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Ouchi K, Sunakawa Y, Tsuji A, Shiozawa M, Kawai T, Yasui H, Ota H, Kochi M, Manaka D, Ohori H, Miyake T, Yamaguchi T, Matsuura M, Sagawa T, Makiyama A, Takeuchi M, Ichikawa W, Fujii M, Ishioka C. Genome-wide DNA methylation status as a biomarker for clinical outcomes of first-line treatment in patients with RAS wild-type metastatic colorectal cancer: JACCRO CC-13AR. ESMO Open 2025; 10:105076. [PMID: 40334314 DOI: 10.1016/j.esmoop.2025.105076] [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: 11/18/2024] [Revised: 02/12/2025] [Accepted: 04/04/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND Several retrospective studies have demonstrated an association between genome-wide DNA methylation status (GWMS) and clinical outcomes after treatment with anti-epidermal growth factor receptor antibody in metastatic colorectal cancer (mCRC). This biomarker study evaluated the association of GWMS with clinical outcomes in mCRC patients who were enrolled in a randomized phase II DEEPER trial of comparing modified (m)-FOLFOXIRI plus bevacizumab (Bev) and m-FOLFOXIRI plus cetuximab (Cet) as first-line treatment. PATIENTS AND METHODS GWMS was measured using tumor tissues which were collected from patients with tissue samples available in the DEEPER trial. In addition, tumor tissues were classified into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC) groups. The correlation between GWMS and survival was analyzed by comparing progression-free survival (PFS) and overall survival (OS) between the two different groups of GWMS. RESULTS Of the 137 patients, 15 were classified into the HMCC group, and 122 were classified into the LMCC group; 71 patients were treated with Bev, and 66 were treated with Cet. In the Bev arm, OS was significantly shorter in the HMCC group than in the LMCC group (median 24.2 versus 48.9 months, P = 0.03). In the Cet arm, both PFS and OS were significantly shorter in the HMCC group than in the LMCC group (median 4.0 versus 14.3 months, P < 0.01 and median 13.6 versus 42.7 months, P < 0.01). The interaction tests revealed that GWMS was a significant predictor of PFS and OS in the Cet arm. CONCLUSIONS GWMS was associated with survival in RAS wild-type mCRC patients treated with initial chemotherapy. Also, it may serve as a predictor for selection of molecular-targeted antibodies in first-line treatment.
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Affiliation(s)
- K Ouchi
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan
| | - Y Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.
| | - A Tsuji
- Department of Clinical Oncology, Faculty of Medicine, Kagawa University, Miki-Gun, Japan
| | - M Shiozawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - T Kawai
- Department of Surgery, Japanese Red Cross Society Himeji Hospital, Himeji, Japan
| | - H Yasui
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan
| | - H Ota
- Department of Gastroenterological Surgery, Ikeda City Hospital, Ikeda, Japan
| | - M Kochi
- Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - D Manaka
- Department of Surgery, Gastro-Intestinal Center, Kyoto Katsura Hospital, Kyoto, Japan
| | - H Ohori
- Department of Medical Oncology, Ishinomaki Red Cross Hospital, Ishinomaki, Japan
| | - T Miyake
- Department of Surgery, Shiga University of Medical Science Hospital, Otsu, Japan
| | - T Yamaguchi
- Department of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan
| | - M Matsuura
- Department of Surgery, Nishikobe Medical Center, Kobe, Japan
| | - T Sagawa
- Division of Gastroenterology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan
| | - A Makiyama
- Cancer Center, Gifu University Hospital, Gifu, Japan
| | - M Takeuchi
- Graduate School of Mathematical Sciences, The University of Tokyo, Tokyo, Japan
| | - W Ichikawa
- Division of Medical Oncology, Showa University Fujigaoka Hospital, Kanagawa, Japan
| | - M Fujii
- Japan Clinical Cancer Research Organization, Tokyo, Japan
| | - C Ishioka
- Department of Medical Oncology, Tohoku University Hospital, Sendai, Japan; JR Sendai Hospital, Sendai, Japan
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Reyila A, Gao X, Yu J, Nie Y. Insight into the role of DNA methylation in prognosis and treatment response prediction of gastrointestinal cancers. Epigenomics 2025; 17:475-488. [PMID: 40084815 PMCID: PMC12026041 DOI: 10.1080/17501911.2025.2476380] [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: 09/19/2024] [Accepted: 03/04/2025] [Indexed: 03/16/2025] Open
Abstract
Gastrointestinal (GI) cancers impose a significant disease burden, underscoring the critical importance of accurate prognosis prediction and treatment response evaluation. DNA methylation, one of the most extensively studied epigenetic modifications, has gained prominence due to its reliable measurement across various sample types. Numerous studies have reported that DNA methylation was linked to the diagnosis, prognosis and treatment response in malignancies, including GI cancers. While its diagnostic role in GI cancers has been comprehensively reviewed. Recent research has increasingly highlighted its potential in prognosis prediction and treatment response evaluation. However, no existing reviews have exclusively focused on these two aspects. In this review, we retrieved relevant studies and included 230 of them in our discussion, thereby providing an overview of the clinical applicability of aberrant DNA methylation in these two fields among patients with esophageal, gastric, colorectal, pancreatic cancers, and hepatocellular carcinomas. Additionally, we discuss the limitations of the current literature and propose directions for future research. Specifically, we emphasize the need for standardized DNA methylation methodologies and advocate for the integration of gene panels, rather than single genes, to address tumor heterogeneity more effectively.
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Affiliation(s)
- Abudurousuli Reyila
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi’an, Shaanxi, China
- National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Xianchun Gao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi’an, Shaanxi, China
- National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Jun Yu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi’an, Shaanxi, China
- National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yongzhan Nie
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Fourth Military Medical University, Xi’an, Shaanxi, China
- National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, Shaanxi, China
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3
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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 2025; 266:155786. [PMID: 39724851 DOI: 10.1016/j.prp.2024.155786] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [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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Wismayer R, Matthews R, Whalley C, Kiwanuka J, Kakembo FE, Thorn S, Wabinga H, Odida M, Tomlinson I. Determination of the frequency and distribution of APC, PIK3CA, and SMAD4 gene mutations in Ugandan patients with colorectal cancer. BMC Cancer 2024; 24:1212. [PMID: 39350061 PMCID: PMC11440721 DOI: 10.1186/s12885-024-12967-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 09/19/2024] [Indexed: 10/04/2024] Open
Abstract
Uganda is a developing low-income country with a low incidence of colorectal cancer, which is steadily increasing. Ugandan colorectal cancer (CRC) patients are young and present with advanced-stage disease. In our population, there is a scarcity of genetic oncological studies, therefore, we investigated the mutational status of CRC tissues, focusing in particular on the adenomatous polyposis coli (APC), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and SMAD4 genes. Our objective was to determine whether there were any differences between other populations and Ugandan patients. We performed next-generation sequencing on the extracted DNA from formalin-fixed paraffin-embedded adenocarcinoma samples from 127 patients (mean (SD) age: 54.9 (16.0) years; male:female sex ratio: 1.2:1). Most tumours were located in the rectum 56 (44.1%), 14 (11%) tumours were high grade, and 96 (75.6%) were moderate grade CRC. Stage III + IV CRC tumours were found in 109 (85.8%) patients. We identified 48 variants of APC, including 9 novel APC mutations that were all pathogenic or deleterious. For PIK3CA, we found 19 variants, of which 9 were deleterious or pathogenic. Four PIK3CA novel pathogenic or deleterious variants were included (c.1397C > G, c.2399_2400insA, c.2621G > C, c.2632C > G). Three SMAD4 variants were reported, including two pathogenic or deleterious variants (c.1268G > T, c.556dupC) and one tolerant (c.563A > C) variant. One novel SMAD4 deleterious mutation (c.1268G > T) was reported. In conclusion, we provide clinicopathological information and new genetic variation data pertinent to CRC in Uganda.
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Affiliation(s)
- Richard Wismayer
- Department of Surgery, Masaka Regional Referral Hospital, Masaka, Uganda.
- Department of Surgery, Faculty of Health Sciences, Equator University of Science and Technology, Masaka, Uganda.
- Department of Surgery, Faculty of Health Sciences, Habib Medical School, IUIU University, Kampala, Uganda.
- Department of Pathology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda.
- Institute of Genetics and Cancer, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK.
| | - Rosie Matthews
- Institute of Genetics and Cancer, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
| | - Celina Whalley
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Julius Kiwanuka
- Department of Epidemiology and Biostatistics, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Fredrick Elishama Kakembo
- Department of Immunology and Molecular Biology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda
- African Centre of Excellence in Bioinformatics and Data Intensive Sciences, Infectious Diseases Institute, Makerere University, Kampala, Uganda
| | - Steve Thorn
- Institute of Genetics and Cancer, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
- Department of Oncology, University of Oxford, Oxford, UK
| | - Henry Wabinga
- Department of Pathology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda
| | - Michael Odida
- Department of Pathology, School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda
- Department of Pathology, Faculty of Medicine, Gulu University, Gulu, Uganda
| | - Ian Tomlinson
- Institute of Genetics and Cancer, College of Medicine and Veterinary Medicine, University of Edinburgh, Edinburgh, UK
- Department of Oncology, University of Oxford, Oxford, UK
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5
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Kalita M, Devaraja M, Saha I, Chakrabarti A. Global variations in elderly cancer mortality pattern in 2020 & prediction to 2040: A population-based study. Indian J Med Res 2024; 160:165-175. [PMID: 39513212 PMCID: PMC11544570 DOI: 10.25259/ijmr_1671_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 06/27/2024] [Indexed: 11/15/2024] Open
Abstract
Background & objectives Cancer contributes to decreasing life expectancy, especially in low- and middle- income countries (LMIC) and countries in transition where resources for diagnosis and care are limited. As the world population is ageing, and by 2050, two-thirds of the population in LMIC will be elderly, the greater impact of cancer on the expectation of life in years at a given age of an adult will be seen in these countries. Methods Estimated cancer mortality for older adults (60 yr or above) was estimated using statistics available on Globocan 2020 platform (gco.iarc.fr). This platform provided the number of deaths and age-standardized truncated mortality rates (per 100,000) by sex and continent. We calculated the projected cancer deaths in 2040 by applying the projection model, considering a stable rate. Results Globally, with an estimated 7.5 million deaths, cancer deaths in older population represented a total of 71.2 per cent of all cancer-related deaths. The truncated age-adjusted mortality rate among the older population (both sexes) was estimated as 615.1 deaths per 100,000 and the mortality rate was 62.6 per cent higher in elderly (60 yr or above) males as compared to elderly females. The overall future cancer death among the elderly was estimated to increase from 7.05 to 12.7 million deaths, representing a total 80.2 per cent increase in deaths by 2040. Interpretation & conclusions The projected mortality increase will challenge existing healthcare systems, especially in lower or lower medium-income countries where resources are limited. Elderly patients are at an elevated risk of adverse outcomes due to the high prevalence of co-morbid conditions. Geriatric oncology will play an important role in the coming years to ensure the overall health and well-being of elderly patients, which needs to be supported by good stratified data on elderly cancer.
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Affiliation(s)
- Manoj Kalita
- ICMR-Centre for Ageing & Mental Health, Kolkata, India
| | - M. Devaraja
- ICMR-Centre for Ageing & Mental Health, Kolkata, India
| | - Indranil Saha
- ICMR-Centre for Ageing & Mental Health, Kolkata, India
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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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Song J, Kataoka K, Inoue M, Yamada T, Shiozawa M, Beppu N, Kuriyama S, Suto T, Matsuhashi N, Sakura Y, Kanazawa A, Kagawa H, Kanemitsu Y, Ceelen W, Ikeda M. Lymphatic spread patterns in young versus elderly patients with stage III colon cancer. BJS Open 2024; 8:zrae036. [PMID: 38818960 PMCID: PMC11140818 DOI: 10.1093/bjsopen/zrae036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Revised: 03/04/2024] [Accepted: 03/08/2024] [Indexed: 06/01/2024] Open
Abstract
BACKGROUND The anatomical pattern of lymph nodes spread differs between young (aged 45 years or younger) and elderly (aged 80 years or older) patients with stage III colon cancer and is poorly investigated. METHODS Two groups of patients (young and elderly) with stage III colon cancer who underwent upfront extensive (D3) lymphadenectomy at eight Japanese centres between 1998 and 2018 were retrospectively analysed. The primary endpoint was the proportion of positive central lymph nodes. The lymph nodes spreading pattern and its prognostic impact on recurrence-free survival and overall survival in the two groups were also compared. RESULTS Two hundred and ten young patients and 348 elderly patients were identified and compared. The total number of lymph nodes harvested and the total number of invaded lymph nodes were significantly higher in younger patients compared with elderly patients (median of 31.5 (3-151) versus 21 (3-116), P < 0.001 and median of 3 (1-21) versus 2 (1-25), P < 0.001 respectively). The proportion of positive central lymph nodes were higher in younger patients than in elderly patients (9.52% (95% c.i. 6.24 to 14.2%) versus 4.59% (95% c.i. 2.84 to 7.31%), P = 0.012). In multivariate models for recurrence-free survival, central lymph nodes invasion were identified as a poor prognostic factor in younger patients (HR 5.21 (95% c.i. 1.76 to 15.39)) but not in elderly patients (HR 1.73 (95% c.i. 0.80 to 3.76)). CONCLUSION Young patients with stage III colon cancer have a higher risk of central lymph nodes invasion, suggesting a more aggressive disease biology. The presence of central lymph nodes invasion are associated with a worse outcome in young patients.
