestive Diseases, Rush University Medical Center, Chicago, Illinois
| | - Karen H Ma
- Department of Medicine, Division of Digestive Diseases, Rush University Medical Center, Chicago, Illinois
| | - Rebecca Holman
- Clinical Research Unit, Amsterdam University Medical Center, location Academic Medical Center, University of Amsterdam, the Netherlands
| | - Evelien Dekker
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, location Academic Medical Center, University of Amsterdam, the Netherlands
| | - Heiko Pohl
- Department of Gastroenterology, Veterans Affairs Medical Center, White River Junction, Vermont.
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26
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A Retrospective Analysis of Colorectal Serrated Lesions from 2005 to 2014 in a Single Center: Importance of the Establishment of Diagnostic Patterns. Gastroenterol Res Pract 2018; 2018:5946057. [PMID: 30420877 PMCID: PMC6215568 DOI: 10.1155/2018/5946057] [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: 07/23/2018] [Accepted: 09/03/2018] [Indexed: 11/17/2022] Open
Abstract
Background Serrated colorectal lesions are increasingly recognized as an important process in the development of colorectal cancer. Endoscopic and histological diagnosis may be difficult, and knowledge of the serrated lesions is important for the establishment of strategies for treating colorectal lesions. We aimed to analyze serrated lesions diagnosed at a single center and evaluate if there was an increase in their identification over the years. Design and Setting A retrospective analysis of colonoscopy reports was performed at a specialized center from 2005 to 2014. Methods Colonoscopy reports about any resected endoscopic lesions were reviewed and subjected to histological diagnosis from 2005 to 2014. Then, serrated lesions were evaluated based on morphological characterization, location, size, occurrence of synchronous lesions, and the patient's history of colorectal cancer and polyps. Results A total of 2126 colonoscopy examination reports were reviewed, and 3494 lesions were analyzed. On histopathological examination, 1089 (31.2%) were classified as hyperplastic polyps, 22 (0.6%) as sessile serrated adenomas, and 21 (0.6%) as traditional serrated adenomas. There was an increase in the number of cases of sessile and traditional serrated adenomas diagnosed after 2010. Before 2010, two cases of sessile serrated adenomas and seven cases of traditional serrated adenomas were diagnosed; after 2010, 20 cases of sessile serrated adenoma and 14 cases of traditional serrated adenomas were diagnosed. Conclusion There was an increase in the diagnosis of sessile serrated adenomas over the years, which can be attributed to better accuracy in colonoscopy and histological classification.
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27
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Long-term effects of H. pylori eradication on epigenetic alterations related to gastric carcinogenesis. Sci Rep 2018; 8:14369. [PMID: 30254207 PMCID: PMC6156585 DOI: 10.1038/s41598-018-32717-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 09/12/2018] [Indexed: 12/13/2022] Open
Abstract
The risk of gastric cancer (GC) remains in precancerous conditions, including atrophic mucosa and intestinal mucosa (IM), even after H. pylori treatment. To define the molecular changes following H. pylori eradication, molecular alterations in the gastric mucosa with and without GC were evaluated in a long-term follow-up study. A total of 232 biopsy specimens from 78 consecutive patients, including atrophic gastritis patients with follow-up ≥3 y after successful H. pylori eradication (AG group), patients who developed early GC after successful eradication (≥3 y) (GC group), and patients with H. pylori-positive atrophic gastritis (Hp group), were analyzed. H. pylori eradication was associated with significant reductions of methylation of several genes/loci in atrophic mucosa (non-IM), but not in IM. In contrast, the incidence of CpG island methylator phenotype (CIMP) in IM was significantly higher in the GC group than in the AG group. miR-124a-3 methylation and miR-34c methylation were more frequently identified in IM, with very few in non-IM mucosa among the three groups. H. pylori eradication can reverse methylation only in non-IM mucosa. CIMP in IM may have potential as a surrogate maker of GC development, and methylation of miR-124a-3 and miR-34c is a molecular event in IM that may not be associated with GC development.
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28
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Lee H, Kim N, Yoo YJ, Kim H, Jeong E, Choi S, Moon SU, Oh SH, Mills GB, Yoon S, Kim WY. β-catenin/TCF activity regulates IGF-1R tyrosine kinase inhibitor sensitivity in colon cancer. Oncogene 2018; 37:5466-5475. [PMID: 29895971 DOI: 10.1038/s41388-018-0362-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 05/06/2018] [Accepted: 05/25/2018] [Indexed: 12/19/2022]
Abstract
The availability of large-scale drug screening data on cell line panels provides a unique opportunity to identify predictive biomarkers for targeted drug efficacy. Analysis of diverse drug data on ~990 cancer cell lines revealed enhanced sensitivity of insulin-like growth factor 1 receptor/ Insulin Receptor (IGF-1R/IR) tyrosine kinase inhibitors (TKIs) in colon cancer cells. Interestingly, β-catenin/TCF(T cell factor)-responsive promoter activity exhibited a significant positive association with IGF-1R/IR TKI response, while the mutational status of direct upstream genes, such as CTNNB1 and APC, was not significantly associated with the response. The β-catenin/TCF activity high cell lines express components of IGF-1R/IR signaling more than the low cell lines explaining their enhanced sensitivity against IGF-1R/IR TKI. Reinforcing β-catenin/TCF responsive promoter activity by introducing CTNNB1 gain-of-function mutations into IGF-1R/IR TKI-resistant cells increased the expression and activity of IGF-1R/IR signaling components and also sensitized the cells to IGF-1R/IR TKIs in vitro and in vivo. Analysis of TCGA data revealed that the stronger β-catenin/TCF responsive promoter activity was associated with higher IGF-1R and IGF2 transcription in human colon cancer specimens as well. Collectively, compared to the mutational status of upstream genes, β-catenin/TCF responsive promoter activity has potential to be a stronger predictive positive biomarker for IGF-1R/IR TKI responses in colon cancer cells. The present study highlights the potential of transcriptional activity as therapeutic biomarkers for targeted therapies, overcoming the limited ability of upstream genetic mutations to predict responses.
