|
1
|
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 2025:1-14. [PMID: 40084815 DOI: 10.1080/17501911.2025.2476380] [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: 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.
Collapse
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
| |
Collapse
|
|
2
|
Bhattacharjya D, Sivalingam N. Mechanism of 5-fluorouracil induced resistance and role of piperine and curcumin as chemo-sensitizers in colon cancer. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:8445-8475. [PMID: 38878089 DOI: 10.1007/s00210-024-03189-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Accepted: 05/27/2024] [Indexed: 10/30/2024]
Abstract
Among cancer-related deaths worldwide, colorectal cancer ranks second, accounting for 1.2% of deaths in those under 50 years and 0.6% of deaths in those between 50 and 54 years. The anticancer drug 5-fluorouracil is widely used to treat colorectal cancer. Due to a better understanding of the drug's mechanism of action, its anticancer activity has been increased through a variety of therapeutic alternatives. Clinical use of 5-FU has been severely restricted due to drug resistance. The chemoresistance mechanism of 5-FU is challenging to overcome because of the existence of several drug efflux transporters, DNA repair enzymes, signaling cascades, classical cellular processes, cancer stem cells, metastasis, and angiogenesis. Curcumin, a potent phytocompound derived from Curcuma longa, functions as a nuclear factor (NF)-κB inhibitor and sensitizer to numerous chemotherapeutic drugs. Piperine, an alkaloid found in Piper longum, inhibits cancer cell growth, causing cell cycle arrest and apoptosis. This review explores the mechanism of 5-FU-induced chemoresistance in colon cancer cells and the role of curcumin and piperine in enhancing the sensitivity of 5-FU-based chemotherapy. CLINICAL TRIAL REGISTRATION: Not applicable.
Collapse
Affiliation(s)
- Dorothy Bhattacharjya
- Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, Faculty of Engineering and Technology, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, 603 203, Chengalpattu District, Tamil Nadu, India
| | - Nageswaran Sivalingam
- Department of Biotechnology, School of Bioengineering, College of Engineering and Technology, Faculty of Engineering and Technology, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, 603 203, Chengalpattu District, Tamil Nadu, India.
| |
Collapse
|
|
3
|
Li Q, Geng S, Luo H, Wang W, Mo YQ, Luo Q, Wang L, Song GB, Sheng JP, Xu B. Signaling pathways involved in colorectal cancer: pathogenesis and targeted therapy. Signal Transduct Target Ther 2024; 9:266. [PMID: 39370455 PMCID: PMC11456611 DOI: 10.1038/s41392-024-01953-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/25/2024] [Accepted: 08/16/2024] [Indexed: 10/08/2024] Open
Abstract
Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide. Its complexity is influenced by various signal transduction networks that govern cellular proliferation, survival, differentiation, and apoptosis. The pathogenesis of CRC is a testament to the dysregulation of these signaling cascades, which culminates in the malignant transformation of colonic epithelium. This review aims to dissect the foundational signaling mechanisms implicated in CRC, to elucidate the generalized principles underpinning neoplastic evolution and progression. We discuss the molecular hallmarks of CRC, including the genomic, epigenomic and microbial features of CRC to highlight the role of signal transduction in the orchestration of the tumorigenic process. Concurrently, we review the advent of targeted and immune therapies in CRC, assessing their impact on the current clinical landscape. The development of these therapies has been informed by a deepening understanding of oncogenic signaling, leading to the identification of key nodes within these networks that can be exploited pharmacologically. Furthermore, we explore the potential of integrating AI to enhance the precision of therapeutic targeting and patient stratification, emphasizing their role in personalized medicine. In summary, our review captures the dynamic interplay between aberrant signaling in CRC pathogenesis and the concerted efforts to counteract these changes through targeted therapeutic strategies, ultimately aiming to pave the way for improved prognosis and personalized treatment modalities in colorectal cancer.