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Affiliation(s)
- Jihyung Song
- Division of Lower GI, Department of Gastroenterological Surgery, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Kozo Kataoka
- Division of Lower GI, Department of Gastroenterological Surgery, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Manabu Inoue
- Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Takeshi Yamada
- Department of Gastrointestinal and Hepato-Billiary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Manabu Shiozawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Naohito Beppu
- Division of Lower GI, Department of Gastroenterological Surgery, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
| | - Sho Kuriyama
- Department of Gastrointestinal and Hepato-Billiary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Takeshi Suto
- Department of Gastroenterological Surgery, Yamagata Prefectural Central Hospital, Yamagata, Japan
| | - Nobuhisa Matsuhashi
- Department of Gastroenterological Surgery/Pediatric Surgery, Gifu University, Gifu, Japan
| | - Yusuke Sakura
- Department of Gastrointestinal Surgery, Shimane Prefectural Central Hospital, Izumo, Japan
| | - Akiyoshi Kanazawa
- Department of Gastrointestinal Surgery, Shimane Prefectural Central Hospital, Izumo, Japan
| | - Hiroyasu Kagawa
- Division of Colon and Rectal Surgery, Shizuoka Cancer Center, Shunto-gun, Japan
| | - Yukihide Kanemitsu
- Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Wim Ceelen
- Department of GI Surgery, Ghent University Hospital, and Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium
| | - Masataka Ikeda
- Division of Lower GI, Department of Gastroenterological Surgery, School of Medicine, Hyogo Medical University, Nishinomiya, Japan
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8
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Zhao N, Lai C, Wang Y, Dai S, Gu H. Understanding the role of DNA methylation in colorectal cancer: Mechanisms, detection, and clinical significance. Biochim Biophys Acta Rev Cancer 2024; 1879:189096. [PMID: 38499079 DOI: 10.1016/j.bbcan.2024.189096] [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: 10/05/2023] [Revised: 02/18/2024] [Accepted: 03/13/2024] [Indexed: 03/20/2024]
Abstract
Colorectal cancer (CRC) is one of the deadliest malignancies worldwide, ranking third in incidence and second in mortality. Remarkably, early stage localized CRC has a 5-year survival rate of over 90%; in stark contrast, the corresponding 5-year survival rate for metastatic CRC (mCRC) is only 14%. Compounding this problem is the staggering lack of effective therapeutic strategies. Beyond genetic mutations, which have been identified as critical instigators of CRC initiation and progression, the importance of epigenetic modifications, particularly DNA methylation (DNAm), cannot be underestimated, given that DNAm can be used for diagnosis, treatment monitoring and prognostic evaluation. This review addresses the intricate mechanisms governing aberrant DNAm in CRC and its profound impact on critical oncogenic pathways. In addition, a comprehensive review of the various techniques used to detect DNAm alterations in CRC is provided, along with an exploration of the clinical utility of cancer-specific DNAm alterations.
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Affiliation(s)
- Ningning Zhao
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei 230031, China
| | - Chuanxi Lai
- Division of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China
| | - Yunfei Wang
- Zhejiang ShengTing Biotech. Ltd, Hangzhou 310000, China
| | - Sheng Dai
- Division of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China.
| | - Hongcang Gu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei 230031, China.
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9
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Ge R, Zhang J, Lu M, Shi Y, Yan S, Xue Z, Wang Z, Lopez-Beltran A, Cheng L. Primary mucinous adenocarcinoma of the urethra: A clinicopathological analysis of 35 cases. Histopathology 2024; 84:753-764. [PMID: 38114291 DOI: 10.1111/his.15118] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 10/31/2023] [Accepted: 12/01/2023] [Indexed: 12/21/2023]
Abstract
AIM Primary mucinous adenocarcinoma of the urethra represents an extremely rare entity. We sought to characterise further these tumours' clinicopathological, immunohistochemical and molecular features. METHODS AND RESULTS Thirty-five cases were identified, occurring in 18 males and 17 females. The mean age at diagnosis was 65 years (28-89 years). The main presentation symptoms were haematuria and urinary outlet obstruction. Microscopic analysis revealed that all 35 tumours have stromal dissection by mucin. Ten tumours showed villoglandular dysplasia, nine showed mucinous metaplasia, two showed adenocarcinoma in situ and four showed signet ring cell features. All tumours were immunopositive for CEA, while immunonegative for nuclear β-catenin; 19 of 23 (83%) expressed high molecular weight cytokeratin; 19 of 33 (58%) CK7; 28 of 34 (82%) CK20; 32 of 35 (91%) CDX2; 22 of 27 (81%) cadherin-17 (CDH-17); 26 of 29 (90%) SATB2; and one of 31 (3%) GATA3. Mismatch repair gene products, including MLH1, PMS2, MSH2 and MSH6, were immunopositive, suggesting the MSI-low genotype of mucinous adenocarcinoma of the urethra. BRAF V600E and ALK rearrangements were not detected. During the mean follow-up of 20 months, nine patients either developed distant metastasis or succumbed to the illness. CONCLUSION Our study, encompassing the most extensive series of 35 cases of primary mucinous adenocarcinoma of the urethra, provides crucial insights into its precise diagnosis, management and potential targeted treatments. We found a greater CDX2, SATB2 and CDH17 sensitivity in these urethral tumours for the first time, to our knowledge. We identified characteristics such as an MSI-low profile, non-V600E BRAF mutations and an absence of ALK rearrangements.
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Affiliation(s)
- Rongbin Ge
- Department of Pathology and Immunology, Washington University in St Louis, St Louis, MO, USA
| | - Jing Zhang
- Department of Pathology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Min Lu
- Department of Pathology, Peking University Third Hospital, Peking University Health Science Center, Beijing, China
| | - Yuchuan Shi
- Department of Pathology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Shi Yan
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Zixuan Xue
- Department of Urology, Peking University Third Hospital, Beijing, China
| | - Zongwei Wang
- Department of Surgery, Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Antonio Lopez-Beltran
- Department of Morphological Sciences, Cordoba University Medical School, Cordoba, Spain
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, Brown University Warren Alpert Medical School, Lifespan Academic Medical Center and the Legorreta Cancer Center at Brown University, Providence, RI, USA
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10
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Trembath HE, Yeh JJ, Lopez NE. Gastrointestinal Malignancy: Genetic Implications to Clinical Applications. Cancer Treat Res 2024; 192:305-418. [PMID: 39212927 DOI: 10.1007/978-3-031-61238-1_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Advances in molecular genetics have revolutionized our understanding of the pathogenesis, progression, and therapeutic options for treating gastrointestinal (GI) cancers. This chapter provides a comprehensive overview of the molecular landscape of GI cancers, focusing on key genetic alterations implicated in tumorigenesis across various anatomical sites including GIST, colon and rectum, and pancreas. Emphasis is placed on critical oncogenic pathways, such as mutations in tumor suppressor genes, oncogenes, chromosomal instability, microsatellite instability, and epigenetic modifications. The role of molecular biomarkers in predicting prognosis, guiding treatment decisions, and monitoring therapeutic response is discussed, highlighting the integration of genomic profiling into clinical practice. Finally, we address the evolving landscape of precision oncology in GI cancers, considering targeted therapies and immunotherapies.
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Affiliation(s)
- Hannah E Trembath
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Jen Jen Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Nicole E Lopez
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA.
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA.
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11
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Martín-García D, Téllez T, Redondo M, García-Aranda M. The use of SP/Neurokinin-1 as a Therapeutic Target in Colon and Rectal Cancer. Curr Med Chem 2024; 31:6487-6509. [PMID: 37861026 DOI: 10.2174/0109298673261625230924114406] [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: 05/15/2023] [Revised: 08/08/2023] [Accepted: 08/18/2023] [Indexed: 10/21/2023]
Abstract
Different studies have highlighted the role of Substance P / Neurokinin 1 Receptor (SP/NK-1R) axis in multiple hallmarks of cancer including cell transformation, proliferation, and migration as well as angiogenesis and metastasis of a wide range of solid tumors including colorectal cancer. Until now, the selective high-affinity antagonist of human SP/NK1-R aprepitant (Emend) has been authorized by the Food and Drug Administration as a low dosage medication to manage and treat chemotherapy-induced nausea. However, increasing evidence in recent years support the potential utility of high doses of aprepitant as an antitumor agent and thus, opening the possibility to the pharmacological repositioning of SP/NK1-R antagonists as an adjuvant therapy to conventional cancer treatments. In this review, we summarize current knowledge on the molecular basis of colorectal cancer as well as the pathophysiological importance of SP/NK1-R and the potential utility of SP/NK-1R axis as a therapeutic target in this malignancy.
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Affiliation(s)
| | - Teresa Téllez
- Surgical Specialties, Biochemistry and Immunology, University of Malaga, Spain
| | - Maximino Redondo
- Surgical Specialties, Biochemistry and Immunology, University of Malaga, Spain
| | - Marilina García-Aranda
- Surgical Specialties, Biochemistry and Immunology, University of Malaga, Spain
- Research and Innovation Unit, Hospital Costa del Sol, 29602 Marbella, Spain
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12
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Dong Y, Zheng M, Wang X, Yu C, Qin T, Shen X. High expression of CDKN2A is associated with poor prognosis in colorectal cancer and may guide PD-1-mediated immunotherapy. BMC Cancer 2023; 23:1097. [PMID: 37950153 PMCID: PMC10638725 DOI: 10.1186/s12885-023-11603-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 11/02/2023] [Indexed: 11/12/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the most common malignancies worldwide. Immunotherapy targeting the programmed death protein 1(PD-1) and its ligand (PD-L1), is a promising treatment option for many cancers, but has exhibited poor therapeutic efficacy in CRC. This study aimed to identify and validate the prognostic value of immune-related genes and PD-1-associated genes for immunotherapy treatment of CRC. METHODS An extensive analysis of prognostic immune-related DEGs and PD-1-related genes has highlighted CDKN2A as a vital overlapping gene. To further explore its expression in CRC and its prognostic value, we conducted qRT-PCR, Western blot experiments, and consulted various databases. Subsequently, we conducted gene expression analysis, survival and prognostic analysis, enrichment analysis, immune infiltration assessment, and TIDE analysis to assess the significance of CDKN2A. RESULTS In CRC, CDKN2A was highly expressed compared to normal tissue. It was found that CDKN2A expression was related to clinicopathological features such as inflammation and tumor stage. Furthermore, a significant correlation was identified between CDKN2A and immune infiltration, specifically involving CD4 T cells, CD8 T cells, and macrophages. The analysis of the GSEA of CRC samples with high CDKN2A expression identified enrichment of genes involved in MYC target-v2 and metabolism pathways. Furthermore, UBE2I, CDK4, CDK6, TP53, and CCND1 were found to be significantly coexpressed with CDKN2A, suggesting a potential role that these gene play in CRC and immunotherapy. CONCLUSIONS Our study revealed that high CDKN2A expression in CRC is a potentially valuable prognostic biomarker, which may guide PD-1-mediated immunotherapy.
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Affiliation(s)
- Yuying Dong
- Zhejiang Chinese Medical University, Hangzhou, People's Republic of China
| | - Mingming Zheng
- Zhejiang Chinese Medical University, Hangzhou, People's Republic of China
| | - Xiaoxuan Wang
- Zhejiang Chinese Medical University, Hangzhou, People's Republic of China
| | - Chenyue Yu
- Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
| | - Tiantian Qin
- Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People's Republic of China
| | - Xuning Shen
- Affiliated Hospital of Jiaxing University, Jiaxing, Zhejiang, People's Republic of China.
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Meta-Analysis of the Prognostic and Predictive Role of the CpG Island Methylator Phenotype in Colorectal Cancer. DISEASE MARKERS 2022; 2022:4254862. [PMID: 36157209 PMCID: PMC9499813 DOI: 10.1155/2022/4254862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 08/30/2022] [Indexed: 12/24/2022]
Abstract
Background Various studies have produced contradictory results on the prognostic role of the CpG island methylator phenotype (CIMP) among colorectal cancer (CRC) patients. Although a meta-analysis published in 2014 reported a worse prognosis of CIMP among CIMP-high (CIMP-H) CRC patients, the sample sizes of the major included studies were small. In this study, we included the most recent studies with large sample sizes and performed an updated meta-analysis on the relationship between CIMP and CRC prognosis. Methods A search of MEDLINE, Web of Science, and Cochrane for studies related to CIMP and CRC published until July 2021 was conducted based on the PICO (participant, intervention, control, outcome) framework. Data extraction and literature analyses were performed according to PRISMA standards. Results In the present update, 36 eligible studies (20 recently published) reported survival data in 15315 CRC patients, 18.3% of whom were characterized as CIMP-H. Pooled analysis suggested that CIMP-H was associated with poorer overall survival (OS) (hazard ratio [HR] = 1.37, 95% CI: 1.26–1.48) and disease-free survival/progression-free survival/recurrence-free survival (DFS/PFS/RFS) (HR = 1.51, 95% CI: 1.19–1.91) among CRC patients. Subgroup analysis based on tumor stage and DNA mismatch repair (MMR) status showed that only patients with stages III-IV and proficient MMR (pMMR) tumors showed a significant association between CIMP-H and shorter OS, with HRs of 1.52 and 1.37, respectively. Three studies were pooled to explore the predictive value of CIMP on CRC patient DFS after receiving postoperative chemotherapy, and no significant correlation was found. Conclusion CIMP-H is associated with a significantly poor prognosis in CRC patients, especially those with stage III-IV and pMMR tumors. However, the predictive value of CIMP needs to be confirmed by more prospective randomized studies.
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14
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Tanaka T, Takehara K, Yamashita N, Okazawa-Sakai M, Kuraoka K, Teramoto N, Taguchi K, Yamashiro K, Kato H, Mizunoe T, Suzuki R, Yamamoto D, Ueki A, Saito T. Frequency and clinical features of deficient mismatch repair in ovarian clear cell and endometrioid carcinoma. J Gynecol Oncol 2022; 33:e67. [PMID: 36032025 PMCID: PMC9428302 DOI: 10.3802/jgo.2022.33.e67] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 04/20/2022] [Accepted: 06/12/2022] [Indexed: 11/30/2022] Open
Abstract
Objective To clarify the frequency of deficient mismatch repair (dMMR) in Japanese ovarian cancer patients, we examined microsatellite instability (MSI) status and immunohistochemistry (IHC) subtypes, including endometrioid carcinoma (EMC), clear cell carcinoma (CCC), or a mixture of both (Mix). Methods We registered 390 patients who were diagnosed with EMC/CCC/Mix between 2006 and 2015 and treated at seven participating facilities. For 339 patients confirmed eligible by the Central Pathological Review Board, MSI, IHC, and MutL homolog 1 methylation analyses were conducted. The tissues of patients with Lynch syndrome (LS)-related cancer histories, such as colorectal and endometrial cancer, were also investigated. Results MSI-high (MSI-H) status was observed in 2/217 CCC (0.9%), 10/115 EMC (8.7%), and 1/4 Mix (25%). Additionally, loss of MMR protein expression (LoE-MMR) was observed in 5/219 (2.3%), 16/115 (14.0%), and 1/4 (25%) patients with CCC, EMC, and Mix, respectively. Both MSI-H and LoE-MMR were found significantly more often in EMC (p<0.001). The median (range) ages of patients with MMR expression and LoE-MMR were 54 (30–90) and 46 (22–76) (p=0.002), respectively. In the multivariate analysis, advanced stage and histological type were identified as prognostic factors. Conclusion The dMMR rate for EMC/CCC was similar to that reported in Western countries. In Japan, it is assumed that the dMMR frequency is higher because of the increased proportion of CCC. The deficient mismatch repair (dMMR) rate in Japanese patients is currently unknown. This study determined the frequency of dMMR in Japanese ovarian cancer patients. The dMMR rate was similar to that reported in Western countries. We identified potential criteria for implementing microsatellite instability and immunohistochemistry analyses in Lynch syndrome screening.