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Affiliation(s)
- Hani Lee
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.,Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Nayoung Kim
- Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea.,Department of Biological Sciences, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Young Ji Yoo
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.,Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Hyejin Kim
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.,Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Euna Jeong
- Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - SeokGyeong Choi
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea.,Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Sung Un Moon
- Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea
| | - Seung Hyun Oh
- College of Pharmacy, Gachon University, Incheon, 21936, Republic of Korea
| | - Gordon B Mills
- Systems Biology, MD Anderson Cancer Center, University of Texas, Houston, TX, 77030, USA
| | - Sukjoon Yoon
- Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea. .,Department of Biological Sciences, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
| | - Woo-Young Kim
- Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women's University, Seoul, 04310, Republic of Korea. .,Center for Advanced Bioinformatics & Systems Medicine, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
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29
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Nagata S, Mitsuyama K, Kawano H, Noda T, Maeyama Y, Mukasa M, Takedatsu H, Yoshioka S, Kuwaki K, Akiba J, Tsuruta O, Torimura T. Endoscopic analysis of colorectal serrated lesions with cancer. Oncol Lett 2018; 15:8655-8662. [PMID: 29805602 DOI: 10.3892/ol.2018.8386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Accepted: 07/07/2017] [Indexed: 11/06/2022] Open
Abstract
Serrated lesions, including hyperplastic polyps (HPs), traditional serrated adenomas (TSAs) and sessile serrated adenomas/polyps (SSA/Ps), are important contributors to colorectal carcinogenesis. The aim of the present study was to analyze the potential of conventional endoscopy and advanced endoscopic imaging techniques to delineate the characteristic features of serrated lesions with cancer. The present study was a retrospective analysis of the data of 168 patients who had undergone colonoscopy, and a total of 228 serrated lesions (77 HPs, 58 TSAs, 84 SSA/Ps, 9 SSA/P plus TSAs) have been identified in these patients. A cancer component was identified in 2.6% of HPs, 13.8% of TSAs and 10.7% of SSA/Ps, but none of SSA/P plus TSAs. Compared with the lesions without cancer, the lesions with cancer exhibited a larger size (HP, TSA and SSA/P), a reddish appearance (SSA/P), a two-tier raised appearance (HP and SSA/P), a central depression (HP, TSA and SSA/P), the type V pit pattern (HP, TSA and SSA/P), and/or the type III capillary pattern (TSA and SSA/P). Deep invasion was identified in 50.0% of HPs, 12.5% of TSAs and 55.6% of SSA/Ps with cancer. The Ki-67 proliferative zone was distributed diffusely within the area of the cancer, but partially within the non-cancer area of HPs, TSAs and SSA/Ps. The lesion types were also analyzed on the basis of mucin phenotype. The present study suggested that a detailed endoscopic analysis of serrated lesions with cancer is useful for delineating characteristic features, and the analysis aids treatment selection.
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Affiliation(s)
- Shuichiro Nagata
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Keiichi Mitsuyama
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Hiroshi Kawano
- Department of Gastroenterology, St. Mary's Hospital, Kurume, Fukuoka 830-8543, Japan
| | - Tetsuhiro Noda
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Yasuhiko Maeyama
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Michita Mukasa
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Hidetoshi Takedatsu
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Shinichiro Yoshioka
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Kotaro Kuwaki
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Jun Akiba
- Department of Pathology, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Osamu Tsuruta
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Fukuoka 830-0011, Japan
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30
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Natsume S, Yamaguchi T, Takao M, Iijima T, Wakaume R, Takahashi K, Matsumoto H, Nakano D, Horiguchi SI, Koizumi K, Miyaki M. Clinicopathological and molecular differences between right-sided and left-sided colorectal cancer in Japanese patients. Jpn J Clin Oncol 2018; 48:609-618. [DOI: 10.1093/jjco/hyy069] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Accepted: 04/29/2018] [Indexed: 01/05/2023] Open
Affiliation(s)
- Soichiro Natsume
- Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan
| | - Tatsuro Yamaguchi
- Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan
| | - Misato Takao
- Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan
| | - Takeru Iijima
- Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan
| | - Rika Wakaume
- Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan
| | - Keiichi Takahashi
- Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan
| | - Hiroshi Matsumoto
- Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan
| | - Daisuke Nakano
- Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan
| | - Shin-ichiro Horiguchi
- Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan
| | - Koichi Koizumi
- Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan
| | - Michiko Miyaki
- Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan
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31
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Vleugels JLA, Dijkgraaf MGW, Hazewinkel Y, Wanders LK, Fockens P, Dekker E. Effects of Training and Feedback on Accuracy of Predicting Rectosigmoid Neoplastic Lesions and Selection of Surveillance Intervals by Endoscopists Performing Optical Diagnosis of Diminutive Polyps. Gastroenterology 2018; 154:1682-1693.e1. [PMID: 29425923 DOI: 10.1053/j.gastro.2018.01.063] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Revised: 01/22/2018] [Accepted: 01/29/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS Real-time differentiation of diminutive polyps (1-5 mm) during endoscopy could replace histopathology analysis. According to guidelines, implementation of optical diagnosis into routine practice would require it to identify rectosigmoid neoplastic lesions with a negative predictive value (NPV) of more than 90%, using histologic findings as a reference, and agreement with histology-based surveillance intervals for more than 90% of cases. METHODS We performed a prospective study with 39 endoscopists accredited to perform colonoscopies on participants with positive results from fecal immunochemical tests in the Bowel Cancer Screening Program at 13 centers in the Netherlands. Endoscopists were trained in optical diagnosis using a validated module (Workgroup serrAted polypS and Polyposis). After meeting predefined performance thresholds in the training program, the endoscopists started a 1-year program (continuation phase) in which they performed narrow band imaging analyses during colonoscopies of participants in the screening program and predicted histological findings with confidence levels. The endoscopists were randomly assigned to groups that received feedback or no feedback on the accuracy of their predictions. Primary outcome measures were endoscopists' abilities to identify rectosigmoid neoplastic lesions (using histology as a reference) with NPVs of 90% or more, and selecting surveillance intervals that agreed with those determined by histology for at least 90% of cases. RESULTS Of 39 endoscopists initially trained, 27 (69%) completed the training program. During the continuation phase, these 27 endoscopists performed 3144 colonoscopies in which 4504 diminutive polyps were removed. The endoscopists identified neoplastic lesions with a pooled NPV of 90.8% (95% confidence interval 88.6-92.6); their proposed surveillance intervals agreed with those determined by histologic analysis for 95.4% of cases (95% confidence interval 94.0-96.6). Findings did not differ between the group that did vs did not receive feedback. Sixteen endoscopists (59%) identified rectosigmoid neoplastic lesions with NPVs greater than 90% and selected surveillance intervals in agreement with those determined from histology for more than 90% of patients. CONCLUSIONS In a prospective study following a validated training module, we found that a selected group of endoscopists identified rectosigmoid neoplastic lesions with pooled NPVs greater than 90% and accurately selected surveillance intervals for more than 90% of patients over the course of 1 year. Providing regular interim feedback on the accuracy of neoplastic lesion prediction and surveillance interval selection did not lead to differences in those endpoints. Monitoring is suggested, as individual performance varied. ClinicalTrials.gov no: NCT02516748; Netherland Trial Register: NTR4635.
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Affiliation(s)
- Jasper L A Vleugels
- Department of Gastroenterology and Hepatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - Marcel G W Dijkgraaf
- Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - Yark Hazewinkel
- Department of Gastroenterology and Hepatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - Linda K Wanders
- Department of Gastroenterology and Hepatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - Paul Fockens
- Department of Gastroenterology and Hepatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands
| | - Evelien Dekker
- Department of Gastroenterology and Hepatology, Academic Medical Centre, University of Amsterdam, Amsterdam, the Netherlands.