Collapse
Affiliation(s)
- Qing Li
- The Shapingba Hospital, Chongqing University, Chongqing, China
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Shan Geng
- Central Laboratory, The Affiliated Dazu Hospital of Chongqing Medical University, Chongqing, China
| | - Hao Luo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
- Cancer Center, Daping Hospital, Army Medical University, Chongqing, China
| | - Wei Wang
- Chongqing Municipal Health and Health Committee, Chongqing, China
| | - Ya-Qi Mo
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
| | - Qing Luo
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China
| | - Lu Wang
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China
| | - Guan-Bin Song
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, China.
| | - Jian-Peng Sheng
- College of Artificial Intelligence, Nanjing University of Aeronautics and Astronautics, Nanjing, China.
| | - Bo Xu
- Chongqing Key Laboratory of Intelligent Oncology for Breast Cancer, Chongqing University Cancer Hospital and School of Medicine, Chongqing University, Chongqing, China.
| |
Collapse
|
|
4
|
Yuan T, Wankhede D, Edelmann D, Kather JN, Tagscherer KE, Roth W, Bewerunge-Hudler M, Brobeil A, Kloor M, Bläker H, Brenner H, Hoffmeister M. Large-scale external validation and meta-analysis of gene methylation biomarkers in tumor tissue for colorectal cancer prognosis. EBioMedicine 2024; 105:105223. [PMID: 38917511 PMCID: PMC11255517 DOI: 10.1016/j.ebiom.2024.105223] [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: 02/15/2024] [Revised: 04/29/2024] [Accepted: 06/11/2024] [Indexed: 06/27/2024] Open
Abstract
BACKGROUND DNA methylation biomarkers in colorectal cancer (CRC) tissue hold potential as prognostic indicators. However, individual studies have yielded heterogeneous results, and external validation is largely absent. We conducted a comprehensive external validation and meta-analysis of previously suggested gene methylation biomarkers for CRC prognosis. METHODS We performed a systematic search to identify relevant studies investigating gene methylation biomarkers for CRC prognosis until March 2024. Our external validation cohort with long-term follow-up included 2303 patients with CRC from 22 hospitals in southwest Germany. We used Cox regression analyses to assess associations between previously suggested gene methylation biomarkers and prognosis, adjusting for clinical variables. We calculated pooled hazard ratios (HRs) and their 95% confidence intervals (CIs) using random-effects models. FINDINGS Of 151 single gene and 29 multiple gene methylation biomarkers identified from 121 studies, 37 single gene and seven multiple gene biomarkers were significantly associated with CRC prognosis after adjustment for clinical variables. Moreover, the directions of these associations with prognosis remained consistent between the original studies and our validation analyses. Seven single biomarkers and two multi-biomarker signatures were significantly associated with CRC prognosis in the meta-analysis, with a relatively strong level of evidence for CDKN2A, WNT5A, MLH1, and EVL. INTERPRETATION In a comprehensive evaluation of the so far identified gene methylation biomarkers for CRC prognosis, we identified candidates with potential clinical relevance for further investigation. FUNDING The German Research Council, the Interdisciplinary Research Program of the National Center for Tumor Diseases (NCT), Germany, the German Federal Ministry of Education and Research.
Collapse
Affiliation(s)
- Tanwei Yuan
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany
| | - Durgesh Wankhede
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dominic Edelmann
- Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jakob Nikolas Kather
- Else Kroener Fresenius Center for Digital Health, Technical University Dresden, Dresden, Germany
| | | | - Wilfried Roth
- Institute of Pathology, University Medical Center Mainz, Mainz, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Alexander Brobeil
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Matthias Kloor
- Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
| | - Hendrik Bläker
- Institute of Pathology, University of Leipzig Medical Center, Leipzig, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
| |
Collapse
|
|
5
|
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.