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Affiliation(s)
- Tamaki Tanaka
- Department of Perinatology and Gynecology, Kagawa University Graduate School of Medicine, Kida, Japan.,Department of Gynecologic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Kazuhiro Takehara
- Department of Gynecologic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.
| | - Natsumi Yamashita
- Department of Clinical Research Center, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Mika Okazawa-Sakai
- Department of Gynecologic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Kazuya Kuraoka
- Department of Diagnostic Pathology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan
| | - Norihiro Teramoto
- Department of Pathology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Kenichi Taguchi
- Department of Pathology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | | | - Hidenori Kato
- Department of Gynecologic Oncology, National Hospital Organization Hokkaido Cancer Center, Sapporo, Japan
| | - Tomoya Mizunoe
- Department of Obstetrics and Gynecology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan
| | - Rie Suzuki
- Department of Obstetrics and Gynecology, National Defense Medical Collage Hospital, Tokorozawa, Japan
| | - Dan Yamamoto
- Department of Gynecology, National Hospital Organization Fukuyama Medical Center, Fukuyama, Japan
| | - Arisa Ueki
- Department of Clinical Genetic Oncology, Cancer Institute Hospital of JFCR, Tokyo, Japan
| | - Toshiaki Saito
- Gynecology Service, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
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15
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Hu Y, Ding J, Wu C, Gao H, Ge M, Shao Q, Liu Y, Ye Q. Differential Expression and Prognostic Correlation of Immune Related Factors Between Right and Left Side Colorectal Cancer. Front Oncol 2022; 12:845765. [PMID: 35936748 PMCID: PMC9353740 DOI: 10.3389/fonc.2022.845765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 06/20/2022] [Indexed: 11/13/2022] Open
Abstract
Background Growing evidence suggests that colorectal cancer (CRC) should be considered a heterogeneous disease. The right side (RCC) and left side (LCC) colorectal cancer have different clinical characteristics and immune landscapes. The aim of this study was to analyze differential expression and prognostic correlation of immune-related factors between RCC and LCC. Methods The gene expression profile and clinical characteristics of CRC patients were retrieved from The Cancer Genome Atlas data portal (n=525). Using a deconvolution algorithm, immune cell infiltration in RCC and LCC based on the RNA-seq data was analyzed. Differentially expressed genes (DEGs) were obtained by performing differential gene expression analysis. Immune-related DEGs were derived by the intersection with immune-related factors downloaded from the IMMPORT database. To further validate the findings, we applied immunohistochemical (IHC) staining of a CRC tissue microarray (TMA). The distribution of immune cells in RCC and LCC and changes in the expression of immune molecules on their membranes were verified. The expression levels of circulating cytokines were measured by flow cytometry to detect the cytokines secreted by immune cells in RCC and LCC. Furthermore, to reveal the prognostic value of differential immune factors on RCC and LCC patients, survival analysis based on mRNA levels using TCGA cohort and survival analysis using protein levels was performed using our CRC patients. Results The infiltration of immune cells differed between RCC and LCC, the infiltration degree of macrophages M0 was significantly higher in LCC, while the infiltration degree of differentiated macrophages M1 and M2, CD4+ T and CD8+ T cells was significantly higher in RCC. The expression of related molecules by immune cells also differed between RCC and LCC. The expression of 7 genes in RCC was higher than that in LCC, which were CCR5, CD209, CD8A, HCK, HLA-DPB1, HLA-DQA1, HLA-DRA, respectively. Meanwhile, the expression of 2 genes in LCC was higher than in RCC, which were IL-34 and PROCR. Patients with RCC having high expression of HLA-DQA1 mRNA or proteins had better survival and LCC patients with high expression of IL 34 mRNA or protein had better survival. Conclusions In this study, we comprehensively compared differences in immune cells and regulating factors between left and right colorectal cancer. Different expression patterns and their effects on survival were identified. The analysis of immune-related factors may provide a theoretical basis for precise immunotherapy of RCC and LCC.
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Affiliation(s)
- Yue Hu
- Biobank of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jie Ding
- Biobank of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Chengjiang Wu
- Department of Clinical Laboratory, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Hong Gao
- Biobank of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Meiling Ge
- Biobank of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Qixiang Shao
- Jiangsu Key Laboratory of Medical Science and Laboratory Medicine, Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Yanhong Liu
- Biobank of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
- *Correspondence: Yanhong Liu, ; Qing Ye,
| | - Qing Ye
- Department of Pathology, The First Affiliated Hospital of University of Science and Technology of China (USTC), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- *Correspondence: Yanhong Liu, ; Qing Ye,
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Shubin V, Shelygin Y, Achkasov S, Sushkov O, Nazarov I, Ponomarenko A, Alimova I, Loginova A, Tsukanov A. Microsatellite Instability in Russian Patients with Colorectal Cancer. Int J Mol Sci 2022; 23:7062. [PMID: 35806077 PMCID: PMC9266820 DOI: 10.3390/ijms23137062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 06/20/2022] [Accepted: 06/23/2022] [Indexed: 11/16/2022] Open
Abstract
The aim of this study was to determine the characteristics of Russian patients with microsatellite instability (MSI) tumors. MSI in the tumor was determined in 514 patients with colon cancer using PCR and subsequent fragment analysis for five markers (NR21, NR24, BAT25, BAT26, and NR27). In the presence of microsatellite instability, the mismatch repair (MMR) system genes were examined using the NGS and MLPA methods to establish the diagnosis of Lynch syndrome. The overall frequency of MSI tumors was 15%: at stage I—19% (9/48), at stage II—21% (44/213), at stage III—16% (26/160), and at stage IV—2% (2/93). Patients with MSI tumors differed in the age of diagnosis, tumor localization, time of cancer recurrence, and stage of the disease. The overall and disease-free survival of patients whose tumors had MSI status was higher than that of patients with microsatellite-stable status, p = 0.04 and p = 0.02, respectively. Analysis of overall and disease-free survival of patients with Lynch syndrome and patients with sporadic colon cancer, but with MSI status, did not reveal significant differences, p = 0.52 and p = 0.24, respectively. The age of patients with Lynch syndrome was significantly younger than that of patients with sporadic colon cancer whose tumors had MSI status (p < 0.001).
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Affiliation(s)
- Vitaly Shubin
- Ryzhikh National Medical Research Center of Coloproctology, 123423 Moscow, Russia; (Y.S.); (S.A.); (O.S.); (I.N.); (A.P.); (I.A.); (A.L.)
| | | | | | | | | | | | | | | | - Aleksey Tsukanov
- Ryzhikh National Medical Research Center of Coloproctology, 123423 Moscow, Russia; (Y.S.); (S.A.); (O.S.); (I.N.); (A.P.); (I.A.); (A.L.)
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Paul S, Roy D, Pati S, Sa G. The Adroitness of Andrographolide as a Natural Weapon Against Colorectal Cancer. Front Pharmacol 2021; 12:731492. [PMID: 34795581 PMCID: PMC8592893 DOI: 10.3389/fphar.2021.731492] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 09/28/2021] [Indexed: 12/15/2022] Open
Abstract
The conventional carcinoma treatment generally encompasses the employment of radiotherapy, chemotherapy, surgery or use of cytotoxic drugs. However, recent advances in pharmacological research have divulged the importance of traditional treatments in cancer. The aim of the present review is to provide an overview of the importance of one such medicinal herb of Chinese and Indian origin: Andrographis paniculate on colorectal cancer with special emphasis on its principal bioactive component andrographolide (AGP) and its underlying mechanisms of action. AGP has long been known to possess medicinal properties. Studies led by numerous groups of researchers shed light on its molecular mechanism of action. AGP has been shown to act in a multi-faceted manner in context of colorectal cancer by targeting matrix metalloproteinase-9, Toll-like receptor or NFκB signaling pathways. In this review, we highlighted the recent studies that show that AGP can act as an effective immunomodulator by harnessing effective anti-tumor immune response. Recent studies strongly recommend further research on this compound and its analogues, especially under in-vivo condition to assess its actual potential as a prospective and efficient candidate against colorectal cancer. The current review deals with the roles of this phytomedicine in context of colorectal cancer and briefly describes its perspectives to emerge as an essential anti-cancer drug candidate. Finally, we also point out the drawbacks and difficulties in administration of AGP and indicate the use of nano-formulations of this phytomedicine for better therapeutic efficacy.
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Affiliation(s)
- Silpita Paul
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Dia Roy
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Subhadip Pati
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Gaurisankar Sa
- Division of Molecular Medicine, Bose Institute, Kolkata, India
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18
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Van Herck Y, Feyaerts A, Alibhai S, Papamichael D, Decoster L, Lambrechts Y, Pinchuk M, Bechter O, Herrera-Caceres J, Bibeau F, Desmedt C, Hatse S, Wildiers H. Is cancer biology different in older patients? THE LANCET HEALTHY LONGEVITY 2021; 2:e663-e677. [DOI: 10.1016/s2666-7568(21)00179-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Revised: 07/14/2021] [Accepted: 07/15/2021] [Indexed: 12/13/2022]
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Toh JWT, Phan K, Reza F, Chapuis P, Spring KJ. Rate of dissemination and prognosis in early and advanced stage colorectal cancer based on microsatellite instability status: systematic review and meta-analysis. Int J Colorectal Dis 2021; 36:1573-1596. [PMID: 33604737 DOI: 10.1007/s00384-021-03874-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/27/2021] [Indexed: 02/04/2023]
Abstract
INTRODUCTION For the past two decades, microsatellite instability (MSI) has been reported as a robust clinical biomarker associated with survival advantage attributed to its immunogenicity. However, MSI is also associated with high-risk adverse pathological features (poorly differentiated, mucinous, signet cell, higher grade) and exhibits a double-edged sword phenomenon. We performed a systematic review and meta-analysis to evaluate the rate of dissemination and the prognosis of early and advanced stage colorectal cancer based on MSI status. METHODS A systematic literature search of original studies was performed on Ovid searching MEDLINE, Embase, Cochrane Database of Systematic Reviews, American College of Physicians ACP Journal Club, Database of Abstracts of Reviews of Effects DARE, Clinical Trials databases from inception of database to June 2019. Colorectal cancer, microsatellite instability, genomic instability and DNA mismatch repair were used as key words or MeSH terms. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Data were pooled using a random-effects model with odds ratio (OR) as the effect size. Statistical analysis was performed using RevMan ver 5.3 Cochrane Collaboration. RESULTS From 5288 studies, 136 met the inclusion criteria (n = 92,035; MSI-H 11,746 (13%)). Overall, MSI-H was associated with improved OS (OR, 0.81; 95% CI 0.73-0.90), DFS (OR, 0.73; 95% CI 0.66-0.81) and DSS (OR, 0.69; 95% CI 0.52-0.90). Importantly, MSI-H had a protective effect against dissemination with a significantly lower rate of lymph node and distant metastases. By stage, the protective effect of MSI-H in terms of OS and DFS was observed clearly in stage II and stage III. Survival in stage I CRC was excellent irrespective of MSI status. In stage IV CRC, without immunotherapy, MSI-H was not associated with any survival benefit. CONCLUSIONS MSI-H CRC was associated with an overall survival benefit with a lower rate of dissemination. Survival benefit was clearly evident in both stage II and III CRC, but MSI-H was neither a robust prognostic marker in stage I nor stage IV CRC without immunotherapy.
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Affiliation(s)
- James W T Toh
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia. .,Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. .,Discipline of Surgery, The University of New South Wales, Sydney, NSW, Australia. .,Medical Oncology, Ingham Institute for Applied Medical Research, School of Medicine Western Sydney University and South Western Clinical School, University of New South Wales, NSW, Sydney, Australia.
| | - Kevin Phan
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Faizur Reza
- Department of Surgery, Division of Colorectal Surgery, Westmead Hospital, Sydney, NSW, Australia
| | - Pierre Chapuis
- Discipline of Surgery, Sydney Medical School, University of Sydney, Sydney, NSW, Australia
| | - Kevin J Spring
- Medical Oncology, Ingham Institute for Applied Medical Research, School of Medicine Western Sydney University and South Western Clinical School, University of New South Wales, NSW, Sydney, Australia
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Yan W, Zhou H, Shi S, Lin J, Lin Q. Association Between Chemotherapy and Survival in T1 Colon Cancer With Lymph Node Metastasis: A Propensity-Score Matched Analysis. Front Oncol 2021; 11:699400. [PMID: 34395267 PMCID: PMC8361445 DOI: 10.3389/fonc.2021.699400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 06/28/2021] [Indexed: 12/09/2022] Open
Abstract
This study aimed to comprehensively examine the efficacy of chemotherapy in T1 colon cancer patients with lymph node metastasis.
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Affiliation(s)
- Wangxin Yan
- Department of Colorectal and Anal Surgery, The Third Affiliated Hospital of Shanghai University, Wenzhou People's Hospital, Wenzhou No. 3 Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou, China
| | - Huizhen Zhou
- Department of Colorectal and Anal Surgery, The Third Affiliated Hospital of Shanghai University, Wenzhou People's Hospital, Wenzhou No. 3 Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou, China
| | - Si Shi
- Department of Colorectal and Anal Surgery, The Third Affiliated Hospital of Shanghai University, Wenzhou People's Hospital, Wenzhou No. 3 Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou, China
| | - Jixu Lin
- Department of Colorectal and Anal Surgery, The Third Affiliated Hospital of Shanghai University, Wenzhou People's Hospital, Wenzhou No. 3 Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou, China
| | - Qiangkang Lin
- Department of Colorectal and Anal Surgery, The Third Affiliated Hospital of Shanghai University, Wenzhou People's Hospital, Wenzhou No. 3 Clinical Institute Affiliated to Wenzhou Medical University, Wenzhou, China
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Nakayama Y, Iijima T, Inokuchi T, Kojika E, Takao M, Takao A, Koizumi K, Horiguchi SI, Hishima T, Yamaguchi T. Clinicopathological features of sporadic MSI colorectal cancer and Lynch syndrome: a single-center retrospective cohort study. Int J Clin Oncol 2021; 26:1881-1889. [PMID: 34148153 DOI: 10.1007/s10147-021-01968-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 06/07/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND The clinical and pathological features of sporadic microsatellite instability-high (MSI) colorectal cancer (CRC) are still unclear. The present study aimed to clarify the clinicopathological features of sporadic MSI CRC in comparison with those of Lynch syndrome (LS) exploratorily. METHODS The present study was a single-center, retrospective cohort study. Sporadic MSI CRC was defined as MSI CRC with aberrant promoter hypermethylation of the MLH1 gene, while hereditary MSI CRC was defined colorectal cancer in patients with LS. RESULTS In total, 2653 patients were enrolled; of these, 120 (4.5%) had MSI CRC, 98 had sporadic MSI CRC, and 22 had LS. Patients with sporadic MSI CRC were significantly older (p < 0.001) than those with LS and had a right-sided colonic tumor (p < 0.001) which was pathologically poorly differentiated or mucinous (p = 0.025). The overall survival rate was significantly lower in patients with stage I, II or III MSI CRC than in those with LS (p = 0.024). However, the recurrence-free survival rate did not differ significantly (p = 0.85). CONCLUSIONS We concluded that patients with sporadic MSI are significantly older, tumors more likely to locate in the right-sided colon, pathologically poorly differentiated or mucinous, and worse overall survival than in those with LS.