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Sugai T, Eizuka M, Habano W, Fujita Y, Sato A, Sugimoto R, Otsuka K, Yamamoto E, Matsumoto T, Suzuki H. Comprehensive molecular analysis based on somatic copy number alterations in intramucosal colorectal neoplasias and early invasive colorectal cancers. Oncotarget 2018; 9:22895-22906. [PMID: 29796160 PMCID: PMC5955401 DOI: 10.18632/oncotarget.25112] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 03/15/2018] [Indexed: 12/16/2022] Open
Abstract
It is unclear whether somatic copy number alterations (SCNAs) contribute to the development of colorectal cancer (CRC). Here, we aimed to identify the molecular profiles of early colorectal carcinogenesis based on SCNAs and determine the associations of other molecular abnormalities for the detection of neoplasia in both intramucosal neoplasia (IMN) and invasive CRC with invasion into the muscular layer without metastasis (early invasive CRC). A single nucleotide polymorphism array was used to examine 100 colorectal IMNs (low-grade adenoma [LGA], 40; high-grade adenoma [HGA], 25; intramucosal adenocarcinoma [IMA], 35) and early invasive CRC (20 tumors). In addition, genetic mutations (KRAS, BRAF), TP53 overexpression, microsatellite instability (MSI), and DNA methylation (low, intermediate, high) were examined. Hierarchical clustering analysis based on the SCNA pattern was carried out to identify molecular profiles in IMNs and early invasive CRC. Colorectal tumors were classified into three subgroups based on SCNA patterns. Subgroup 1 was characterized by multiple SCNAs, subgroup 3 was closely associated with infrequent SCNAs, and subgroup 2 was an intermediate subgroup in SCNA pattern between subgroups 1 and 3. Although mutations in KRAS were commonly found in all three subgroups, overexpression of TP53 was observed primarily in subgroup 1 and 2. DNA methylation showed a low/intermediate type. Finally, no MSI was detected. Each subgroup was correlated with histology (subgroup 1, early invasive CRC; subgroup 2, LGA; subgroups 2 and 3, HGA and IMA). Considerable SCNAs may be required for acquisition of invasive ability in CRC. Our results provide novel insights into early CRC.
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Affiliation(s)
- Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Makoto Eizuka
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Wataru Habano
- Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Morioka, Japan
| | - Yasuko Fujita
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Ayaka Sato
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Kouki Otsuka
- Department of Surgery, Iwate Medical University, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Eiichiro Yamamoto
- Department of Molecular Biology, Sapporo Medical University, School of Medicine, Cyuuouku, Sapporo, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University, School of Medicine, Cyuuouku, Sapporo, Japan
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33
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Eizuka M, Kawasaki K, Toya Y, Akasaka R, Otsuka K, Sasaki A, Matsumoto T, Sugai T. Colorectal Adenocarcinoma with an Alternative Serrated Pathway. Case Rep Gastroenterol 2018; 12:116-124. [PMID: 29805354 PMCID: PMC5968291 DOI: 10.1159/000488192] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 02/28/2018] [Indexed: 01/08/2023] Open
Abstract
In a 64-year-old woman, we identified a flat, elevated lesion that was located at the caecum and was composed of 3 different areas (areas A, B, and C). We diagnosed it as “carcinoma with sessile serrated adenoma/polyp (SSA/P)” histologically. Although area A was diagnosed as classical SSA/P, area B was regarded as a high-grade SSA/P. In contrast, area C showed a differentiated-type adenocarcinoma that invaded the submucosa. The patient had a recurrence of cancer 1.5 years after endoscopic resection. Overexpression of TP53 was detected in area C. Although BRAF mutation was detected in all areas, CpG island methylator phenotype-high cancer was found only in area C. The genomic phenotype of the cancerous tissue was classified as microsatellite stable (MLH1 gene not methylated). In the present case, we showed that a lesion with genetic alterations based on the histological sequence SSA/P → high-grade SSA/P → cancer in SSA/P and an alternative serrated pathway may exhibit aggressive behavior.
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Affiliation(s)
- Makoto Eizuka
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Keisuke Kawasaki
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Yosuke Toya
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Risaburo Akasaka
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Koki Otsuka
- Department of Surgery, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Akira Sasaki
- Department of Surgery, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
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Itatani Y, Kawada K, Sakai Y. Treatment of Elderly Patients with Colorectal Cancer. BIOMED RESEARCH INTERNATIONAL 2018; 2018:2176056. [PMID: 29713641 PMCID: PMC5866880 DOI: 10.1155/2018/2176056] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 02/11/2018] [Indexed: 12/15/2022]
Abstract
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. As society ages, the number of elderly patients with CRC will increase. The percentage of patients with right-sided colon cancer and the incidence of microsatellite instability are higher in elderly than in younger patients with CRC. Moreover, the higher incidence of comorbid diseases in elderly patients indicates the need for less invasive treatment strategies. For example, care should be taken in performing additional surgery after endoscopic submucosal dissection for elderly patients with high-risk T1 CRC. Minimally invasive surgery, such as laparoscopic colectomy, would be preferable for elderly patients with CRC. Chemotherapy for elderly patients requires careful monitoring for adverse events. The aim of this review is to summarize the clinicopathological features of CRC in elderly patients, optical surgical strategies, including endoscopic and laparoscopic resection, and chemotherapeutic strategies, including postoperative adjuvant chemotherapy and systemic chemotherapy for unresectable CRC.
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Affiliation(s)
- Yoshiro Itatani
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Kenji Kawada
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
| | - Yoshiharu Sakai
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan
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35
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Russo A, Sala P, Alberici P, Gazzoli I, Radice P, Montefusco C, Torrini M, Mareni C, Fornasarig M, Santarosa M, Viel A, Benatti P, Pedroni M, De Leon MP, Lucci-Cordisco E, Genuardi M, Messerini L, Stigliano V, Cama A, Curia MC, De Lellis L, Signoroni S, Pierotti MA, Bertario L. Prognostic Relevance of MLH1 and MSH2 Mutations in Hereditary Non-Polyposis Colorectal Cancer Patients. TUMORI JOURNAL 2018; 95:731-8. [DOI: 10.1177/030089160909500616] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Aims and Background Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients. Methods A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLH1-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family. Results Five-year survival rates were 0.73 (95% CI, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% CI, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P = 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% CI, 0.51-0.98) for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006). Conclusions Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related colorectal carcinoma patients depends on the associated constitutional mismatch repair genotype.