Collapse
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.
| |
Collapse
|
|
6
|
Oh CK, Cho YS. Pathogenesis and biomarkers of colorectal cancer by epigenetic alteration. Intest Res 2024; 22:131-151. [PMID: 38295766 PMCID: PMC11079515 DOI: 10.5217/ir.2023.00115] [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: 09/05/2023] [Revised: 11/16/2023] [Accepted: 12/29/2023] [Indexed: 05/12/2024] Open
Abstract
Colorectal cancer (CRC) ranks third in cancer incidence and stands as the second leading cause of cancer-related deaths globally. CRC tumorigenesis results from a cumulative set of genetic and epigenetic alterations, disrupting cancer-regulatory processes like cell proliferation, metabolism, angiogenesis, cell death, invasion, and metastasis. Key epigenetic modifications observed in cancers encompass abnormal DNA methylation, atypical histone modifications, and irregularities in noncoding RNAs, such as microRNAs and long noncoding RNAs. The advancement in genomic technologies has positioned these genetic and epigenetic shifts as potential clinical biomarkers for CRC patients. This review concisely covers the fundamental principles of CRC-associated epigenetic changes, and examines in detail their emerging role as biomarkers for early detection, prognosis, and treatment response prediction.
Collapse
Affiliation(s)
- Chang Kyo Oh
- Division of Gastroenterology, Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Young-Seok Cho
- Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| |
Collapse
|
|
7
|
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.
Collapse
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
| |
Collapse
|
|
8
|
Ko B, Hanna M, Yu M, Grady WM. Epigenetic Alterations in Colorectal Cancer. EPIGENETICS AND HUMAN HEALTH 2023:331-361. [DOI: 10.1007/978-3-031-42365-9_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
9
|
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.
Collapse
|
|
10
|
Ghavami S, Zamani M, Ahmadi M, Erfani M, Dastghaib S, Darbandi M, Darbandi S, Vakili O, Siri M, Grabarek BO, Boroń D, Zarghooni M, Wiechec E, Mokarram P. Epigenetic regulation of autophagy in gastrointestinal cancers. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166512. [PMID: 35931405 DOI: 10.1016/j.bbadis.2022.166512] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 07/11/2022] [Accepted: 07/28/2022] [Indexed: 11/09/2022]
Abstract
The development of novel therapeutic approaches is necessary to manage gastrointestinal cancers (GICs). Considering the effective molecular mechanisms involved in tumor growth, the therapeutic response is pivotal in this process. Autophagy is a highly conserved catabolic process that acts as a double-edged sword in tumorigenesis and tumor inhibition in a context-dependent manner. Depending on the stage of malignancy and cellular origin of the tumor, autophagy might result in cancer cell survival or death during the GICs' progression. Moreover, autophagy can prevent the progression of GIC in the early stages but leads to chemoresistance in advanced stages. Therefore, targeting specific arms of autophagy could be a promising strategy in the prevention of chemoresistance and treatment of GIC. It has been revealed that autophagy is a cytoplasmic event that is subject to transcriptional and epigenetic regulation inside the nucleus. The effect of epigenetic regulation (including DNA methylation, histone modification, and expression of non-coding RNAs (ncRNAs) in cellular fate is still not completely understood. Recent findings have indicated that epigenetic alterations can modify several genes and modulators, eventually leading to inhibition or promotion of autophagy in different cancer stages, and mediating chemoresistance or chemosensitivity. The current review focuses on the links between autophagy and epigenetics in GICs and discusses: 1) How autophagy and epigenetics are linked in GICs, by considering different epigenetic mechanisms; 2) how epigenetics may be involved in the alteration of cancer-related phenotypes, including cell proliferation, invasion, and migration; and 3) how epidrugs modulate autophagy in GICs to overcome chemoresistance.