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Affiliation(s)
- Yujiro Nakayama
- Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-0021, Japan
- Department of Minimally Invasive Surgical and Medical Oncology, Fukushima Medical University, Hikarigaoka, Fukushima, 960-1247, Japan
- Department of Surgery, Southern Tohoku General Hospital, Fukushima, 963-8052, Japan
| | - Takeru Iijima
- Department of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-0021, Japan
| | - Takuhiko Inokuchi
- Department of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-0021, Japan
| | - Ekumi Kojika
- Department of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-0021, Japan
| | - Misato Takao
- Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-0021, Japan
| | - Akinari Takao
- Department of Gastroenterology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-0021, Japan
| | - Koichi Koizumi
- Department of Gastroenterology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-0021, Japan
| | - Shin-Ichiro Horiguchi
- Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-0021, Japan
| | - Tsunekazu Hishima
- Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-0021, Japan
| | - Tatsuro Yamaguchi
- Department of Surgery, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-0021, Japan.
- Department of Clinical Genetics, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-0021, Japan.
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22
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Randrian V, Evrard C, Tougeron D. Microsatellite Instability in Colorectal Cancers: Carcinogenesis, Neo-Antigens, Immuno-Resistance and Emerging Therapies. Cancers (Basel) 2021; 13:3063. [PMID: 34205397 PMCID: PMC8235567 DOI: 10.3390/cancers13123063] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/15/2021] [Accepted: 06/16/2021] [Indexed: 12/20/2022] Open
Abstract
A defect in the DNA repair system through a deficient mismatch repair system (dMMR) leads to microsatellite instability (MSI). Microsatellites are located in both coding and non-coding sequences and dMMR/MSI tumors are associated with a high mutation burden. Some of these mutations occur in coding sequences and lead to the production of neo-antigens able to trigger an anti-tumoral immune response. This explains why non-metastatic MSI tumors are associated with high immune infiltrates and good prognosis. Metastatic MSI tumors result from tumor escape to the immune system and are associated with poor prognosis and chemoresistance. Consequently, immune checkpoint inhibitors (ICI) are highly effective and have recently been approved in dMMR/MSI metastatic colorectal cancers (mCRC). Nevertheless, some patients with dMMR/MSI mCRC have primary or secondary resistance to ICI. This review details carcinogenesis and the mechanisms through which MSI can activate the immune system. After which, we discuss mechanistic hypotheses in an attempt to explain primary and secondary resistances to ICI and emerging strategies being developed to overcome this phenomenon by targeting other immune checkpoints or through vaccination and modification of microbiota.
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Affiliation(s)
- Violaine Randrian
- Gastroenterology and Hepatology Department, Poitiers University Hospital, 86000 Poitiers, France;
- Faculty of Medicine and Pharmacy, 86000 Poitiers, France
| | - Camille Evrard
- Medical Oncology Department, Poitiers University Hospital, 86000 Poitiers, France;
| | - David Tougeron
- Gastroenterology and Hepatology Department, Poitiers University Hospital, 86000 Poitiers, France;
- Faculty of Medicine and Pharmacy, 86000 Poitiers, France
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Bellio H, Fumet JD, Ghiringhelli F. Targeting BRAF and RAS in Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13092201. [PMID: 34063682 PMCID: PMC8124706 DOI: 10.3390/cancers13092201] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/29/2021] [Accepted: 04/30/2021] [Indexed: 01/05/2023] Open
Abstract
Simple Summary In colorectal cancer, mutations of the KRAS and BRAF genes are quite common and can contribute to the activation of cell signaling pathways that lead to cell proliferation and differentiation. These processes promote cancer growth, and in some cases, they may cause cells to develop resistance to certain types of treatment, notably EGFR inhibitors. We summarize recent knowledge regarding the effects of KRAS and BRAF mutations in the setting of colorectal cancer and discuss the new therapies under development. Abstract Colorectal cancer (CRC) is still one of the most frequent forms of cancer in the world in terms of incidence. Around 40% of CRC patients carry a mutation of the Kirsten rat sarcoma (KRAS) gene, while 10% have a mutation in the B-Raf proto-oncogene serine/threonine kinase (BRAF) gene. These mutations are responsible for dysregulation of the mitogen-associated protein kinase (MAPK) pathway, leading to the proliferation, differentiation, angiogenesis, and resistance to apoptosis of cells. Activation of the MAPK pathway results in adaptive therapeutic resistance, rendering EGFR inhibitors ineffective. This review aims to highlight the recent findings that have improved our understanding of KRAS and BRAF mutations in colorectal cancer and to describe new targeted therapies, used alone or in combination.
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Affiliation(s)
- Helene Bellio
- University of Burgundy-Franche Comté, Maison de l’université Esplanade Erasme, 21000 Dijon, France; (H.B.); (J.D.F.)
- Department of Medical Oncology, Georges François Leclerc Cancer Center—UNICANCER, 1 rue du Professeur Marion, 21000 Dijon, France
| | - Jean David Fumet
- University of Burgundy-Franche Comté, Maison de l’université Esplanade Erasme, 21000 Dijon, France; (H.B.); (J.D.F.)
- Department of Medical Oncology, Georges François Leclerc Cancer Center—UNICANCER, 1 rue du Professeur Marion, 21000 Dijon, France
- Platform of Transfer in Biological Oncology, Georges François Leclerc Cancer Center—UNICANCER, 1 rue du Professeur Marion, 21000 Dijon, France
- UMR INSERM 1231, 7 Boulevard Jeanne d’Arc, 21000 Dijon, France
- Genomic and Immunotherapy Medical Institute, Dijon University Hospital, 14 rue Paul Gaffarel, 21000 Dijon, France
| | - Francois Ghiringhelli
- University of Burgundy-Franche Comté, Maison de l’université Esplanade Erasme, 21000 Dijon, France; (H.B.); (J.D.F.)
- Department of Medical Oncology, Georges François Leclerc Cancer Center—UNICANCER, 1 rue du Professeur Marion, 21000 Dijon, France
- Platform of Transfer in Biological Oncology, Georges François Leclerc Cancer Center—UNICANCER, 1 rue du Professeur Marion, 21000 Dijon, France
- UMR INSERM 1231, 7 Boulevard Jeanne d’Arc, 21000 Dijon, France
- Genomic and Immunotherapy Medical Institute, Dijon University Hospital, 14 rue Paul Gaffarel, 21000 Dijon, France
- Correspondence:
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Devall MA, Casey G. Controlling for cellular heterogeneity using single-cell deconvolution of gene expression reveals novel markers of colorectal tumors exhibiting microsatellite instability. Oncotarget 2021; 12:767-782. [PMID: 33889300 PMCID: PMC8057268 DOI: 10.18632/oncotarget.27935] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Accepted: 03/22/2021] [Indexed: 12/15/2022] Open
Abstract
Approximately 15% of colorectal cancer (CRC) cases present with high levels of microsatellite instability (MSI-H). Bulk RNA-sequencing approaches have been employed to elucidate transcriptional differences between MSI-H and microsatellite stable (MSS) CRC tumors. These approaches are frequently confounded by the complex cellular heterogeneity of tumors. We performed single-cell deconvolution of bulk RNA-sequencing on The Cancer Genome Atlas colon adenocarcinoma (TCGA-COAD) dataset. Cell composition within each dataset was estimated using CIBERSORTx. Cell composition differences were analyzed using linear regression. Significant differences in abundance were observed for 13 of 19 cell types between MSI-H and MSS/MSI-L tumors in TCGA-COAD. This included a novel finding of increased enteroendocrine (q = 3.71E-06) and reduced colonocyte populations (q = 2.21E-03) in MSI-H versus MSS/MSI-L tumors. We were able to validate some of these differences in an independent biopsy dataset. By incorporating cell composition into our regression model, we identified 3,193 differentially expressed genes (q = 0.05), of which 556 were deemed novel. We subsequently validated many of these genes in an independent dataset of colon cancer cell lines. In summary, we show that some of the challenges associated with cellular heterogeneity can be overcome using single-cell deconvolution, and through our analysis we highlight several novel gene targets for further investigation.
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Affiliation(s)
- Matthew A.M. Devall
- Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
| | - Graham Casey
- Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
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25
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Association between risk factors, molecular features and CpG island methylator phenotype colorectal cancer among different age groups in a Taiwanese cohort. Br J Cancer 2021; 125:48-54. [PMID: 33846524 DOI: 10.1038/s41416-021-01300-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 01/27/2021] [Accepted: 02/03/2021] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND CpG island methylator phenotype (CIMP) represents a carcinogenesis pathway of colorectal cancer (CRC) and the association between CIMP CRC, molecular features and risk factors in East Asian population is less studied. METHODS We prospectively enrolled newly diagnosed CRC patients at the National Taiwan University Hospital. Clinicopathological data and risk factors for CRC were collected during interview. The tumour samples were subjected to CIMP, RAS/BRAF mutation and microsatellite instability tests. CIMP-high was determined when ≧3 methylated loci of p16, MINT1, MINT2, MINT31 and MLH1 were identified. Multivariate logistic regression was used to evaluate the association between risk factors and CIMP-high CRC. RESULTS Compared with CIMP-low/negative CRC, CIMP-high CRC was associated with more stage IV disease, BRAF V600E mutation and high body mass index (BMI ≧ 27.5 kg/m2) in younger patients (age < 50 y), and more right-sided tumour, BRAF V600E mutation, MSI-high and colorectal polyp in elder patients (age ≧ 50 y). Multivariate analyses showed that BMI ≧27.5 kg/m2 was significantly associated with CIMP-high CRC in younger patients. CONCLUSIONS We identified distinct clinicopathological features for CIMP-high CRC among different age groups in Taiwan. Our data suggest the association between BMI ≧27.5 kg/m2 and CIMP-high CRC in patients younger than 50 years.
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26
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Mao R, Yang F, Wang Z, Xu C, Liu Q, Liu Y, Zhang T. Clinical Significance of a Novel Tumor Progression-Associated Immune Signature in Colorectal Adenocarcinoma. Front Cell Dev Biol 2021; 9:625212. [PMID: 33732694 PMCID: PMC7959763 DOI: 10.3389/fcell.2021.625212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 01/13/2021] [Indexed: 12/13/2022] Open
Abstract
Background Some colorectal adenocarcinoma (CRC) patients are susceptible to recurrence, and they rapidly progress to advanced cancer stages and have a poor prognosis. There is an urgent need for efficient screening criteria to identify patients who tend to relapse in order to treat them earlier and more systematically. Methods We identified two groups of patients with significantly different outcomes by unsupervised cluster analysis of GSE39582 based on 101 significantly differentially expressed immune genes. To develop an accurate and specific signature based on immune-related genes to predict the recurrence of CRC, a multivariate Cox risk regression model was constructed with a training cohort composed of 519 CRC samples. The model was then validated using 129, 292, and 446 samples in the real-time quantitative reverse transcription PCR (qRT-PCR), test, and validation cohorts, respectively. Results This classification system can also be used to predict the prognosis in clinical subgroups and patients with different mutation states. Four independent datasets, including qRT-PCR and The Cancer Genome Atlas (TCGA), demonstrated that they can also be used to accurately predict the overall survival of CRC patients. Further analysis suggested that high-risk patients were characterized by worse effects of chemotherapy and immunotherapy, as well as lower immune scores. Ultimately, the signature was identified as an independent prognostic factor. Conclusion The signature can accurately predict recurrence and overall survival in patients with CRC and may serve as a powerful prognostic tool to further optimize cancer immunotherapy.
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Affiliation(s)
- Rui Mao
- The Center of Gastrointestinal and Minimally Invasive Surgery, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
| | - Fan Yang
- Emergency Department, Peking University Third Hospital, School of Medicine, Peking University, Beijing, China
| | - Zheng Wang
- Department of Colorectal Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chenxin Xu
- The Center of Gastrointestinal and Minimally Invasive Surgery, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China
| | - Qian Liu
- Department of Colorectal Surgery, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yanjun Liu
- The Center of Gastrointestinal and Minimally Invasive Surgery, Affiliated Hospital of Southwest Jiaotong University, Chengdu, China.,The Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, Chengdu, China
| | - Tongtong Zhang
- The Center of Gastrointestinal and Minimally Invasive Surgery, Department of General Surgery, The Third People's Hospital of Chengdu, Chengdu, China.,Medical Research Center, The Third People's Hospital of Chengdu, The Affiliated Hospital of Southwest Jiaotong University, The Second Chengdu Hospital Affiliated to Chongqing Medical University, Chengdu, China
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27
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Ili C, Buchegger K, Demond H, Castillo-Fernandez J, Kelsey G, Zanella L, Abanto M, Riquelme I, López J, Viscarra T, García P, Bellolio E, Saavedra D, Brebi P. Landscape of Genome-Wide DNA Methylation of Colorectal Cancer Metastasis. Cancers (Basel) 2020; 12:E2710. [PMID: 32971738 PMCID: PMC7564781 DOI: 10.3390/cancers12092710] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 09/02/2020] [Accepted: 09/09/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer is a heterogeneous disease caused by both genetic and epigenetics factors. Analysing DNA methylation changes occurring during colorectal cancer progression and metastasis formation is crucial for the identification of novel epigenetic markers of patient prognosis. Genome-wide methylation sequencing of paired samples of colon (normal adjacent, primary tumour and lymph node metastasis) showed global hypomethylation and CpG island (CGI) hypermethylation of primary tumours compared to normal. In metastasis we observed high global and non-CGI regions methylation, but lower CGI methylation, compared to primary tumours. Gene ontology analysis showed shared biological processes between hypermethylated CGIs in metastasis and primary tumours. After complementary analysis with The Cancer Genome Atlas (TCGA) cohort, FIGN, HTRA3, BDNF, HCN4 and STAC2 genes were found associated with poor survival. We mapped the methylation landscape of colon normal tissues, primary tumours and lymph node metastasis, being capable of identified methylation changes throughout the genome. Furthermore, we found five genes with potential for methylation biomarkers of poor prognosis in colorectal cancer patients.
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Affiliation(s)
- Carmen Ili
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (C.I.); (K.B.); (H.D.); (L.Z.); (J.L.); (T.V.)
| | - Kurt Buchegger
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (C.I.); (K.B.); (H.D.); (L.Z.); (J.L.); (T.V.)
- Departamento Ciencias Básicas, Facultad de Medicina, Universidad de La Frontera, Temuco 4811230, Chile
| | - Hannah Demond
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (C.I.); (K.B.); (H.D.); (L.Z.); (J.L.); (T.V.)
- Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK; (J.C.-F.); (G.K.)
| | - Juan Castillo-Fernandez
- Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK; (J.C.-F.); (G.K.)
| | - Gavin Kelsey
- Epigenetics Programme, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK; (J.C.-F.); (G.K.)
- Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 1TN, UK
| | - Louise Zanella
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (C.I.); (K.B.); (H.D.); (L.Z.); (J.L.); (T.V.)
| | - Michel Abanto
- Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4811230, Chile;
| | - Ismael Riquelme
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Temuco 4810101, Chile;
| | - Jaime López
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (C.I.); (K.B.); (H.D.); (L.Z.); (J.L.); (T.V.)
| | - Tamara Viscarra
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (C.I.); (K.B.); (H.D.); (L.Z.); (J.L.); (T.V.)
| | - Patricia García
- Department of Pathology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8330034, Chile;
| | - Enrique Bellolio
- Departamento Anatomía Patológica, Facultad de Medicina, Universidad de La Frontera, Temuco 4781180, Chile;
- Departamento de Medicina Interna, Hospital Hernán Henríquez Aravena, Temuco 4781151, Chile;
| | - David Saavedra
- Departamento de Medicina Interna, Hospital Hernán Henríquez Aravena, Temuco 4781151, Chile;
- Clínica Alemana de Temuco, Temuco 4810297, Chile
| | - Priscilla Brebi
- Laboratory of Integrative Biology (LIBi), Centro de Excelencia en Medicina Traslacional (CEMT), Scientific and Technological Bioresource Nucleus (BIOREN), Universidad de La Frontera, Temuco 4810296, Chile; (C.I.); (K.B.); (H.D.); (L.Z.); (J.L.); (T.V.)
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Cervena K, Siskova A, Buchler T, Vodicka P, Vymetalkova V. Methylation-Based Therapies for Colorectal Cancer. Cells 2020; 9:E1540. [PMID: 32599894 PMCID: PMC7349319 DOI: 10.3390/cells9061540] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/22/2020] [Accepted: 06/23/2020] [Indexed: 02/08/2023] Open
Abstract
Colorectal carcinogenesis (CRC) is caused by the gradual long-term accumulation of both genetic and epigenetic changes. Recently, epigenetic alterations have been included in the classification of the CRC molecular subtype, and this points out their prognostic impact. As epigenetic modifications are reversible, they may represent relevant therapeutic targets. DNA methylation, catalyzed by DNA methyltransferases (DNMTs), regulates gene expression. For many years, the deregulation of DNA methylation has been considered to play a substantial part in CRC etiology and evolution. Despite considerable advances in CRC treatment, patient therapy response persists as limited, and their profit from systemic therapies are often hampered by the introduction of chemoresistance. In addition, inter-individual changes in therapy response in CRC patients can arise from their specific (epi)genetic compositions. In this review article, we summarize the options of CRC treatment based on DNA methylation status for their predictive value. This review also includes the therapy outcomes based on the patient's methylation status in CRC patients. In addition, the current challenge of research is to develop therapeutic inhibitors of DNMT. Based on the essential role of DNA methylation in CRC development, the application of DNMT inhibitors was recently proposed for the treatment of CRC patients, especially in patients with DNA hypermethylation.
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Affiliation(s)
- Klara Cervena
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14 200 Prague, Czech Republic; (K.C.); (A.S.); (P.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic
| | - Anna Siskova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14 200 Prague, Czech Republic; (K.C.); (A.S.); (P.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic
| | - Tomas Buchler
- Department of Oncology, First Faculty of Medicine, Charles University and Thomayer Hospital, Videnska 800, 140 59 Prague, Czech Republic;
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14 200 Prague, Czech Republic; (K.C.); (A.S.); (P.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 323 00 Pilsen, Czech Republic
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14 200 Prague, Czech Republic; (K.C.); (A.S.); (P.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 128 00 Prague, Czech Republic
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 323 00 Pilsen, Czech Republic
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Molina-Cerrillo J, San Román M, Pozas J, Alonso-Gordoa T, Pozas M, Conde E, Rosas M, Grande E, García-Bermejo ML, Carrato A. BRAF Mutated Colorectal Cancer: New Treatment Approaches. Cancers (Basel) 2020; 12:cancers12061571. [PMID: 32545884 PMCID: PMC7353017 DOI: 10.3390/cancers12061571] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/09/2020] [Accepted: 06/10/2020] [Indexed: 12/14/2022] Open
Abstract
Colon cancer is one of the most frequently diagnosed malignancies in adults, considering both its incidence and prevalence. Anatomically, the right colon is considered as being from the cecum to the splenic flexure, and the left colon is from the splenic flexure to the rectum. Sidedness is a surrogate of a wide spectrum of colorectal cancer (CRC) biology features (embryology, microbiome, methylation, microsatellite instability (MSI), BRAF, aging, KRAS, consensus molecular subtypes (CMS), etc.), which result in prognostic factors. Different molecular subtypes have been identified, according to genomic and transcriptomic criteria. A subgroup harboring a BRAF mutation has been described, and represents approximately 10% of the patients diagnosed with colon cancer. This subgroup has morphological, clinical, and therapeutic characteristics that differ substantially from patients who do not carry this genetic alteration. Unfortunately, there is no established standard of care for this particular cohort of patients. This manuscript aims to study the biology of this subgroup of colon cancer, to understand the current approach in clinical research.
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Affiliation(s)
- Javier Molina-Cerrillo
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
- CIBERONC, The Ramón y Cajal Health Research Institute (IRYCIS), 28034 Madrid, Spain
- Medicine School, Alcalá University, 28805 Madrid, Spain
- Correspondence: or
| | - María San Román
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
| | - Javier Pozas
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
| | - Teresa Alonso-Gordoa
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
- CIBERONC, The Ramón y Cajal Health Research Institute (IRYCIS), 28034 Madrid, Spain
- Medicine School, Alcalá University, 28805 Madrid, Spain
| | - Miguel Pozas
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
| | - Elisa Conde
- Biomarkers and Therapeutic Targets Group and Core Facility, The Ramón y Cajal Health Research Institute (IRYCIS), CIBERONC, 28034 Madrid, Spain; (E.C.); (M.L.G.-B.)
| | - Marta Rosas
- Pathology department, University Hospital Ramon y Cajal, 28034 Madrid, Spain;
| | - Enrique Grande
- Department of Medical Oncology, MD Anderson Cancer Center, 28033 Madrid, Spain;
| | - María Laura García-Bermejo
- Biomarkers and Therapeutic Targets Group and Core Facility, The Ramón y Cajal Health Research Institute (IRYCIS), CIBERONC, 28034 Madrid, Spain; (E.C.); (M.L.G.-B.)
| | - Alfredo Carrato
- Medical Oncology Department, University Hospital Ramon y Cajal, 28034 Madrid, Spain; (M.S.R.); (J.P.); (T.A.-G.); (M.P.); (A.C.)
- CIBERONC, The Ramón y Cajal Health Research Institute (IRYCIS), 28034 Madrid, Spain
- Medicine School, Alcalá University, 28805 Madrid, Spain
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Zaanan A, Shi Q, Taieb J, Alberts SR, Meyers JP, Smyrk TC, Julie C, Zawadi A, Tabernero J, Mini E, Goldberg RM, Folprecht G, Van Laethem JL, Le Malicot K, Sargent DJ, Laurent-Puig P, Sinicrope FA. Clinical Outcomes in Patients With Colon Cancer With Microsatellite Instability of Sporadic or Familial Origin Treated With Adjuvant FOLFOX With or Without Cetuximab: A Pooled Analysis of the PETACC8 and N0147 Trials. JCO Precis Oncol 2020; 4:1900237. [PMID: 32923882 PMCID: PMC7446392 DOI: 10.1200/po.19.00237] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2020] [Indexed: 12/31/2022] Open
Abstract
PURPOSE The microsatellite instability (MSI) or deficient mismatch repair (dMMR) phenotype is usually regarded as a single biologic entity, given the absence of comparative analyses regarding prognosis and response to chemotherapy between sporadic and familial dMMR cancers. PATIENTS AND METHODS Patients with stage III colon cancers were randomly assigned to FOLFOX (leucovorin, fluorouracil, and oxaliplatin) with or without cetuximab in 2 large adjuvant phase III trials (N = 5,577). Among patients with MSI and KRAS exon 2 wild-type (WT) tumors, the prognostic and predictive impacts of sporadic versus familial dMMR cancers and BRAF V600E mutational status were determined. Multivariable Cox proportional hazards models were used to assess disease-free survival (DFS) by treatment arm, adjusting for age, sex, tumor grade, Eastern Cooperative Oncology Group performance status, pT/pN stage, and primary tumor location. RESULTS Among patients with MSI status with complete data for dMMR mechanism analysis (n = 354), 255 (72%) had sporadic (BRAF mutation and/or MLH1 methylation) and 99 (28%) had familial tumors (BRAF WT and unmethylated MLH1 or loss of MSH2/MSH6/PMS2 protein expression). A large proportion of dMMR sporadic tumors were mutated for BRAF (n = 200). In patients treated with FOLFOX, DFS did not differ statistically by dMMR mechanism, whereas in patients treated with FOLFOX plus cetuximab, those with sporadic tumors had worse DFS than those with familial cancers (multivariable hazard ratio, 2.69; 95% CI, 1.02 to 7.08; P = .04). Considering the predictive utility, the interaction between treatment and dMMR mechanism was significant (P = .03). Furthermore, a nonsignificant trend toward a deleterious effect of adding cetuximab to FOLFOX was observed in patients with BRAF-mutant but not BRAF WT tumors. CONCLUSION The addition of cetuximab to adjuvant FOLFOX was associated with shorter DFS in patients with sporadic dMMR colon cancer. Additional studies are needed to validate these results in metastatic disease.
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Affiliation(s)
- Aziz Zaanan
- Department of Medicine, Mayo Clinic,
Rochester, MN,Department of Gastroenterology and
Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique
Hôpitaux de Paris (APHP), Paris, France,Aziz Zaanan, MD, PhD, Department of Gastroenterology and
Digestive Oncology, European Georges Pompidou Hospital, Paris Descartes
University, Paris, France; e-mail:
| | - Qian Shi
- Alliance Statistics and Data Center, Mayo
Clinic, Rochester, MN
| | - Julien Taieb
- Centre de Recherche des Cordeliers,
INSERM, Sorbonne Université, Université Paris Descartes,
Université Paris Diderot, Université Sorbonne Paris Cité,
Paris, France,Department of Gastroenterology and
Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique
Hôpitaux de Paris (APHP), Paris, France
| | | | | | - Thomas C. Smyrk
- Laboratory Medicine and Pathology, Mayo
Clinic, Rochester, MN
| | - Catherine Julie
- Department of Pathology, Ambroise
Paré Hospital, APHP, Boulogne-Billancourt, France,Versailles Saint-Quentin-en-Yvelines
University, Boulogne-Billancourt, France
| | - Ayman Zawadi
- Radiotherapy Unit, Departmental Hospital
Center, La Roche-Sur-Yon, France
| | - Josep Tabernero
- Medical Oncology Department, Vall
d‘Hebron University Hospital, Barcelona, Spain,Vall d‘Hebron Institute of
Oncology, University of Vic, IOB-Quiron, Barcelona, Spain
| | - Enrico Mini
- Section of Clinical Pharmacology and
Oncology, Department of Health Sciences, University of Florence, Florence,
Italy,DENOTHE Excellence Center, University of
Florence, Florence, Italy
| | | | - Gunnar Folprecht
- First Medical Department, University
Hospital Carl Gustav Carus, Dresden, Germany
| | | | - Karine Le Malicot
- Department of Statistics,
Fédération Francophone de Cancérologie Digestive, Dijon,
France
| | | | - Pierre Laurent-Puig
- Centre de Recherche des Cordeliers,
INSERM, Sorbonne Université, Université Paris Descartes,
Université Paris Diderot, Université Sorbonne Paris Cité,
Paris, France,Department of Biology, European Georges
Pompidou Hospital, APHP, Paris, France
| | - Frank A. Sinicrope
- Department of Medicine, Mayo Clinic,
Rochester, MN,Mayo Comprehensive Cancer Center,
Rochester, MN
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Sveen A, Kopetz S, Lothe RA. Biomarker-guided therapy for colorectal cancer: strength in complexity. Nat Rev Clin Oncol 2020; 17:11-32. [PMID: 31289352 PMCID: PMC7577509 DOI: 10.1038/s41571-019-0241-1] [Citation(s) in RCA: 218] [Impact Index Per Article: 43.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/05/2019] [Indexed: 12/16/2022]
Abstract
The number of molecularly stratified treatment options available to patients with colorectal cancer (CRC) is increasing, with a parallel rise in the use of biomarkers to guide prognostication and treatment decision-making. The increase in both the number of biomarkers and their use has resulted in a progressively complex situation, evident both from the extensive interactions between biomarkers and from their sometimes complex associations with patient prognosis and treatment benefit. Current and emerging biomarkers also reflect the genomic complexity of CRC, and include a wide range of aberrations such as point mutations, amplifications, fusions and hypermutator phenotypes, in addition to global gene expression subtypes. In this Review, we provide an overview of current and emerging clinically relevant biomarkers and their role in the management of patients with CRC, illustrating the intricacies of biomarker interactions and the growing treatment opportunities created by the availability of comprehensive molecular profiling.
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Affiliation(s)
- Anita Sveen
- Department of Molecular Oncology, Institute for Cancer Research & K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway.
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ragnhild A Lothe
- Department of Molecular Oncology, Institute for Cancer Research & K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
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Xie B, Bai B, Xu Y, Liu Y, Lv Y, Gao X, Wu F, Fang Z, Lou Y, Pan H, Han W. Tumor-suppressive function and mechanism of HOXB13 in right-sided colon cancer. Signal Transduct Target Ther 2019; 4:51. [PMID: 31815008 PMCID: PMC6882800 DOI: 10.1038/s41392-019-0086-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 10/07/2019] [Accepted: 10/10/2019] [Indexed: 01/05/2023] Open
Abstract
Right-sided colon cancer (RCC) and left-sided colon cancer (LCC) differ in their clinical and molecular features. An investigation of differentially expressed genes (DEGs) between RCC and LCC could contribute to targeted therapy for colon cancer, especially RCC, which has a poor prognosis. Here, we identified HOXB13, which was significantly less expressed in RCC than in LCC and associated with prognosis in RCC, by using 5 datasets from the Gene Expression Omnibus (GEO). Tissue sample analysis showed that HOXB13 was differentially expressed between normal and only RCC tumor tissues. HOXB13 inhibited colon cancer cell proliferation and induced apoptosis both in vitro and in vivo. Furthermore, we found that HOXB13 might be regulated by DNMT3B and suppress C-myc expression to exert antitumor effects via β-catenin/TCF4 signals in RCC. In conclusion, the current study is the first to demonstrate that HOXB13 has a tumor-suppressive effect in RCC. High expression levels of HOXB13 are associated with prolonged overall survival in patients with RCC. The DNMT3B-HOXB13-C-myc signaling axis might be a molecular target for the treatment of RCC.