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Affiliation(s)
| | - Paola Sala
- Department of Preventive-Predictive Medicine, IRCCS Istituto Nazionale Tumori Foundation, Milan
| | - Paola Alberici
- Department of Experimental Oncology and Molecular Medicine, IRCCS Istituto Nazionale Tumori Foundation, Milan
| | - Isabella Gazzoli
- Department of Experimental Oncology and Molecular Medicine, IRCCS Istituto Nazionale Tumori Foundation, Milan
| | - Paolo Radice
- Department of Experimental Oncology and Molecular Medicine, IRCCS Istituto Nazionale Tumori Foundation, Milan
| | - Claudia Montefusco
- Department of Experimental Oncology and Molecular Medicine, IRCCS Istituto Nazionale Tumori Foundation, Milan
| | | | | | - Mara Fornasarig
- Gastroenterology Unit, National Cancer Institute, Aviano (PN)
| | | | - Alessandra Viel
- Experimental Oncology 1, National Cancer Institute, Aviano (PN)
| | - Piero Benatti
- First Medical Division, Department of Medicine and Medical Specialties, University of Modena and Reggio Emilia, Modena
| | - Monica Pedroni
- First Medical Division, Department of Medicine and Medical Specialties, University of Modena and Reggio Emilia, Modena
| | - Maurizio Ponz De Leon
- First Medical Division, Department of Medicine and Medical Specialties, University of Modena and Reggio Emilia, Modena
| | | | - Maurizio Genuardi
- Genetics Unit, Department of Clinical Pathophysiology, University of Florence, Florence
| | - Luca Messerini
- Department of Clinical Pathology, University of Florence, Florence
| | - Vittoria Stigliano
- Gastroenterology and Digestive Endoscopy Unit, Regina Elena Cancer Institute, Rome
| | - Alessandro Cama
- Department of Oncology and Neurosciences, University “G. D'Annunzio”, and Center of Excellence on Aging “G. D'Annunzio”, Chieti
| | - Maria Cristina Curia
- Department of Oncology and Neurosciences, University “G. D'Annunzio”, and Center of Excellence on Aging “G. D'Annunzio”, Chieti
| | - Laura De Lellis
- Department of Oncology and Neurosciences, University “G. D'Annunzio”, and Center of Excellence on Aging “G. D'Annunzio”, Chieti
| | - Stefano Signoroni
- Department of Preventive-Predictive Medicine, IRCCS Istituto Nazionale Tumori Foundation, Milan
| | - Marco A Pierotti
- IRCCS Istituto Nazionale Tumori Foundation, Milan, and Molecular Genetics of Cancer, FIRC Institute of Molecular Oncology Foundation, Milan, Italy
| | - Lucio Bertario
- Department of Preventive-Predictive Medicine, IRCCS Istituto Nazionale Tumori Foundation, Milan
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Wagner J, Kline CL, Zhou L, Khazak V, El-Deiry WS. Anti-tumor effects of ONC201 in combination with VEGF-inhibitors significantly impacts colorectal cancer growth and survival in vivo through complementary non-overlapping mechanisms. J Exp Clin Cancer Res 2018; 37:11. [PMID: 29357916 PMCID: PMC5778752 DOI: 10.1186/s13046-018-0671-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 01/01/2018] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Small molecule ONC201 is an investigational anti-tumor agent that upregulates intra-tumoral TRAIL expression and the integrated stress response pathway. A Phase I clinical trial using ONC201 therapy in advanced cancer patients has been completed and the drug has progressed into Phase II trials in several cancer types. Colorectal cancer (CRC) remains one of the leading causes of cancer worldwide and metastatic disease has a poor prognosis. Clinical trials in CRC and other tumor types have demonstrated that therapeutics targeting the vascular endothelial growth factor (VEGF) pathway, such as bevacizumab, are effective in combination with certain chemotherapeutic agents. METHODS We investigated the potential combination of VEGF inhibitors such as bevacizumab and its murine-counterpart; along with other anti-angiogenic agents and ONC201 in both CRC xenograft and patient-derived xenograft (PDX) models. We utilized non-invasive imaging and immunohistochemistry to determine potential mechanisms of action. RESULTS Our results demonstrate significant tumor regression or complete tumor ablation in human xenografts with the combination of ONC201 with bevacizumab, and in syngeneic MC38 colorectal cancer xenografts using a murine VEGF-A inhibitor. Imaging demonstrated the impact of this combination on decreasing tumor growth and tumor metastasis. Our results indicate that ONC201 and anti-angiogenic agents act through distinct mechanisms while increasing tumor cell death and inhibiting proliferation. CONCLUSION With the use of both a murine VEGF inhibitor in syngeneic models, and bevacizumab in human cell line-derived xenografts, we demonstrate that ONC201 in combination with anti-angiogenic therapies such as bevacizumab represents a promising approach for further testing in the clinic for the treatment of CRC.
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Affiliation(s)
- Jessica Wagner
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Molecular Therapeutics Program and Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - C Leah Kline
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Molecular Therapeutics Program and Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Lanlan Zhou
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Molecular Therapeutics Program and Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | | | - Wafik S El-Deiry
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Molecular Therapeutics Program and Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.
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Ghosh S, Gupta B, Verma P, Vishnubathla S, Pal S, Dash NR, Gupta SD, Das P. Topographic, histological and molecular study of aberrant crypt foci identified in human colon in different clinical groups. Intest Res 2018; 16:116-125. [PMID: 29422806 PMCID: PMC5797258 DOI: 10.5217/ir.2018.16.1.116] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2017] [Revised: 09/23/2017] [Accepted: 09/27/2017] [Indexed: 12/12/2022] Open
Abstract
Background/Aims Aberrant crypt foci (ACF) are early microscopic lesions of the colonic mucosa, which can be detected by magnified chromoendoscopy. Herein, we have investigated whether ACF identified in different clinical groups can be differentiated based on their characteristics. Methods Macroscopically unremarkable mucosal flaps were collected from 270 fresh colectomies and divided into 3 clinical groups: colorectal carcinoma (group A), disease controls having known pre-neoplastic potential (group Bc), and disease controls without risk of carcinoma development (group Bn). Topographic and histologic analysis, immunohistochemistry, and molecular studies (high-resolution melt curve analysis, real-time polymerase chain reaction, and Sanger sequencing) were conducted for certain neoplasia-associated markers. Results ACF were seen in 107 cases, out of which 72 were left colonic ACF and 35 right colonic ACF (67.2% vs. 32.7%, P=0.02). The overall density of left colonic ACF was 0.97/cm, which was greater than the right colonic ACF density of 0.81/cm. Hypercrinia was present in 41 out of 72 left colonic ACF and in 14 out of 35 right colonic ACF (P=0.01). Immunohistochemical expression of p53 was also greater in left colonic ACF than in right colonic ACF (60.5% vs. 38.2%, P=0.03). However, ACF identified among the 3 clinical groups did not show any distinguishing topographic, histological, or genetic changes. Conclusions Left colonic ACF appear to be high-risk based on their morphological and prototypic tumor marker signature. ACF identified in different clinical groups do not show significant genotypic or topographic differences. Further detailed genetic studies are required to elucidate them further.
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Affiliation(s)
- Shouriyo Ghosh
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Brijnandan Gupta
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Pavan Verma
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | | | - Sujoy Pal
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Nihar R Dash
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | | | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
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Sugai T, Eizuka M, Fujita Y, Kawasaki K, Yamamoto E, Ishida K, Yamano H, Suzuki H, Matsumoto T. Molecular Profiling Based on KRAS/BRAF Mutation, Methylation, and Microsatellite Statuses in Serrated Lesions. Dig Dis Sci 2018; 63:2626-2638. [PMID: 29974407 PMCID: PMC6153566 DOI: 10.1007/s10620-018-5167-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 06/09/2018] [Indexed: 12/30/2022]
Abstract
AIM The aim of your study is to characterize serrated lesions according to their molecular patterns, specifically BRAF/KRAS mutation, methylation, and microsatellite statuses. We evaluated the molecular patterns of 163 serrated lesions, including 37 microvesicular hyperplastic polyps, 73 sessile serrated adenomas/polyps (SSA/Ps), 31 traditional serrated adenomas, and 22 SSA/Ps with cytological dysplasia/adenocarcinoma. METHODS Mutations in BRAF (V600E)/KRAS (exon 2) and microsatellite status [microsatellite stability (MSS) vs. MSI] were examined using a pyrosequencer and the PCR-based microsatellite method, respectively. DNA methylation status was classified as low (LME), intermediate (IME), or high methylation epigenotype (HME) according to a PCR-based two-step method. In addition, mucin and annexin A10 expression was examined. Finally, we performed a hierarchical clustering analysis of the BRAF/KRAS mutation, DNA methylation, and microsatellite statuses. RESULTS The molecular patterns observed in the serrated lesions could be divided into five subgroups: lesions characterized by (1) BRAF mutation, HME, and MSI; (2) BRAF mutation, HME, and MSS; (3) BRAF mutation, LME/IME, and MSS; (4) no BRAF/KRAS mutations, LME/IME, and MSS; and (5) KRAS mutation, LME/IME, and MSS. In addition, we demonstrated that these observed molecular patterns help identify the associations of the molecular patterns and markers (i.e., mucin and annexin A10) with the clinicopathological findings, including histological features and histological diagnosis. CONCLUSIONS We suggest that the identified molecular patterns play an important role in the pathway of serrated lesion development.