Collapse
Affiliation(s)
- Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Research Institute of Hematology and Oncology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada; Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland.
| | - Mozhdeh Zamani
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mazaher Ahmadi
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Mehran Erfani
- Department of Biochemistry, School of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Sanaz Dastghaib
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahsa Darbandi
- Fetal Health Research Center, Hope Generation Foundation, Tehran, Iran; Gene Therapy and Regenerative Medicine Research Center, Hope Generation Foundation, Tehran, Iran
| | - Sara Darbandi
- Fetal Health Research Center, Hope Generation Foundation, Tehran, Iran; Gene Therapy and Regenerative Medicine Research Center, Hope Generation Foundation, Tehran, Iran
| | - Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Morvarid Siri
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Beniamin Oskar Grabarek
- Department of Histology, Cytophysiology, and Embryology in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland; Department of Gynecology and Obstetrics in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland
| | - Dariusz Boroń
- Department of Histology, Cytophysiology, and Embryology in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland; Department of Gynecology and Obstetrics in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland
| | - Maryam Zarghooni
- Department of Laboratory Medicine and Pathobiology, University of Toronto Alumni, Toronto, Canada
| | - Emilia Wiechec
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, 58185 Linköping, Sweden
| | - Pooneh Mokarram
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| |
Collapse
|
|
11
|
Effect of DNA methylation status on first-line anti-epidermal growth factor receptor treatment in patients with metastatic colorectal cancer. Int J Colorectal Dis 2022; 37:1439-1447. [PMID: 35612620 DOI: 10.1007/s00384-022-04177-9] [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] [Accepted: 05/01/2022] [Indexed: 02/04/2023]
Abstract
PURPOSE The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer (CRC). However, there is a lack of consensus on CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patients with metastatic CRC (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors. METHODS We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment. We analyzed the incidence and clinicopathological characteristics of highly methylated CRC (HMCC) and associations between genome-wide DNA methylation status and response rate (RR), progression-free survival (PFS), and overall survival (OS). RESULTS In total, 169 patients were included in the final analyses. The frequency of HMCC was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAF V600E mutation (P < 0.0001). Patients with HMCC showed worse clinical outcomes than those with low-methylated CRC in terms of RR (P = 0.017), PFS (P = 0.004), and OS (P = 0.019). In the multivariate analysis, peritoneal metastasis (P = 0.017), methylation status (P = 0.037), and BRAF V600E mutations (P = 0.0001) were independent factors for shorter PFS. CONCLUSIONS Genome-wide DNA methylation status is an independent factor associated with PFS in patients with mCRC treated with first-line EGFR inhibitors.
Collapse
|
|
12
|
Serrated Colorectal Lesions: An Up-to-Date Review from Histological Pattern to Molecular Pathogenesis. Int J Mol Sci 2022; 23:ijms23084461. [PMID: 35457279 PMCID: PMC9032676 DOI: 10.3390/ijms23084461] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/16/2022] [Accepted: 04/17/2022] [Indexed: 12/10/2022] Open
Abstract
Until 2010, colorectal serrated lesions were generally considered as harmless lesions and reported as hyperplastic polyps (HPs) by pathologists and gastroenterologists. However, recent evidence showed that they may bear the potential to develop into colorectal carcinoma (CRC). Therefore, the World Health Organization (WHO) classification has identified four categories of serrated lesions: hyperplastic polyps (HPs), sessile serrated lesions (SSLs), traditional serrated adenoma (TSAs) and unclassified serrated adenomas. SSLs with dysplasia and TSAs are the most common precursors of CRC. CRCs arising from serrated lesions originate via two different molecular pathways, namely sporadic microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP), the latter being considered as the major mechanism that drives the serrated pathway towards CRC. Unlike CRCs arising through the adenoma-carcinoma pathway, APC-inactivating mutations are rarely shown in the serrated neoplasia pathway.