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Affiliation(s)
- Binbin Xie
- Department of Medical Oncology; Sir Run Run Shaw Hospital; School of Medicine, Zhejiang University, Hangzhou, 310016 PR China
| | - Bingjun Bai
- Department of Colorectal Surgery; Sir Run Run Shaw Hospital; School of Medicine, Zhejiang University, Hangzhou, 310016 PR China
| | - Yuzi Xu
- Department of Stomatology; Stomatology Hospital; School of Medicine, Zhejiang University, Hangzhou, 310000 PR China
| | - Yunlong Liu
- Department of Medical Oncology; Sir Run Run Shaw Hospital; School of Medicine, Zhejiang University, Hangzhou, 310016 PR China
| | - Yiming Lv
- Department of Colorectal Surgery; Sir Run Run Shaw Hospital; School of Medicine, Zhejiang University, Hangzhou, 310016 PR China
| | - Xing Gao
- Department of Medical Oncology; The Second Affiliated Hospital of Suzhou University; School of Medicine, Suzhou University, Suzhou, 215000 PR China
| | - Fei Wu
- School of Medicine, Anhui University of Science and Technology, Huainan, 232001 PR China
| | - Zhipeng Fang
- Department of Medical Oncology; Sir Run Run Shaw Hospital; School of Medicine, Zhejiang University, Hangzhou, 310016 PR China
| | - Ying Lou
- Department of Medical Oncology; Sir Run Run Shaw Hospital; School of Medicine, Zhejiang University, Hangzhou, 310016 PR China
| | - Hongming Pan
- Department of Medical Oncology; Sir Run Run Shaw Hospital; School of Medicine, Zhejiang University, Hangzhou, 310016 PR China
| | - Weidong Han
- Department of Medical Oncology; Sir Run Run Shaw Hospital; School of Medicine, Zhejiang University, Hangzhou, 310016 PR China
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Advani SM, Advani PS, Brown DW, DeSantis SM, Korphaisarn K, VonVille HM, Bressler J, Lopez DS, Davis JS, Daniel CR, Sarshekeh AM, Braithwaite D, Swartz MD, Kopetz S. Global differences in the prevalence of the CpG island methylator phenotype of colorectal cancer. BMC Cancer 2019; 19:964. [PMID: 31623592 PMCID: PMC6796359 DOI: 10.1186/s12885-019-6144-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 09/10/2019] [Indexed: 02/07/2023] Open
Abstract
Background CpG Island Methylator Phenotype (CIMP) is an epigenetic phenotype in CRC characterized by hypermethylation of CpG islands in promoter regions of tumor suppressor genes, leading to their transcriptional silencing and loss of function. While the prevalence of CRC differs across geographical regions, no studies have compared prevalence of CIMP-High phenotype across regions. The purpose of this project was to compare the prevalence of CIMP across geographical regions after adjusting for variations in methodologies to measure CIMP in a meta-analysis. Methods We searched PubMed, Medline, and Embase for articles focusing on CIMP published from 2000 to 2018. Two reviewers independently identified 111 articles to be included in final meta-analysis. We classified methods used to quantify CIMP into 4 categories: a) Classical (MINT marker) Panel group b) Weisenberg-Ogino (W-O) group c) Human Methylation Arrays group and d) Miscellaneous group. We compared the prevalence of CIMP across geographical regions after correcting for methodological variations using meta-regression techniques. Results The pooled prevalence of CIMP-High across all studies was 22% (95% confidence interval:21–24%; I2 = 94.75%). Pooled prevalence of CIMP-H across Asia, Australia, Europe, North America and South America was 22, 21, 21, 27 and 25%, respectively. Meta-regression analysis identified no significant differences in the prevalence of CIMP-H across geographical regions after correction for methodological variations. In exploratory analysis, we observed variations in CIMP-H prevalence across countries. Conclusion Although no differences were found for CIMP-H prevalence across countries, further studies are needed to compare the influence of demographic, lifestyle and environmental factors in relation to the prevalence of CIMP across geographical regions.
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Affiliation(s)
- Shailesh Mahesh Advani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0426, Houston, TX, 77030, USA. .,Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, 20007, USA. .,Social Behavioral Research Branch, National Human Genome Research Institute, National Institute of Health, Bethesda, MD, 20892, USA.
| | - Pragati Shailesh Advani
- Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Institutes of Health, National Cancer Institute, Rockville, MD, 20850, USA
| | - Derek W Brown
- Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Stacia M DeSantis
- Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Krittiya Korphaisarn
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0426, Houston, TX, 77030, USA
| | - Helena M VonVille
- Library, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Jan Bressler
- Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - David S Lopez
- Division of Urology- UTHealth McGovern Medical School, Houston, TX, 77030, USA.,Department of Preventive Medicine and Community Health, UTMB Health-School of Medicine, Galveston, TX, 77555-1153, USA
| | - Jennifer S Davis
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Carrie R Daniel
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Amir Mehrvarz Sarshekeh
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0426, Houston, TX, 77030, USA
| | - Dejana Braithwaite
- Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, 20007, USA
| | - Michael D Swartz
- Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0426, Houston, TX, 77030, USA.
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A Novel Prognostic DNA Methylation Panel for Colorectal Cancer. Int J Mol Sci 2019; 20:ijms20194672. [PMID: 31547144 PMCID: PMC6801964 DOI: 10.3390/ijms20194672] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 09/16/2019] [Accepted: 09/17/2019] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers and the second leading cause of cancer-related deaths. Discrepancies in clinical outcomes are observed even among patients with same-stage CRC due to molecular heterogeneity. Thus, biomarkers for predicting prognosis in CRC patients are urgently needed. We previously demonstrated that stage II CRC patients with NKX6.1 methylation had poor 5-year overall survival. However, the methylation frequency of NKX6.1 was only 23% in 151 pairs of CRC tissues. Thus, we aimed to develop a more robust prognostic panel for CRC using NKX6.1 in combination with three genes: LIM homeobox transcription factor 1α (LMX1A), sex-determining region Y-box 1 (SOX1), and zinc finger protein 177 (ZNF177). Through quantitative methylation analysis, we found that LMX1A, SOX1, and ZNF177 were hypermethylated in CRC tissues. LMX1A methylation was significantly associated with poor 5-year overall, and disease-free survivals in stage I and II CRC patients. Sensitivity and specificity analyses of the four-gene combination revealed the best sensitivity and optimal specificity. Moreover, patients with the four-gene methylation profile exhibited poorer disease-free survival than those without methylation. A significant effect of the four-gene methylation status on overall survival and disease-free survival was observed in early stage I and II CRC patients (p = 0.0016 and p = 0.0230, respectively). Taken together, these results demonstrate that the combination of the methylation statuses of NKX6.1, LMX1A, SOX1, and ZNF177 creates a novel prognostic panel that could be considered a molecular marker for outcomes in CRC patients.
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Xie X, Yin J, Zhou Z, Dang C, Zhang H, Zhang Y. Young age increases the risk for lymph node metastasis in patients with early Colon Cancer. BMC Cancer 2019; 19:803. [PMID: 31412872 PMCID: PMC6693219 DOI: 10.1186/s12885-019-5995-4] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Accepted: 07/30/2019] [Indexed: 02/08/2023] Open
Abstract
Background The risk of lymph node positivity in early-stage colon cancer is a parameter that impacts therapeutic recommendations. However, little is known about the effect of age on lymph node positivity in colon cancer with mucosal invasion. In this study, we aimed to quantify the effect of younger age on lymph node positivity in colon cancer with mucosal invasion. Methods All patients were identified between 2004 and 2014 in the Surveillance, Epidemiology, and End Results database. Patients were stage T1-T2, did not undergo preoperative radiotherapy, had at least one lymph node examined, and underwent a standard colon cancer operation. Demographics and pathological data were compared between different age ranges. A nomogram model was built to estimate the probability of nodal involvement according to different characteristics. Decision curve analysis was performed by calculating the net benefits for a range of threshold probabilities. Results This study identified 41,490 patients who met the eligibility criteria for our study. 1.4% (n = 620) of patients were under 40 years old; 5.9% (n = 2571) were between 40 and 49 years old. Within each T stage, positive lymph node rates decreased with increasing age. In univariate analyses, the positive lymph node rates for patients 20 to 39 years of age were significantly higher than in patients in the reference group for stages T1 and T2. After dividing the colon into the left and right parts, these trends remained. The lymph node metastatic rate was higher in the right colon than in the left colon in terms of different age ranges. The nomogram prediction system represents a novel model with which to estimate lymph node metastasis in early T stage colon adenocarcinomas based on four risk factors with a C-index of 0.657 (95% CI: 0.658–0666). Conclusions Our study demonstrates that the risk of lymph node metastasis was higher in young (< 40 years) patients with early-stage colon adenocarcinomas. Therefore, more aggressive screening and therapeutic strategies should be considered for young patients with colon adenocarcinoma.
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Affiliation(s)
- Xin Xie
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Jianhao Yin
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Zhangjian Zhou
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Chengxue Dang
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Hao Zhang
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
| | - Yong Zhang
- Department of Surgical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
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The Molecular Hallmarks of the Serrated Pathway in Colorectal Cancer. Cancers (Basel) 2019; 11:cancers11071017. [PMID: 31330830 PMCID: PMC6678087 DOI: 10.3390/cancers11071017] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Revised: 07/15/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a leading cause of cancer death worldwide. It includes different subtypes that differ in their clinical and prognostic features. In the past decade, in addition to the conventional adenoma-carcinoma model, an alternative multistep mechanism of carcinogenesis, namely the “serrated pathway”, has been described. Approximately, 15 to 30% of all CRCs arise from neoplastic serrated polyps, a heterogeneous group of lesions that are histologically classified into three morphologic categories: hyperplastic polyps, sessile serrated adenomas/polyps, and the traditional serrated adenomas/polyps. Serrated polyps are characterized by genetic (BRAF or KRAS mutations) and epigenetic (CpG island methylator phenotype (CIMP)) alterations that cooperate to initiate and drive malignant transformation from normal colon mucosa to polyps, and then to CRC. The high heterogeneity of the serrated lesions renders their diagnostic and pathological interpretation difficult. Hence, novel genetic and epigenetic biomarkers are required for better classification and management of CRCs. To date, several molecular alterations have been associated with the serrated polyp-CRC sequence. In addition, the gut microbiota is emerging as a contributor to/modulator of the serrated pathway. This review summarizes the state of the art of the genetic, epigenetic and microbiota signatures associated with serrated CRCs, together with their clinical implications.
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Sun H, Huang H, Li D, Zhang L, Zhang Y, Xu J, Liu Y, Liu Y, Zhao Y. PBX3 hypermethylation in peripheral blood leukocytes predicts better prognosis in colorectal cancer: A propensity score analysis. Cancer Med 2019; 8:4001-4011. [PMID: 31140752 PMCID: PMC6639175 DOI: 10.1002/cam4.2321] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 04/15/2019] [Accepted: 05/16/2019] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE The significance of gene methylation in peripheral blood leukocytes (PBLs) for assessing cancer prognosis is poorly understood. Our purpose is to assess the association between PBX3 methylation in PBLs and colorectal cancer (CRC) prognosis. METHODS A total of 369 CRC patients were followed up for up to 10 years in this cohort study. PBL PBX3 methylation levels were determined by methylation-sensitive high-resolution melting. Cox regression models and Log-rank tests were used to analyze the associations between PBX3 methylation status and CRC prognosis with a propensity score (PS) method to control confounding biases. RESULTS In this study, we found that CRC patients with PBL PBX3 hypermethylation status had a better overall survival (OS) (hazard ratio [HRPS-adjusted ], 0.72 [95% CI, 0.52-1.00]; P = 0.049). Subgroup analyses showed that the beneficial effect of PBX3 hypermethylation status on CRC 10-years OS remained significant among UICC stage III patients ([HRPS-adjusted ], 0.60 [95% CI, 0.38 to 0.95]; P = 0.029) and colon cancer patients ([HRPS-adjusted ], 0.49 [95% CI, 0.26 to 0.92]; P = 0.027). CONCLUSION PBL PBX3 hypermethylation is positively associated with better prognosis of CRC, especially for the UICC stage III CRC patients and colon cancer patients.
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Affiliation(s)
- Hongru Sun
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| | - Hao Huang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| | - Dapeng Li
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| | - Lei Zhang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| | - Yuanyuan Zhang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| | - Jing Xu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| | - Ying Liu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| | - Yupeng Liu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
| | - Yashuang Zhao
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin, The People's Republic of China
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Wang J, Shen J, Huang C, Cao M, Shen L. Clinicopathological Significance of BRAFV600E Mutation in Colorectal Cancer: An Updated Meta-Analysis. J Cancer 2019; 10:2332-2341. [PMID: 31258736 PMCID: PMC6584400 DOI: 10.7150/jca.30789] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 04/20/2019] [Indexed: 12/18/2022] Open
Abstract
Background and Aims: Numerous studies have identified BRAFV600E mutation as a predictive factor of anti-EGFR antibodies in colorectal cancer (CRC). However, the association between BRAFV600E mutation and clinicopathological features remains unclear. Therefore, we aimed to conduct an updated and comprehensive meta-analysis to evaluate the above issues. Methods: We performed a systematic literature search from PubMed, Web of Science, Embase, and PMC database examining the association between BRAFV600E mutation and clinicopathological features in CRC patients. Odds ratio with 95% confidence interval were used to estimate the effects of BRAFV600E mutation on each clinicopathological parameter with fixed-effect model or random-effect model. Results: Sixty-one studies published, including 32407 CRC patients from multiple countries, were included in the meta-analysis. The overall BRAFV600E mutation rate was 11.38%, and BRAFV600E mutation was positively related to high disease stage (OR=0.81; 95% CI=0.72-0.92; P=0.001), high T stage (OR=0.51; 95% CI=0.40-0.65; P<0.00001), proximal colon (OR=4.76; 95% CI=3.81-5.96; P<0.00001) or right colon (OR=5.15; 95% CI=4.35-6.10, P<0.00001) tumor location, poor tumor differentiation (OR=0.27; 95% CI=0.21-0.34; P<0.00001), mucinous histology (OR=2.97; 95% CI=2.37-3.72; P<0.00001), K-ras-wild type (OR=0.04; 95% CI=0.02-0.07; P<0.00001), TP53-wild type (OR=0.50; 95% CI=0.31-0.78; P=0.003), deficient DNA mismatch repair (OR=2.93; 95% CI=1.78-4.82; P<0.00001), high microsatellite instability (OR=11.15; 95% CI=8.51-14.61; P<0.00001) and high CpG island methylator phenotype (OR=0.04; 95% CI=0.03-0.08; P<0.00001). Conclusions: Our updated meta-analysis demonstrated that BRAFV600E mutation was related to poor prognosis of CRC and associated with the distinct molecular phenotypes.