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Affiliation(s)
- Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Makoto Eizuka
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Yasuko Fujita
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Keisuke Kawasaki
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Eiichiro Yamamoto
- Department of Molecular Biology, School of Medicine, Sapporo Medical University, Cyuuouku, Sapporo, 060-0061 Japan
| | - Kazuyuki Ishida
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Hiroo Yamano
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Sapporo Medical University, 19-1, Cyuuouku, Sapporo, 060-0061 Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, School of Medicine, Sapporo Medical University, Cyuuouku, Sapporo, 060-0061 Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
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Sugai T, Eizuka M, Arakawa N, Osakabe M, Habano W, Fujita Y, Yamamoto E, Yamano H, Endoh M, Matsumoto T, Suzuki H. Molecular profiling and comprehensive genome-wide analysis of somatic copy number alterations in gastric intramucosal neoplasias based on microsatellite status. Gastric Cancer 2018; 21:765-775. [PMID: 29468422 PMCID: PMC6097076 DOI: 10.1007/s10120-018-0810-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 02/09/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND We attempted to identify the molecular profiles of gastric intramucosal neoplasia (IMN; low-grade dysplasia, LGD; high-grade dysplasia, HGD; intramucosal cancer, IMC) by assessing somatic copy number alterations (SCNAs) stratified by microsatellite status (microsatellite stable, MSS; microsatellite instable, MSI). Thus, microsatellite status was determined in 84 tumors with MSS status and 16 tumors with MSI status. METHODS One hundred differentiated type IMNs were examined using SCNAs. In addition, genetic mutations (KRAS, BRAF, PIK3CA, and TP53) and DNA methylation status (low, intermediate and high) were also analyzed. Finally, we attempted to identify molecular profiles using a hierarchical clustering analysis. RESULTS Three patterns could be categorized according to SCNAs in IMNs with the MSS phenotype: subgroups 1 and 2 showing a high frequency of SCNAs, and subgroup 3 displaying a low frequency of SCNAs (subgroup 1 > 2 > 3 for SCNA). Subgroup 1 could be distinguished from subgroup 2 by the numbers of total SCNAs (gains and losses) and SCN gains (subgroup 1 > 2). The SCNA pattern of LGD was different from that of HGD and IMC. Moreover, IMNs with the MSI phenotype could be categorized into two subtypes: high frequency of SCNAs and low frequency of SCNAs. Genetic mutations and DNA methylation status did not differ among subgroups in IMNs. CONCLUSION Molecular profiles stratified by SCNAs based on microsatellite status may be useful for elucidation of the mechanisms of early gastric carcinogenesis.
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Affiliation(s)
- Tamotsu Sugai
- 0000 0000 9613 6383grid.411790.aDepartment of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Makoto Eizuka
- 0000 0000 9613 6383grid.411790.aDepartment of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Noriyuki Arakawa
- 0000 0000 9613 6383grid.411790.aDepartment of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Mitsumasa Osakabe
- 0000 0000 9613 6383grid.411790.aDepartment of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Wataru Habano
- 0000 0000 9613 6383grid.411790.aDepartment of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Yasuko Fujita
- 0000 0000 9613 6383grid.411790.aDepartment of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Eiichiro Yamamoto
- 0000 0001 0691 0855grid.263171.0Department of Molecular Biology, Sapporo Medical University, School of Medicine, Cyuuouku, Sapporo, 060-0061 Japan
| | - Hiroo Yamano
- 0000 0001 0691 0855grid.263171.0Department of Gastroenterology, Sapporo Medical University, School of Medicine, Cyuuouku, Sapporo, 060-0061 Japan
| | - Masaki Endoh
- 0000 0000 9613 6383grid.411790.aDivision of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Takayuki Matsumoto
- 0000 0000 9613 6383grid.411790.aDivision of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 19-1, Uchimaru, Morioka, 020-8505 Japan
| | - Hiromu Suzuki
- 0000 0001 0691 0855grid.263171.0Department of Molecular Biology, Sapporo Medical University, School of Medicine, Cyuuouku, Sapporo, 060-0061 Japan
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Sugai T, Takahashi Y, Eizuka M, Sugimoto R, Fujita Y, Habano W, Otsuka K, Sasaki A, Yamamoto E, Matsumoto T, Suzuki H. Molecular profiling and genome-wide analysis based on somatic copy number alterations in advanced colorectal cancers. Mol Carcinog 2017; 57:451-461. [PMID: 29230882 PMCID: PMC5814737 DOI: 10.1002/mc.22769] [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: 09/13/2017] [Revised: 11/18/2017] [Accepted: 11/20/2017] [Indexed: 12/13/2022]
Abstract
To characterize somatic alterations in colorectal cancer (CRC), we conducted a genome-scale analysis of 106 CRC specimens. We assessed comprehensive somatic copy number alterations (SCNAs) in these CRC specimens. In addition, we examined microsatellite instability (MSI; low and high), genetic mutations (KRAS, BRAF, TP53, and PIK3CA), and DNA methylation status (classified into low, intermediate, and high type). We stratified molecular alterations in the CRCs using a hierarchical cluster analysis. The examined CRCs could be categorized into three subgroups using hierarchical cluster analysis. Tumors in subgroup 1 were characterized by a low frequency of SCNAs and a high frequency of MSI-high status, whereas tumors in subgroups 2 and 3 were closely associated with a high frequency of SCNAs. Tumors in subgroup 1 were preferentially present in the right-sided colon and showed frequent MSI-high status. Subgroup 3 was distinguished by specific alterations, including gains at 1q23-44, 1p11-36, 10q11-26, 10p11-13, 12q24-24, and 13q33-33. In contrast, tumors in subgroup 2 were characterized by copy-neutral LOH at 12p12-13, 1q24-25, and 10q22. In addition, KRAS mutations were more frequently found in subgroup 3 than in subgroup 1. TP53 mutations and intermediate levels of DNA methylation were common alterations in the three subgroups. SCNAs contributed to sporadic CRC, and there were three subgroups based on SCNAs that played a different role in driving the development of this disease.