Collapse
|
|
13
|
van den Berg I, Smid M, Coebergh van den Braak RRJ, van de Wiel MA, van Deurzen CHM, de Weerd V, Martens JWM, IJzermans JNM, Wilting SM. A panel of DNA methylation markers for the classification of consensus molecular subtypes 2 and 3 in patients with colorectal cancer. Mol Oncol 2021; 15:3348-3362. [PMID: 34510716 PMCID: PMC8637568 DOI: 10.1002/1878-0261.13098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 08/04/2021] [Accepted: 09/09/2021] [Indexed: 12/25/2022] Open
Abstract
Consensus molecular subtypes (CMSs) can guide precision treatment of colorectal cancer (CRC). We aim to identify methylation markers to distinguish between CMS2 and CMS3 in patients with CRC, for which an easy test is currently lacking. To this aim, fresh‐frozen tumor tissue of 239 patients with stage I‐III CRC was analyzed. Methylation profiles were obtained using the Infinium HumanMethylation450 BeadChip. We performed adaptive group‐regularized logistic ridge regression with post hoc group‐weighted elastic net marker selection to build prediction models for classification of CMS2 and CMS3. The Cancer Genome Atlas (TCGA) data were used for validation. Group regularization of the probes was done based on their location either relative to a CpG island or relative to a gene present in the CMS classifier, resulting in two different prediction models and subsequently different marker panels. For both panels, even when using only five markers, accuracies were > 90% in our cohort and in the TCGA validation set. Our methylation marker panel accurately distinguishes between CMS2 and CMS3. This enables development of a targeted assay to provide a robust and clinically relevant classification tool for CRC patients.
Collapse
Affiliation(s)
- Inge van den Berg
- Department of Surgery, Erasmus MC - University Medical Center Rotterdam, The Netherlands
| | - Marcel Smid
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, The Netherlands
| | | | - Mark A van de Wiel
- Department of Epidemiology & Data Science, Amsterdam University Medical Center, Amsterdam Public Health research institute, The Netherlands
| | | | - Vanja de Weerd
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, The Netherlands
| | - John W M Martens
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, The Netherlands
| | - Jan N M IJzermans
- Department of Surgery, Erasmus MC - University Medical Center Rotterdam, The Netherlands
| | - Saskia M Wilting
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, The Netherlands
| |
Collapse
|
|
14
|
Chen F, Pei L, Liu S, Lin Y, Han X, Meng E, Wang X, Hong S, Wang D, Liu F, Fei Y, Wang G. Identification of a Novel Immune-Related CpG Methylation Signature to Predict Prognosis in Stage II/III Colorectal Cancer. Front Genet 2021; 12:684349. [PMID: 34262597 PMCID: PMC8273301 DOI: 10.3389/fgene.2021.684349] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/07/2021] [Indexed: 12/13/2022] Open
Abstract
With the increasing incidence of colorectal cancer (CRC) and continued difficulty in treating it using immunotherapy, there is an urgent need to identify an effective immune-related biomarker associated with the survival and prognosis of patients with this disease. DNA methylation plays an essential role in maintaining cellular function, and changes in methylation patterns may contribute to the development of autoimmunity, aging, and cancer. In this study, we aimed to identify a novel immune-related methylated signature to aid in predicting the prognosis of patients with CRC. We investigated DNA methylation patterns in patients with stage II/III CRC using datasets from The cancer genome atlas (TCGA). Overall, 182 patients were randomly divided into training (n = 127) and test groups (n = 55). In the training group, five immune-related methylated CG sites (cg11621464, cg13565656, cg18976437, cg20505223, and cg20528583) were identified, and CG site-based risk scores were calculated using univariate Cox proportional hazards regression in patients with stage II/III CRC. Multivariate Cox regression analysis indicated that methylated signature was independent of other clinical parameters. The Kaplan-Meier analysis results showed that CG site-based risk scores could significantly help distinguish between high- and low-risk patients in both the training (P = 0.000296) and test groups (P = 0.022). The area under the receiver operating characteristic curve in the training and test groups were estimated to be 0.771 and 0.724, respectively, for prognosis prediction. Finally, stratified analysis results suggested the remarkable prognostic value of CG site-based risk scores in CRC subtypes. We identified five methylated CG sites that could be used as an efficient overall survival (OS)-related biomarker for stage II/III CRC patients.