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Affiliation(s)
- Jianhua Wang
- Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.,Department of General Surgery, Affiliated Hospital of Integrated Chinese and Western Medicine of Nanjing University of Chinese Medicine, Nanjing 210028, China
| | - Jiajia Shen
- Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China
| | - Chi Huang
- Department of General Surgery, Affiliated Hospital of Integrated Chinese and Western Medicine of Nanjing University of Chinese Medicine, Nanjing 210028, China
| | - Meng Cao
- Lab of cellular and molecular biology, Affiliated Hospital of Integrated Chinese and Western Medicine of Nanjing University of Chinese Medicine, Nanjing 210028, China
| | - Lizong Shen
- Division of Gastrointestinal Surgery, Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing 210029, China.,Department of Surgical Oncology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210029, China
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Li J, Wei Z, Cao S, Tan X, Liu S, Yao Z, Sun T, Li Y, Zhang D, Zhou Y. A pilot study on clinicopathological features and intestinal microflora changes in colorectal cancer patients born over a nine-year period encompassing three years before and after the Great Chinese famine. Cancer Epidemiol 2019; 59:166-172. [PMID: 30776583 DOI: 10.1016/j.canep.2019.02.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2018] [Revised: 01/17/2019] [Accepted: 02/05/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Exposure to energy restriction during childhood is associated with a lower risk of developing colorectal cancer (CRC). To date, the association between this critical period of growth and prognosis of CRC has rarely been investigated. Changes in microbiota and epigenetic dysregulation may be key underlying mechanisms. METHODOLOGY Tissues collected from patients born between 1956 and 1964 were grouped based on time-period. The differences in overall survival among patients from the three time-periods were examined via univariate analysis. The 16S rRNA gene sequencing approach was to determine differences in microbiota among the groups. Samples were randomly selected to detect BRAF mutations, microsatellite instability (MSI) and promoter CpG island methylator phenotype (CIMP) status. The chi-square test was to assess the relationship between alterations in these molecules and microbiota differences. RESULTS Patients from the three groups differed in terms of location of CRC (P = 0.034) and carcinoembryonic antigen (CEA) level (P = 0.036). A survival advantage was observed in the famine group compared with the other two groups. Fusobacterium nucleatum, Bacteroides fragilis and Escherichia coli were more abundant in the two comparing groups. Abundance of B. fragilis was associated with BRAF mutations, microsatellite instability (MSI) and abundance of E. coli. Moreover, the incidence of CIMP and MSI was higher in patients with greater abundance of F. nucleatum. CONCLUSIONS Limitation of energy intake during childhood may affect the composition of gut microbiota, resulting in persistent epigenetic changes that subsequently influence the prognosis of patients with CRC.
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Affiliation(s)
- Jiante Li
- Department of Anorectal Surgery, Wenzhou Medical University Second Affiliated Hospital, Zhejiang, China
| | - Zhiliang Wei
- Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shougen Cao
- Department of General Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaojie Tan
- Department of General Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Shanglong Liu
- Department of General Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Zengwu Yao
- Department of General Surgery, Yantai Yuhuangding Hospital, Yantai, China
| | - Teng Sun
- Department of General Surgery, Qingdao municipal hospital, Qingdao, China
| | - Yi Li
- Department of General Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
| | - Dongfeng Zhang
- Department of Epidemiology and Health Statistics, Qingdao University Medical College, Qingdao, China
| | - Yanbing Zhou
- Department of General Surgery, Affiliated Hospital of Qingdao University, Qingdao, China.
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Liu R, Su X, Long Y, Zhou D, Zhang X, Ye Z, Ma J, Tang T, Wang F, He C. A systematic review and quantitative assessment of methylation biomarkers in fecal DNA and colorectal cancer and its precursor, colorectal adenoma. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2019; 779:45-57. [PMID: 31097151 DOI: 10.1016/j.mrrev.2019.01.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 11/15/2018] [Accepted: 01/16/2019] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) arises from accumulated genetic and epigenetic alterations, which provide the possibility to identify tumor-specific biomarkers by analyzing fecal DNA. Methylation status in human genes from tumor tissue is highlighted as promising biomarker in the early detection of CRC. A number of studies have documented altered methylation levels in DNA extracted from stool samples, but generated heterogeneous results. We performed a systematic review and quantitative assessment of existing studies to compare levels of DNA methylation in most frequently studied genes and their diagnostic value in CRC and its precursor, colorectal adenoma, with their counterparts in healthy subjects. Robust searches of the literature were performed in our study with explicit strategies and definite inclusion/exclusion criteria. Pooled data revealed that methylation levels of SFRP2, SFRP1, TFPI2, BMP3, NDRG4, SPG20, and BMP3 plus NDRG4 genes exceeded a sensitivity of 70% and a specificity of 80% for CRC detection. The DOR of the seven candidate biomarkers ranged from 19.80 to 334.33, indicating a good diagnostic power in discriminating cancer from normal tissues. The AUC range was from 0.88 to 0.95, indicating a good or very good discriminatory performance. When test results for BMP3 and NDRG4 were combined, the DOR of CRC detection was 98.36, which was higher than that for BMP3 and NDRG4 separately. As for adenoma detection, the DOR of methylated NDRG4 is higher than that for CRC (CRC vs. adenoma: 54.86 vs. 57.22). Both the sensitivity and specificity of NDRG4 for adenoma detection exceeded 70%. These findings demonstrate the eligibility and feasibility of DNA methylation as a minimally invasive biomarker in feces in the diagnosis of CRC and adenoma. The use of DNA from human stools has the potential to be readily applicable to detect aberrant DNA methylation levels among many subjects for CRC early screening.
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Affiliation(s)
- Rongbin Liu
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xuan Su
- Department of Head and Neck, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, China
| | - Yakang Long
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Dalei Zhou
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xiao Zhang
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zulu Ye
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jiangjun Ma
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Tao Tang
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Fang Wang
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
| | - Caiyun He
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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Chen KH, Lin LI, Tseng LH, Lin YL, Liau JY, Tsai JH, Liang JT, Lin BR, Cheng AL, Yeh KH. CpG Island Methylator Phenotype May Predict Poor Overall Survival of Patients with Stage IV Colorectal Cancer. Oncology 2018; 96:156-163. [PMID: 30540994 DOI: 10.1159/000493387] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 08/29/2018] [Indexed: 11/19/2022]
Abstract
OBJECTIVE We aimed to study the prognostic role of CpG island methylator phenotype (CIMP) in patients with different stages of colorectal cancer (CRC). MATERIAL AND METHODS We analyzed CIMP in stage I-IV CRC specimens from patients who were diagnosed between 2005 and 2013. CIMP status was determined using a 5-gene MethyLight-based assay. The clinicopathologic characteristics were reviewed and the overall survival (OS) was compared between patients with CIMP-high CRC and those with CIMP-low/negative CRC. RESULTS Among 450 CRC specimens with successfully determined CIMP statuses, 74 (16.4%) were CIMP-high CRC. Although there was no difference in OS between patients with CIMP-high and CIMP-low/negative CRC across all stages (p = 0.4526), intriguingly, patients with stage IV CIMP-high CRC had significantly worse OS than those with stage IV CIMP-low/negative CRC (p = 0.0047). In a multivariate analysis, CIMP status remained an independent prognostic factor for overall mortality (HR = 5.60, 95% CI: 2.12-14.79, p = 0.0005) in metastatic CRC after adjusting for clinicopathologic variables and anti-cancer therapies. CONCLUSION Our results revealed that the presence of CIMP independently predicts poor OS in patients with stage IV CRC.
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Affiliation(s)
- Kuo-Hsing Chen
- Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan.,National Taiwan University Cancer Center, Taipei City, Taiwan.,Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City, Taiwan
| | - Liang-In Lin
- Department of Laboratory Medicine, National Taiwan University Hospital, Taipei City, Taiwan.,Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei City, Taiwan
| | - Li-Hui Tseng
- Department of Medical Genetics, National Taiwan University Hospital, Taipei City, Taiwan
| | - Yu-Lin Lin
- Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan.,Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City, Taiwan
| | - Jau-Yu Liau
- Department of Pathology, National Taiwan University Hospital, Taipei City, Taiwan
| | - Jia-Huei Tsai
- Department of Pathology, National Taiwan University Hospital, Taipei City, Taiwan
| | - Jin-Tung Liang
- Department of Surgery, National Taiwan University Hospital, Taipei City, Taiwan
| | - Been-Ren Lin
- Department of Surgery, National Taiwan University Hospital, Taipei City, Taiwan
| | - Ann-Lii Cheng
- Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan.,Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan.,National Taiwan University Cancer Center, Taipei City, Taiwan.,Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City, Taiwan
| | - Kun-Huei Yeh
- Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan, .,National Taiwan University Cancer Center, Taipei City, Taiwan, .,Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei City, Taiwan, .,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei City, Taiwan,
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Abstract
Colorectal cancer (CRC) is a heterogeneous disease, and the search for clinical and molecular prognostic and predictive factors is thus necessary to better tailor each individual patient's management. Primary tumor location (PTL) seems to act as a master prognostic factor pooling different clinical, pathological, and molecular poor prognostic factors. In fact, right-sided (RS) CRC patients are more frequently female and elderly with microsatellite unstable, BRAF mutated, CpG island methylator phenotype (CIMP)-high, poorly differentiated tumors, compared to left-sided (LS) CRC patients. PTL does not seem to clearly influence disease-free survival (DFS) in localised colon cancer even though the opposite prognostic value of RS tumors on DFS depending on RAS/BRAF mutational status has been recently suggested in these patients. In metastatic CRC (mCRC), the poor prognosis associated with RS tumors is confirmed in the most recent publications in the era of double and triple chemotherapeutic regimens and targeted agents. Concerning the predictive value of PTL, in patients with RAS wild-type mCRC in the first-line setting, anti-epidermal growth factor receptor (EGFR) therapy combined with chemotherapy appears to be more effective than bevacizumab in LS CRC, while patients with RS CRC benefit less from anti-EGFR therapy, and intensive chemotherapy plus bevacizumab may be more appropriate but EGFR antibodies remain an option if objective response is needed. Due to the limitation of the current data (unplanned and retrospective analyses), these conclusions must be interpreted with caution. Clinical trials in RS CRC may be of interest to clarify what is the best treatment strategy in these patients.
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Chouhan H, Sammour T, L Thomas M, W Moore J. Prognostic significance of BRAF mutation alone and in combination with microsatellite instability in stage III colon cancer. Asia Pac J Clin Oncol 2018; 15:69-74. [PMID: 30421554 DOI: 10.1111/ajco.13096] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Accepted: 09/09/2018] [Indexed: 11/30/2022]
Abstract
PURPOSE The prognostic significance of biomarkers in colorectal cancer is still being defined. This study aimed to determine the prognostic significance of BRAF mutation alone and in combination with microsatellite instability (MSI), in stage III colon cancer. METHODS Curatively resected stage III colon cancers were studied from a 33-year period. Clinicopathological data were collated (adjuvant chemotherapy, age, gender, obstruction, perforation, tumour location, grade, presence of mucin, nodal stage, extramural vascular, and perineural invasion). MSI status was established and molecular testing for BRAF (V600E) was performed. Four mutation categories were examined: "traditional" (microsatellite stable [MSS]/BRAF -ve), "presumed Lynch" (MSI/BRAF -ve), "sporadic MSI" (MSI/BRAF +ve), and "other BRAF" (MSS/BRAF +ve). These factors were correlated with cancer-specific survival. RESULTS In total, 686 unselected cases met our inclusion criteria, of which 15.7% had a BRAF mutation and 13.8% showed MSI. In the adjusted analysis, neither BRAF mutation nor MSI mutation were independently prognostic. On univariate analysis, survival in presumed Lynch cancers was similar to traditional cancers (5-year survival: 62% and 61%, respectively). While there was no difference in cancer-specific survival between sporadic MSI and other BRAF, both these tumour group had poorer outcome when compared to traditional or presumed Lynch cancers. Adjusted analysis of the four groups, however, showed that none of the subgroups were independently prognostic. CONCLUSION BRAF-mutated cancers demonstrated a trend toward poorer outcomes, however, when adjusted for clinicopathological factors and chemotherapy, BRAF mutation was not found to be an independent prognostic biomarker in stage III colon cancer, even when combined with MSI.
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Affiliation(s)
- Hanumant Chouhan
- Department of Colorectal Surgery, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Tarik Sammour
- Department of Colorectal Surgery, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Michelle L Thomas
- Department of Colorectal Surgery, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - James W Moore
- Department of Colorectal Surgery, Royal Adelaide Hospital, Adelaide, South Australia, Australia
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Taniguchi H, Okamoto W, Muro K, Akagi K, Hara H, Nishina T, Kajiwara T, Denda T, Hironaka S, Kudo T, Satoh T, Yamanaka T, Abe Y, Fukushima Y, Yoshino T. Clinical Validation of Newly Developed Multiplex Kit Using Luminex xMAP Technology for Detecting Simultaneous RAS and BRAF Mutations in Colorectal Cancer: Results of the RASKET-B Study. Neoplasia 2018; 20:1219-1226. [PMID: 30412858 PMCID: PMC6226617 DOI: 10.1016/j.neo.2018.10.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/11/2018] [Accepted: 10/11/2018] [Indexed: 12/22/2022] Open
Abstract
Detection of RAS and BRAF mutations is essential to determine the optimal treatment strategy for metastatic colorectal cancer (CRC). We prospectively evaluated the MEBGEN RASKET-B KIT (RASKET-B), a novel multiplex kit, simultaneously detecting 48 types of RAS mutations and the BRAF V600E mutation using Luminex xMAP technology. The aim was to obtain market approval for RASKET-B as an in vitro diagnostic (IVD) option in Japan. Genomic DNA was extracted from 302 formalin-fixed paraffin-embedded tissues obtained from CRC patients. The primary endpoints were the concordance rate (CR) between the results from RASKET-B and the previously approved IVD kit (RASKET) for RAS mutations, and CR between the results from RASKET-B and direct sequencing (DS) for BRAF mutations. The secondary endpoints included the CR between RASKET-B and DS for RAS mutations and between RASKET-B and the pyrosequencing (PYRO) for the BRAF V600E mutation. Among the 302 samples, 142 RAS mutations (47%) and 18 BRAF V600E mutations (6.0%) were detected by RASKET-B. All mutations detected in the recruited patients were mutually exclusive. Both RAS and BRAF mutation rates were statistically higher in right-sided than left-sided CRC. The CR between RASKET-B and RASKET for RAS gene and RASKET-B and DS for BRAF V600E mutation was 100% for both (95% CI: 99%-100%). The results from RASKET-B were also highly concordant with DS for RAS (97.4%) and with PYRO for the BRAF (V600E) gene (99.7%). RASKET-B thus provides rapid, precise, and simultaneous detection of RAS and BRAF mutations in CRC.