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Affiliation(s)
- Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Yayoi Takahashi
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Makoto Eizuka
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Yasuko Fujita
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Wataru Habano
- Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Morioka, Japan
| | - Kouki Otsuka
- Department of Surgery, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Akira Sasaki
- Department of Surgery, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Eiichiro Yamamoto
- Department of Molecular Biology, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, School of Medicine, Sapporo Medical University, Sapporo, Japan
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Drew DA, Mo A, Grady JJ, Stevens RG, Levine JB, Brenner BM, Anderson JC, Forouhar F, O'Brien MJ, Devers TJ, Rosenberg DW. Proximal Aberrant Crypt Foci Associate with Synchronous Neoplasia and Are Primed for Neoplastic Progression. Mol Cancer Res 2017; 16:486-495. [PMID: 29222172 DOI: 10.1158/1541-7786.mcr-17-0380] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 10/11/2017] [Accepted: 11/08/2017] [Indexed: 12/27/2022]
Abstract
Aberrant crypt foci (ACF) are the earliest morphologically identifiable lesion found within the human colon. Despite their relatively high frequency in the distal colon, few studies have examined the molecular characteristics of ACF within the proximal colon. In the following study, clinical participants (n = 184) were screened for ACF using high-definition chromoendoscopy with contrast dye-spray. Following pathologic confirmation, ACF biopsies were subjected to laser capture microdissection (LCM), and epithelial cells were evaluated for somatic mutations with a customized colorectal cancer mutation panel using DNA-mass spectrometry. Samples were further characterized for microsatellite instability (MSI). Logistic models were used to associate proximal ACF with synchronous (detected during the same procedure) neoplasia. Thirty-nine percent of participants had at least one histologically confirmed proximal ACF. Individuals with a proximal ACF were significantly more likely to present with a synchronous neoplasm (P = 0.001), and specifically, a proximal, tubular, or tubulovillous adenoma (multivariable OR = 2.69; 95% confidence interval, 1.12-6.47; P = 0.027). Proximal ACF were more likely to be dysplastic (52%) compared with distal ACF (13%; P < 0.0001). Somatic mutations to APC, BRAF, KRAS, NRAS, and ERBB2 were detected in 37% of proximal ACF. Hyperplastic ACF were more often MSI-high, but there were no differences in MSI status observed by colonic location. In summary, ACF are identified in the proximal colons of approximately 40% of individuals undergoing chromoendoscopy and more often in patients with synchronous proximal adenomas.Implications: This study provides the most complete set of data, to date, that ACF represent the earliest step in the adenoma-carcinoma sequence but remain below the detection limit of conventional endoscopy.Visual Overview: http//mcr.accrjournals.org/content/molcanres/16/3/486/F1.large.jpg Mol Cancer Res; 16(3); 486-95. ©2017 AACR.
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Affiliation(s)
- David A Drew
- Center for Molecular Medicine, University of Connecticut Health, Farmington, Connecticut
| | - Allen Mo
- Center for Molecular Medicine, University of Connecticut Health, Farmington, Connecticut
| | - James J Grady
- Connecticut Institute for Clinical and Translational Science, University of Connecticut Health, Farmington, Connecticut
| | - Richard G Stevens
- Division of Epidemiology and Biostatistics, University of Connecticut Health, Farmington, Connecticut.,Department of Community Medicine and Health Care
| | - Joel B Levine
- Colon Cancer Prevention Program, University of Connecticut Health, Farmington, Connecticut
| | - Bruce M Brenner
- Division of Gastroenterology, University of Connecticut Health, Farmington, Connecticut
| | - Joseph C Anderson
- Division of Gastroenterology, University of Connecticut Health, Farmington, Connecticut
| | - Faripour Forouhar
- Department of Anatomic Pathology, School of Medicine, University of Connecticut Health, Farmington, Connecticut
| | - Michael J O'Brien
- Department of Pathology, School of Medicine, Boston University, Boston, Massachusetts
| | - Thomas J Devers
- Division of Gastroenterology, University of Connecticut Health, Farmington, Connecticut
| | - Daniel W Rosenberg
- Center for Molecular Medicine, University of Connecticut Health, Farmington, Connecticut. .,Colon Cancer Prevention Program, University of Connecticut Health, Farmington, Connecticut
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Horpaopan S, Kirfel J, Peters S, Kloth M, Hüneburg R, Altmüller J, Drichel D, Odenthal M, Kristiansen G, Strassburg C, Nattermann J, Hoffmann P, Nürnberg P, Büttner R, Thiele H, Kahl P, Spier I, Aretz S. Exome sequencing characterizes the somatic mutation spectrum of early serrated lesions in a patient with serrated polyposis syndrome (SPS). Hered Cancer Clin Pract 2017; 15:22. [PMID: 29213343 PMCID: PMC5707812 DOI: 10.1186/s13053-017-0082-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 11/21/2017] [Indexed: 01/01/2023] Open
Abstract
Background Serrated or Hyperplastic Polyposis Syndrome (SPS, HPS) is a yet poorly defined colorectal cancer (CRC) predisposition characterised by the occurrence of multiple and/or large serrated polyps throughout the colon. A serrated polyp-CRC sequence (serrated pathway) of CRC formation has been postulated, however, to date only few molecular signatures of serrated neoplasia (BRAF, KRAS, RNF43 mutations, CpG Island Methylation, MSI) have been described in a subset of SPS patients and neither the etiology of the syndrome nor the distinct genetic alterations during tumorigenesis have been identified. Methods To identify somatic point mutations in potential novel candidate genes of SPS-associated lesions and the involved pathways we performed exome sequencing of eleven early serrated polyps obtained from a 41 year-old female patient with clinically confirmed SPS. For data filtering and analysis, standard pipelines were used. Somatic mutations were identified by comparison with leukocyte DNA and were validated by Sanger sequencing. Results The BRAF p.V600E or KRAS p.G12D mutation was identified in six polyps (~50%) and not found in polyps from the distal colon. In addition, we found seven unique rare somatic alterations of seven different genes in four serrated tumours, all of which are missense variants. The variant in ABI3BP and CATSPERB are predicted to be deleterious. No established cancer gene or candidate genes related to serrated tumorigenesis were affected. Conclusions Somatic mutations seem to be rare events in early hyperplastic and serrated lesions of SPS patients. Neither frequently affected genes nor enrichment of specific pathways were observed. Thus, other alterations such as non-coding variants or epigenetic changes might be the major driving force of tumour progression in SPS. Electronic supplementary material The online version of this article (10.1186/s13053-017-0082-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sukanya Horpaopan
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Anatomy, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand.,Center of Excellence in Medical Biotechnology, Naresuan University, Phitsanulok, Thailand
| | - Jutta Kirfel
- Institute of Pathology, University of Bonn, Bonn, Germany.,Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Sophia Peters
- Institute of Human Genetics, University of Bonn, Bonn, Germany
| | - Michael Kloth
- Institute of Pathology, University of Cologne, Cologne, Germany
| | - Robert Hüneburg
- Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Janine Altmüller
- Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.,Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Dmitriy Drichel
- Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
| | | | - Glen Kristiansen
- Institute of Pathology, University of Bonn, Bonn, Germany.,Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Christian Strassburg
- Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Jacob Nattermann
- Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Per Hoffmann
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.,Institute of Medical Genetics and Pathology, University Hospital Basel and Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Peter Nürnberg
- Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
| | | | - Holger Thiele
- Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
| | - Philip Kahl
- Heinz-Werner-Seifert-Institut für Dermatopathologie Bonn, Bonn, Germany
| | - Isabel Spier
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Stefan Aretz
- Institute of Human Genetics, University of Bonn, Bonn, Germany.,Center for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany.,Institute of Human Genetics, Center for Hereditary Tumor Syndromes, University of Bonn, Sigmund-Freud-Str. 25, D-53127 Bonn, Germany
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Comparison of a Prototype Reverse Hybridization Assay and MethyLight for Detection of SFRP2 Promotor Methylation in Fecal DNA. Int J Biol Markers 2017; 32:e467-e470. [DOI: 10.5301/ijbm.5000289] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/14/2017] [Indexed: 02/06/2023]
Abstract
Background This study aimed to evaluate the diagnostic performance of a novel nonquantitative methylation-specific reverse hybridization (MSRH) assay to detect secreted frizzled-related protein 2 ( SFRP2) promotor methylation in fecal DNA. Methods SFRP2 promoter methylation was investigated in stool DNA isolated from 18 colorectal cancer (CRC) patients and 22 healthy controls using the MSRH assay based on methylation-specific DNA amplification followed by reverse hybridization of biotinylated amplicons to sequence-specific methylation detection probes, with MethyLight serving as a reference method. Results SFRP2 promotor methylation as determined by MSRH vs. MethyLight showed a sensitivity and specificity of 61.1% and 86.3% vs. 77.7% and 77.3%, respectively. Moderate agreement (κ = 0.54, 95% confidence interval [95% CI], 0.29-0.80, p<0.001) was observed between the 2 methods. However, the differences in SFRP2 promotor methylation observed between CRC patients and healthy individuals by both assays were statistically significant (p<0.001). Conclusions Our findings, although limited by the small sample size, do not support the use of the MSRH assay for CRC screening in stool.