Collapse
Affiliation(s)
- Feng Chen
- Department of General Surgery, The Fourth Medical Center of PLA General Hospital, Beijing, China
| | - Lijuan Pei
- Department of General Surgery, The Fourth Medical Center of PLA General Hospital, Beijing, China
| | - Siyao Liu
- ChosenMed Technology Co., Ltd., Beijing, China
| | - Yan Lin
- Library, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xinyin Han
- Computer Network Information Center, Chinese Academy of Sciences, Beijing, China.,University of the Chinese Academy of Sciences, Beijing, China
| | - Erhong Meng
- ChosenMed Technology Co., Ltd., Beijing, China
| | | | - Shuai Hong
- ChosenMed Technology Co., Ltd., Beijing, China
| | | | - Feide Liu
- Department of General Surgery, The Fourth Medical Center of PLA General Hospital, Beijing, China
| | - Yang Fei
- Department of General Surgery, The Fourth Medical Center of PLA General Hospital, Beijing, China
| | - Guangda Wang
- Department of Radiology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| |
Collapse
|
|
15
|
Grady WM. Epigenetic alterations in the gastrointestinal tract: Current and emerging use for biomarkers of cancer. Adv Cancer Res 2021; 151:425-468. [PMID: 34148620 DOI: 10.1016/bs.acr.2021.02.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Colorectal cancer is a leading cause of cancer related deaths worldwide. One of the hallmarks of cancer and a fundamental trait of virtually all gastrointestinal cancers is genomic and epigenomic DNA alterations. Cancer cells acquire genetic and epigenetic alterations that drive the initiation and progression of the cancers by altering the molecular and cell biological process of the cells. These alterations, as well as other host and microenvironment factors, ultimately mediate the initiation and progression of cancers, including colorectal cancer. Epigenetic alterations, which include changes affecting DNA methylation, histone modifications, chromatin structure, and noncoding RNA expression, have emerged as a major class of molecular alteration in colon polyps and colorectal cancer. The classes of epigenetic alterations, their status in colorectal polyps and cancer, their effects on neoplasm biology, and their application to clinical care will be discussed.
Collapse
Affiliation(s)
- William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA, United States.
| |
Collapse
|
|
16
|
Zhang X, Zhang W, Cao P. Advances in CpG Island Methylator Phenotype Colorectal Cancer Therapies. Front Oncol 2021; 11:629390. [PMID: 33718206 PMCID: PMC7952756 DOI: 10.3389/fonc.2021.629390] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 01/18/2021] [Indexed: 01/05/2023] Open
Abstract
With the aging of the population, the incidence of colorectal cancer in China is increasing. One of the epigenetic alterations: CpG island methylator phenotype (CIMP) plays an important role in the incidence of colorectal cancer. Recent studies have shown that CIMP is closely related to some specific clinicopathological phenotypes and multiple molecular phenotypes in colorectal cancer. In this paper, the newest progress of CIMP colorectal cancer in chemotherapeutic drugs, targeted agents and small molecular methylation inhibitors are going to be introduced. We hope to provide potential clinical treatment strategies for personalized and precise treatment of colorectal cancer patients.