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Affiliation(s)
- Hiroya Taniguchi
- Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya-shi Aichi-ken, 464-8681, Japan; Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan.
| | - Wataru Okamoto
- Biobank translational research support section, Translational research management division, Clinical Research Support Office, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan
| | - Kei Muro
- Department of Clinical Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya-shi Aichi-ken, 464-8681, Japan
| | - Kiwamu Akagi
- Division of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, 818 Komuro, Ina-machi Kitaadachi-gun, Saitama-ken, 362-0806, Japan
| | - Hiroki Hara
- Department of Gastroenterology, Saitama Cancer Center, 818 Komuro, Ina-machi Kitaadachi-gun, Saitama-ken, 362-0806, Japan
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto-machi, Matsuyama-shi, Ehime-ken, 791-0280, Japan
| | - Takeshi Kajiwara
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, 160 Kou, Minamiumemoto-machi, Matsuyama-shi, Ehime-ken, 791-0280, Japan
| | - Tadamichi Denda
- Division of Gastroenterology, Chiba Cancer Center Hospital, 666-2 Nitona-Cho, Chuo-ku, Chiba-ken, 260-8717, Japan
| | - Shuichi Hironaka
- Department of Medical Oncology and Hematology, Faculty of Medicine, Oita University, 1-1 Idaigaoka, Hasama-machi, Yufu-shi, Oita-ken, 879-5593, Japan
| | - Toshihiro Kudo
- Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita-shi, Osaka-fu, 565-0871, Japan
| | - Taroh Satoh
- Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita-shi, Osaka-fu, 565-0871, Japan
| | - Takeharu Yamanaka
- Department of Biostatistics, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa, 236-0004, Japan
| | - Yukiko Abe
- Medical and Biological Laboratories Co. Ltd., KDX Nagoya Sakae Building 10F 4-5-3 Sakae, Naka-ku Nagoya-shi, Aichi-ken 460-0008, Japan
| | - Yoshiyuki Fukushima
- Medical and Biological Laboratories Co. Ltd., KDX Nagoya Sakae Building 10F 4-5-3 Sakae, Naka-ku Nagoya-shi, Aichi-ken 460-0008, Japan
| | - Takayuki Yoshino
- Department of Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa-shi, Chiba-ken, 277-8577, Japan
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Ye X, Mo M, Xu S, Yang Q, Wu M, Zhang J, Chen B, Li J, Zhong Y, Huang Q, Cai C. The hypermethylation of p16 gene exon 1 and exon 2: potential biomarkers for colorectal cancer and are associated with cancer pathological staging. BMC Cancer 2018; 18:1023. [PMID: 30348132 PMCID: PMC6198490 DOI: 10.1186/s12885-018-4921-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 10/09/2018] [Indexed: 02/06/2023] Open
Abstract
Background Tumor suppressor gene p16 promoter hypermethylation has been widely studied in colorectal cancer (CRC), yet its clinicopathological significance remains controversial. The methylation alterations of other regions within p16 gene are still rarely researched. The present study aimed to explore the methylation changes of p16 gene body in CRC and to find whether they were associated with clinicopathological staging of CRC. Methods Paired colorectal cancer tissues and corresponding adjacent normal tissues from 30 CRC patients were collected. The methylation levels of two CpG islands within p16 gene body, exon 1 and exon 2, were accurately assessed simultaneously by a LC-MS/MS method. The p16 protein expressions were assessed by immunohistochemistry assay. Statistical analyses were carried out using SPSS 17.0 software. Heat-map analysis was carried out by HemI 1.0 software. Results In the present study, CRC tissues showed more highly methylated than adjacent normal tissues at both CpG islands of p16 gene. And exon 2 hypermethylation was higher and more frequent than exon 1. The ROC curve analysis showed that the simultaneous use of both indicators had excellent sensitivity and specificity for distinguishing CRC tissues and adjacent normal tissues. Following, the methylation level of p16 exon 1/2 was negatively related to p16 protein expression. Further correlation analysis revealed that p16 exon 1 hypermethylation was associated with N/Dukes staging (p = 0.033), and p16 exon 2 hypermethylaiton was associated with T staging (p = 0.035). Conclusions The p16 gene body was remarkably hyper-methylated in CRC tissues and associated with p16 protein expression and cancer clinicopathological staging. The combination of p16 exon 1 and exon 2 could better reflect the overall methylation status of p16 gene body and provide potential biomarkers of CRC.
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Affiliation(s)
- Xiaoxia Ye
- Department of Histology and Embryology, Guangdong Medical University, Zhanjiang, 524023, People's Republic of China
| | - Mingming Mo
- Analysis Center, Guangdong Medical University, Zhanjiang, 524023, People's Republic of China
| | - Simin Xu
- Institute of Neurology, Affiliated Hospital, Guangdong Medical University, No. 2 Wenming Dong Road, Zhanjiang, Guangdong, 524023, People's Republic of China
| | - Qingjin Yang
- Analysis Center, Guangdong Medical University, Zhanjiang, 524023, People's Republic of China
| | - Minhua Wu
- Department of Histology and Embryology, Guangdong Medical University, Zhanjiang, 524023, People's Republic of China
| | - Junjie Zhang
- Analysis Center, Guangdong Medical University, Zhanjiang, 524023, People's Republic of China
| | - Bin Chen
- Analysis Center, Guangdong Medical University, Zhanjiang, 524023, People's Republic of China
| | - Jian Li
- Analysis Center, Guangdong Medical University, Zhanjiang, 524023, People's Republic of China
| | - Yu Zhong
- Analysis Center, Guangdong Medical University, Zhanjiang, 524023, People's Republic of China
| | - Qionglin Huang
- Analysis Center, Guangdong Medical University, Zhanjiang, 524023, People's Republic of China
| | - Chun Cai
- Analysis Center, Guangdong Medical University, Zhanjiang, 524023, People's Republic of China.
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Cheng HH, Lin JK, Chen WS, Jiang JK, Yang SH, Chang SC. Clinical significance of the BRAFV600E mutation in Asian patients with colorectal cancer. Int J Colorectal Dis 2018; 33:1173-1181. [PMID: 29869121 DOI: 10.1007/s00384-018-3095-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/22/2018] [Indexed: 02/04/2023]
Abstract
BACKGROUND To investigate the clinicopathological features and prognostic significance of the BRAFV600E mutation in Asian patients with colorectal cancer. METHODS We retrospectively reviewed the medical records of 1969 patients with colorectal cancer admitted to Taipei Veterans General Hospital for surgical treatment between 2000 and 2013. The measured endpoint was overall survival after surgery. The prognostic value of the BRAFV600E mutation was analyzed using the log-rank test and Cox regression analysis. RESULTS The BRAFV600E mutation was detected in 106 (5.4%) patients and associated with female gender, abnormal cancer antigen (CA)19-9 at diagnosis, microsatellite status, right-sided primary tumors, mucinous histology, poor differentiation, and lymphovascular invasion. Metastatic patterns were more common in non-regional lymph node metastasis (20.8 vs. 7.4%, p = 0.06) and peritoneal seeding (41. vs. 21.2%, p = 0.04). Mutations were not prognostic in the overall survival of the entire study group but only in specific patients: age < 65, normal carcinoembryonic antigen at diagnosis, and stage IV disease. CONCLUSION The BRAFV600E mutation was associated with distinct clinicopathological features and metastatic patterns. The overall survival rate was lower in selected colorectal patients with the BRAFV600E mutation.
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Affiliation(s)
- Hou-Hsuan Cheng
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Division of Colon & Rectal Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Jen-Kou Lin
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Wei-Shone Chen
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Jeng-Kai Jiang
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.,Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Shung-Haur Yang
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. .,Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan.
| | - Shih-Ching Chang
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan. .,Department of Surgery, Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan. .,Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan.
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Vedeld HM, Goel A, Lind GE. Epigenetic biomarkers in gastrointestinal cancers: The current state and clinical perspectives. Semin Cancer Biol 2018; 51:36-49. [PMID: 29253542 PMCID: PMC7286571 DOI: 10.1016/j.semcancer.2017.12.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 11/17/2017] [Accepted: 12/12/2017] [Indexed: 02/07/2023]
Abstract
Each year, almost 4.1 million people are diagnosed with gastrointestinal (GI) cancers. Due to late detection of this disease, the mortality is high, causing approximately 3 million cancer-related deaths annually, worldwide. Although the incidence and survival differs according to organ site, earlier detection and improved prognostication have the potential to reduce overall mortality burden from these cancers. Epigenetic changes, including aberrant promoter DNA methylation, are common events in both cancer initiation and progression. Furthermore, such changes may be identified non-invasively with the use of PCR based methods, in bodily fluids of cancer patients. These features make aberrant DNA methylation a promising substrate for the development of disease biomarkers for early detection, prognosis and for predicting response to therapy. In this article, we will provide an update and current clinical perspectives for DNA methylation alterations in patients with colorectal, gastric, pancreatic, liver and esophageal cancers, and discuss their potential role as cancer biomarkers.
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Affiliation(s)
- Hege Marie Vedeld
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Ajay Goel
- Center for Gastrointestinal Research, and Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA.
| | - Guro E Lind
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
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48
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Clinical, Pathological, and Molecular Characteristics of CpG Island Methylator Phenotype in Colorectal Cancer: A Systematic Review and Meta-analysis. Transl Oncol 2018; 11:1188-1201. [PMID: 30071442 PMCID: PMC6080640 DOI: 10.1016/j.tranon.2018.07.008] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 07/10/2018] [Accepted: 07/10/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND: CpG island methylator phenotype (CIMP) tumors, comprising 20% of colorectal cancers, are associated with female sex, age, right-sided location, and BRAF mutations. However, other factors potentially associated with CIMP have not been robustly examined. This meta-analysis provides a comprehensive assessment of the clinical, pathologic, and molecular characteristics that define CIMP tumors. METHODS: We conducted a comprehensive search of the literature from January 1999 through April 2018 and identified 122 articles, on which comprehensive data abstraction was performed on the clinical, pathologic, molecular, and mutational characteristics of CIMP subgroups, classified based on the extent of DNA methylation of tumor suppressor genes assessed using a variety of laboratory methods. Associations of CIMP with outcome parameters were estimated using pooled odds ratio or standardized mean differences using random-effects model. RESULTS: We confirmed prior associations including female sex, older age, right-sided tumor location, poor differentiation, and microsatellite instability. In addition to the recognized association with BRAF mutations, CIMP was also associated with PIK3CA mutations and lack of mutations in KRAS and TP53. Evidence of an activated immune response was seen with high rates of tumor-infiltrating lymphocytes (but not peritumoral lymphocytes), Crohn-like infiltrates, and infiltration with Fusobacterium nucleatum bacteria. Additionally, CIMP tumors were associated with advance T-stage and presence of perineural and lymphovascular invasion. CONCLUSION: The meta-analysis highlights key features distinguishing CIMP in colorectal cancer, including molecular characteristics of an active immune response. Improved understanding of this unique molecular subtype of colorectal cancer may provide insights into prevention and treatment.
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49
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Wong CC, Li W, Chan B, Yu J. Epigenomic biomarkers for prognostication and diagnosis of gastrointestinal cancers. Semin Cancer Biol 2018; 55:90-105. [PMID: 29665409 DOI: 10.1016/j.semcancer.2018.04.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 04/04/2018] [Accepted: 04/10/2018] [Indexed: 12/12/2022]
Abstract
Altered epigenetic regulation is central to many human diseases, including cancer. Over the past two decade, major advances have been made in our understanding of the role of epigenetic alterations in carcinogenesis, particularly for DNA methylation, histone modifications and non-coding RNAs. Aberrant hypermethylation of DNA at CpG islands is a well-established phenomenon that mediates transcriptional silencing of tumor suppressor genes, and it is an early event integral to gastrointestinal cancer development. As such, detection of aberrant DNA methylation is being developed as biomarkers for prognostic and diagnostic purposes in gastrointestinal cancers. Diverse tissue types are suitable for the analyses of methylated DNA, such as tumor tissues, blood, plasma, and stool, and some of these markers are already utilized in the clinical setting. Recent advances in the genome-wide epigenomic approaches are enabling the comprehensive mapping of the cancer methylome, thus providing new avenues for mining novel biomarkers for disease prognosis and diagnosis. Here, we review the current knowledge on DNA methylation biomarkers for the prognostication and non-invasive diagnosis of gastrointestinal cancers and highlight their clinical application.
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Affiliation(s)
- Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
| | - Weilin Li
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong; Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Bertina Chan
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
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50
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Bahrami A, Hassanian SM, Khazaei M, Gharib M, Rahmani M, Fiuji H, Jazayeri MH, Moetamani-Ahmadi M, Ferns GA, Avan A. The 9p21 locus as a potential therapeutic target and prognostic marker in colorectal cancer. Pharmacogenomics 2018; 19:463-474. [DOI: 10.2217/pgs-2017-0096] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) is a major cause of cancer-related-death worldwide. Despite extensive efforts to identify valid biomarkers for the risk stratification of CRC patients, there are few of proven clinical utility. It is recognized that genetic factors play a major role in determining susceptibility to CRC. Recent genome-wide association studies have demonstrated common genetic variants in a region on chromosome 9p21 associated with an increased risk of CRC. Several genetic polymorphisms have been identified in this region that are associated with CRC. Three genes are located at this locus; CDKN2B(encoding-p15ink4b), CDKN2A (encoding-p16ink4a/p14ARF) and 3′ end of CDKN2BAS (termed-antisense-noncoding-RNA in the INK4-locus [ANRIL]). ANRIL has a post-transcriptional modulatory activity, which has been shown to perturb the expression of nearby genes. It also plays an important role in coordinating tissue remodeling through regulation of cell proliferation, apoptosis, aging, extra-cellular matrix remodeling and inflammatory response. However, the role of ANRIL is not well understood in CRC. Hypermethylation of the p14ARF and p16INK4a genes is often found in some tumors, including CRC. However, further studies are necessary to explore the clinical utility of these putative markers in risk stratification, and in the assessment of prognosis. In this review, we have summarized the prognostic and therapeutic potential of the p14ARF and p16INK4a genes in patients with colorectal cancer.
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Affiliation(s)
- Afsane Bahrami
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjnad, Iran
- Department of Modern Sciences & Technologies; School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaei
- Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Masoumeh Gharib
- Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahsa Rahmani
- Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Fiuji
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mir Hadi Jazayeri
- Immunology Research Center, and Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | - Gordon A Ferns
- Brighton & Sussex Medical School, Division of Medical Education, Falmer, Brighton, Sussex B. 9PH, UK
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Cancer Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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