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Michigami Y, Watari J, Ito C, Hara K, Yamasaki T, Kondo T, Kono T, Tozawa K, Tomita T, Oshima T, Fukui H, Morimoto T, Das KM, Miwa H. Effects of long-term aspirin use on molecular alterations in precancerous gastric mucosa in patients with and without gastric cancer. Sci Rep 2017; 7:13384. [PMID: 29042646 PMCID: PMC5645329 DOI: 10.1038/s41598-017-13842-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 10/02/2017] [Indexed: 12/13/2022] Open
Abstract
The risk of gastric cancer (GC) remains even after H. pylori eradication; thus, other combination treatments, such as chemopreventive drugs, are needed. We evaluated the effects of aspirin on genetic/epigenetic alterations in precancerous conditions, i.e., atrophic mucosa (AM) and intestinal metaplasia (IM), in patients with chronic gastritis who had taken aspirin for more than 3 years. A total of 221 biopsy specimens from 74 patients, including atrophic gastritis (AG) cases without aspirin use (control), AG cases with aspirin use (AG group), and GC cases with aspirin use (GC group), were analyzed. Aspirin use was associated with a significant reduction of CDH1 methylation in AM (OR: 0.15, 95% CI: 0.06-0.41, p = 0.0002), but was less effective in reversing the methylation that occurred in IM. Frequent hypermethylation including that of CDH1 in AM increased in the GC group compared to the AG group, and CDH1 methylation was an independent predictive marker of GC (OR: 8.50, 95% CI: 2.64-25.33, p = 0.0003). In patients with long-term aspirin use, the changes of molecular events in AM but not IM may be an important factor in the reduction of cancer incidence. In addition, methylation of the CDH1 gene in AM may be a surrogate of GC.
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Affiliation(s)
- Yuki Michigami
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Jiro Watari
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
| | - Chiyomi Ito
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Ken Hara
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Takahisa Yamasaki
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Takashi Kondo
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tomoaki Kono
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Katsuyuki Tozawa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Toshihiko Tomita
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tadayuki Oshima
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Hirokazu Fukui
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Takeshi Morimoto
- Department of Clinical Epidemiology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Kiron M Das
- Division of Gastroenterology and Hepatology, Departments of Medicine and Pathology, Robert Wood Johnson Medical School, Rutgers, Cancer Institute of New Jersey, New Brunswick, United States
| | - Hiroto Miwa
- Division of Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
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45
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Hadjipetrou A, Anyfantakis D, Galanakis CG, Kastanakis M, Kastanakis S. Colorectal cancer, screening and primary care: A mini literature review. World J Gastroenterol 2017; 23:6049-6058. [PMID: 28970720 PMCID: PMC5597496 DOI: 10.3748/wjg.v23.i33.6049] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 06/19/2017] [Accepted: 08/01/2017] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a common health problem, representing the third most commonly diagnosed cancer worldwide and causing a significant burden in terms of morbidity and mortality, with annual deaths estimated at 700000. The western way of life, that is being rapidly adopted in many regions of the world, is a well discussed risk factor for CRC and could be targeted in terms of primary prevention. Furthermore, the relatively slow development of this cancer permits drastic reduction of incidence and mortality through secondary prevention. These facts underlie primary care physicians (PCPs) being assigned a key role in health strategies that enhance prevention and prompt diagnosis. Herein, we review the main topics of CRC in the current literature, in order to better understand its pathogenesis, risk and protective factors, as well as screening techniques. Furthermore, we discuss preventive and screening policies to combat CRC and the crucial role served by PCPs in their successful implementation. Relevant articles were identified through electronic searches of MEDLINE and through manual searches of reference lists.
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Affiliation(s)
- Athanasios Hadjipetrou
- Primary Health Care Centre of Kissamos, Chania, 73400 Crete, Greece
- First Department of Surgery, Saint George General Hospital of Chania, 73300 Crete, Greece
| | - Dimitrios Anyfantakis
- Primary Health Care Centre of Kissamos, Chania, 73400 Crete, Greece
- First Department of Surgery, Saint George General Hospital of Chania, 73300 Crete, Greece
| | | | - Miltiades Kastanakis
- First Department of Surgery, Saint George General Hospital of Chania, 73300 Crete, Greece
| | - Serafim Kastanakis
- Department of Internal Medicine, Saint George General Hospital of Chania, 73300 Crete, Greece
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Kim ST, Lee SJ, Lee J, Park SH, Park JO, Lim HY, Kang WK, Park YS. The Impact of Microsatellite Instability Status and Sidedness of the Primary Tumor on the Effect of Cetuximab-Containing Chemotherapy in Patients with Metastatic Colorectal Cancer. J Cancer 2017; 8:2809-2815. [PMID: 28928870 PMCID: PMC5604213 DOI: 10.7150/jca.18286] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 03/26/2017] [Indexed: 12/18/2022] Open
Abstract
Background: Colorectal cancer (CRC) has been reconsidered as a heterogeneous disease. Among advances of genomic analysis in CRC, the sidedness of tumors (left-sided colon vs. right-sided colon) and microsatellite instability (MSI)-high (H) tumors have been highlighted. Methods: We analyzed 153 CRC patients who were available for evaluation of MSI status and had been treated with cetuximab-containing chemotherapy between April 2008 and January 2013. KRAS mutational status was available in all 153 patients, but BRAF mutational status was only available in 72 patients (47.1%). We evaluated the impact of microsatellite instability status and location of the primary colon tumor on the effect of cetuximab-containing chemotherapy in patients with metastatic colorectal cancer. Results: MSI-H was detected in 3.9% of analyzed patients. Characteristics of patients, with the exception of BRAF mutational status, were generally similar between those with right and left-sided tumors. Right-sided tumors were significantly associated with a BRAF mutation (p=0.023). In addition, patient characteristics with an MSS tumor were not different from those with an MSI-H tumor. For all 153 patients, the most commonly used regimen that included cetuximab was irinotecan alone, irrespective of treatment line. There was no significant difference in treatment efficacy in either RR or disease control rate (DCR) between the MSI-H and MSS groups. There was also no difference in RR and DCR according to the location of the primary tumor (left side vs. right side). No significant difference in PFS was observed between the MSI-H and MSS groups (4.80 months vs. 5.80 months; p=0.238) or the left-side and right-side groups (6.10 months vs. 4.20 months; p=0.278). In a subgroup-analysis of 140 patients with wild-type KRAS, there was no difference in PFS following cetuximab-containing therapy based on MSI status or the location of the primary tumor. Conclusions: MSI status and the location of the primary tumor were not novel biomarkers for response to cetuximab-containing therapy in metastatic CRC. Further prospective validation of the prognostic or predictive capacity of MSI status and the sidedness of tumors is warranted.