Collapse
Affiliation(s)
- Xiaofei Zhang
- Department of Medical Oncology, Dalian University Affiliated Xinhua Hospital, Dalian, China
| | - Wenjun Zhang
- Department of Colorectal Surgery, Dalian University Affiliated Xinhua Hospital, Dalian, China
| | - Pingan Cao
- Department of Medical Oncology, Dalian University Affiliated Xinhua Hospital, Dalian, China
| |
Collapse
|
|
17
|
Grady WM, Yu M, Markowitz SD. Epigenetic Alterations in the Gastrointestinal Tract: Current and Emerging Use for Biomarkers of Cancer. Gastroenterology 2021; 160:690-709. [PMID: 33279516 PMCID: PMC7878343 DOI: 10.1053/j.gastro.2020.09.058] [Citation(s) in RCA: 133] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 09/24/2020] [Accepted: 09/28/2020] [Indexed: 02/06/2023]
Abstract
Colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, and esophageal cancer are leading causes of cancer-related deaths worldwide. A fundamental trait of virtually all gastrointestinal cancers is genomic and epigenomic DNA alterations. Cancer cells acquire genetic and epigenetic alterations that drive the initiation and progression of the cancers by altering the molecular and cell biological processes of the cells. These alterations, as well as other host and microenvironment factors, ultimately mediate the clinical behavior of the precancers and cancers and can be used as biomarkers for cancer risk determination, early detection of cancer and precancer, determination of the prognosis of cancer and prediction of the response to therapy. Epigenetic alterations have emerged as one of most robust classes of biomarkers and are the basis for a growing number of clinical tests for cancer screening and surveillance.
Collapse
Affiliation(s)
- William M. Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA,Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Ming Yu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
| | | |
Collapse
|
|
18
|
Kolenčík D, Shishido SN, Pitule P, Mason J, Hicks J, Kuhn P. Liquid Biopsy in Colorectal Carcinoma: Clinical Applications and Challenges. Cancers (Basel) 2020; 12:E1376. [PMID: 32471160 PMCID: PMC7352156 DOI: 10.3390/cancers12061376] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 05/16/2020] [Accepted: 05/25/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal carcinoma (CRC) is characterized by wide intratumor heterogeneity with general genomic instability and there is a need for improved diagnostic, prognostic, and therapeutic tools. The liquid biopsy provides a noninvasive route of sample collection for analysis of circulating tumor cells (CTCs) and genomic material, including cell-free DNA (cfDNA), as a complementary biopsy to the solid tumor tissue. The solid biopsy is critical for molecular characterization and diagnosis at the time of collection. The liquid biopsy has the advantage of longitudinal molecular characterization of the disease, which is crucial for precision medicine and patient-oriented treatment. In this review, we provide an overview of CRC and the different methodologies for the detection of CTCs and cfDNA, followed by a discussion on the potential clinical utility of the liquid biopsy in CRC patient care, and lastly, current challenges in the field.
Collapse
Affiliation(s)
- Drahomír Kolenčík
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic; (D.K.); (P.P.)
| | - Stephanie N. Shishido
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA; (S.N.S.); (J.M.); (J.H.)
| | - Pavel Pitule
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, 32300 Pilsen, Czech Republic; (D.K.); (P.P.)
| | - Jeremy Mason
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA; (S.N.S.); (J.M.); (J.H.)
- USC Institute of Urology, Catherine & Joseph Aresty Department of Urology, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - James Hicks
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA; (S.N.S.); (J.M.); (J.H.)
| | - Peter Kuhn
- Convergent Science Institute in Cancer, Michelson Center for Convergent Bioscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA 90089, USA; (S.N.S.); (J.M.); (J.H.)