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Affiliation(s)
- Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Su-Jin Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Se Hoon Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Joon Oh Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ho Yeong Lim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won Ki Kang
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Suk Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Abstract
The “chronology of cancer” is a concept that describes the nature of cancers through the measure of time. The field extends from carcinogenesis to development, progression, and metastasis. Carcinogenesis is a multi-step process, which results from the accumulation of multiple genetic or epigenetic alterations. Various chronologies of gastrointestinal cancers have been reported for carcinogenesis caused by different risk factors. These chronologies are useful for developing cancer prevention strategies. The tumor growth rate is one of the most important factors in this field. Combining the factors of time and tumor growth enables us to estimate the time at which cancer or metastasis occurred, retrospectively, and to predict the survival of cancer patients, prospectively. It is noteworthy that these chronologies differ significantly among individual cases, even of cancers derived from the same organ. Thus, they are useful for individualization. We can apply the knowledge obtained in this field to the basic research and the diagnosis and treatment of cancers. The chronology of cancer is a classical but interesting field, which helps us consider and explore the essence of cancer. We review the topics related to the chronology of gastrointestinal cancer, ranging from carcinogenesis to metastasis.
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Pulusu SSR, Lawrance IC. Dysplasia and colorectal cancer surveillance in inflammatory bowel disease. Expert Rev Gastroenterol Hepatol 2017; 11:711-722. [PMID: 28475382 DOI: 10.1080/17474124.2017.1327347] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease (IBD) patients are at an increased risk of developing colorectal cancer (CRC), a devastating complication of which intestinal dysplasia is the precursor. Considerable progress has been made to determine CRC risk in IBD, identification & management of dysplasia and preventative methods. Traditionally, surveillance colonoscopies with random colonic biopsies was used. However recent data suggests that chromoendoscopy is a better method of surveillance. Using 5-aminosalicylic acid agents primarily for chemoprevention is an ongoing debate however, when prescribed along with other strategies to control inflammation, their use is considered of benefit. This review presents current understanding of risk factors of neoplasia focusing on dysplasia and preventive strategies. Areas covered: PubMed search was done using key words to assess current evidence. Along with genetics, risk factors, strategies that modify the risk of dysplasia, and CRC in IBD are discussed in detail. Expert commentary: The role of our strategies in modifying CRC risk needs further assessment. Future research should aim to fill knowledge gaps such as high quality evidence for Chromoendoscopy and development of molecular markers for dysplasia detection. Our ultimate goal would be to eliminate CRC and is possible by better understanding of key pathogenic mechanisms in IBD.
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Affiliation(s)
- Samba Siva Reddy Pulusu
- a Centre for Inflammatory Bowel Diseases , Saint John of God Hospital , Subiaco , WA , Australia
| | - Ian C Lawrance
- a Centre for Inflammatory Bowel Diseases , Saint John of God Hospital , Subiaco , WA , Australia.,b Harry Perkins Institute of Medical Research, School of Medicine and Pharmacology , University of Western Australia , Murdoch , WA , Australia
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Zhang Y, Wang J. MicroRNAs are important regulators of drug resistance in colorectal cancer. Biol Chem 2017; 398:929-938. [PMID: 28095367 PMCID: PMC5911396 DOI: 10.1515/hsz-2016-0308] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 01/08/2017] [Indexed: 12/13/2022]
Abstract
Despite of continuous development of cancer treatment over the past decades, drug resistance is still one of the major hurdles of effective therapy for advanced colorectal cancer (CRC) worldwide and the understanding of its underlying mechanisms remains limited. Data which have emerged suggests that many microRNAs (miRNAs) may contribute to drug resistance in CRC. Major findings on miRNA functions in drug resistance of CRC are systemically reviewed here, with the goal of providing new updates to broaden our comprehension of its mechanisms and evidence to utilize miRNAs as potential therapeutic targets for CRC treatment.
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Analysis of molecular alterations in laterally spreading tumors of the colorectum. J Gastroenterol 2017; 52:715-723. [PMID: 27704264 DOI: 10.1007/s00535-016-1269-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 09/19/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Colorectal laterally spreading tumors (LSTs) are classified into LST-Gs and LST-NGs, according to macroscopic findings. In the present study, we determined the genetic and epigenetic alterations within colorectal LSTs and protruding adenomas. METHODS A crypt isolation method was used to isolate DNA from tumors and normal glands of 73 macroscopically verified colorectal LSTs (histologically defined adenomas; 38 LST-Gs and 35 LST-NGs) and 36 protruding adenomas. The DNA was processed using polymerase chain reaction (PCR) microsatellite assays, single-strand conformation polymorphism (SSCP) assays, and pyrosequencing to detect chromosomal allelic imbalance (AI), mutations in APC, KRAS, and TP53, and the methylation of MLH1, MGMT, CDKN2A, HPP1, RASSF2A, SFRP1, DKK1, ZFP64, and SALL4 genes. In addition, methylation status was examined using the following set of markers: MIN1, MINT2, MINT31, MLH1, and CDKN2A (with classification of negative/low and high). Microsatellite instability (MSI) was also examined. RESULTS 5q AI and methylation of the SFRP1 and SALL4 genes were common molecular events in both LST-Gs and LST-NGs. Neither MSI nor mutations in BRAF ware observed in the LSTs. TP53 mutations were rarely found in LSTs. The frequencies of KRAS and APC mutations and the methylation levels of ZFP64, RASSF2A, and HPP1 genes were significantly higher in LST-Gs than in LST-NGs. Protruding adenomas showed alterations common to LST-Gs. Negative/low methylation status was common among the three types of tumors. CONCLUSION Combined genetic and epigenetic data suggested that the molecular mechanisms of tumorigenesis were different between LST-Gs and LST-NGs.
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