| |
Collapse
|
|
19
|
Jung G, Hernández-Illán E, Moreira L, Balaguer F, Goel A. Epigenetics of colorectal cancer: biomarker and therapeutic potential. Nat Rev Gastroenterol Hepatol 2020; 17:111-130. [PMID: 31900466 PMCID: PMC7228650 DOI: 10.1038/s41575-019-0230-y] [Citation(s) in RCA: 491] [Impact Index Per Article: 98.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/16/2019] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC), a leading cause of cancer-related death worldwide, evolves as a result of the stepwise accumulation of a series of genetic and epigenetic alterations in the normal colonic epithelium, leading to the development of colorectal adenomas and invasive adenocarcinomas. Although genetic alterations have a major role in a subset of CRCs, the pathophysiological contribution of epigenetic aberrations in this malignancy has attracted considerable attention. Data from the past couple of decades has unequivocally illustrated that epigenetic marks are important molecular hallmarks of cancer, as they occur very early in disease pathogenesis, involve virtually all key cancer-associated pathways and, most importantly, can be exploited as clinically relevant disease biomarkers for diagnosis, prognostication and prediction of treatment response. In this Review, we summarize the current knowledge on the best-studied epigenetic modifications in CRC, including DNA methylation and histone modifications, as well as the role of non-coding RNAs as epigenetic regulators. We focus on the emerging potential for the bench-to-bedside translation of some of these epigenetic alterations into clinical practice and discuss the burgeoning evidence supporting the potential of emerging epigenetic therapies in CRC as we usher in the era of precision medicine.
Collapse
Affiliation(s)
- Gerhard Jung
- Gastroenterology Department, Hospital Clínic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Eva Hernández-Illán
- Gastroenterology Department, Hospital Clínic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Leticia Moreira
- Gastroenterology Department, Hospital Clínic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Francesc Balaguer
- Gastroenterology Department, Hospital Clínic de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.,;
| | - Ajay Goel
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA.,Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, California, USA.,;
| |
Collapse
|
|
20
|
Liu J, Tang L, Yi J, Li G, Lu Y, Xu Y, Zhao S, Mao R, Li X, Ren L, Wang K. Unique characteristics of CpG island methylator phenotype (CIMP) in a Chinese population with colorectal cancer. BMC Gastroenterol 2019; 19:173. [PMID: 31690257 PMCID: PMC6833289 DOI: 10.1186/s12876-019-1086-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Accepted: 10/02/2019] [Indexed: 12/21/2022] Open
Abstract
Background Molecular characteristics of CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) have been well documented in Western, but not in Chinese, populations. Methods We investigated the incidence of CIMP, BRAF/KRAS mutation, and microsatellite instability (MSI) in a Chinese population with CRC (n = 401) and analysed associations between CIMP status and clinicopathological and molecular features. Results A total of 41 cases, 310 cases, and 40 cases were classified as CIMP-high, CIMP-low, and CIMP-negative, respectively. We detected a significantly low incidence of BRAF mutation in adenomas (2%) and CRC (0.7%), and a relatively low incidence of KRAS mutation (24.9%) compared with that in other populations. We also detected a relatively low incidence of CIMP-high (10.2%), which was significantly associated with younger age (≤49 years of age), female sex, and proximal tumour location. Conclusions This study revealed unique characteristics of CIMP in a Chinese population with colorectal cancer. Developing specific CIMP markers based on unique populations or ethnic groups will further help to fully elucidate CIMP pathogenesis.
Collapse
Affiliation(s)
- Jiang Liu
- Department of Reproduction and Genetics, the First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China.,Yunnan Engineering Technology Center of Digestive Disease, Kunming, 650032, Yunnan, China.,Kunming Engineering Technology Center of Digestive Disease, Kunming, 650032, Yunnan, China
| | - Li Tang
- Department of Reproduction and Genetics, the First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
| | - Jinhua Yi
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Disease, Kunming, 650032, Yunnan, China.,Yunnan Engineering Technology Center of Digestive Disease, Kunming, 650032, Yunnan, China.,Kunming Engineering Technology Center of Digestive Disease, Kunming, 650032, Yunnan, China
| | - Guimei Li
- Public Technical Service Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650032, Yunnan, China.,Kunming Biological Diversity Regional Center of Large Apparatus and Equipments, Chinese Academy of Sciences, Kunming, 650032, Yunnan, China
| | - Youwang Lu
- Department of Reproduction and Genetics, the First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China.,Yunnan Engineering Technology Center of Digestive Disease, Kunming, 650032, Yunnan, China.,Kunming Engineering Technology Center of Digestive Disease, Kunming, 650032, Yunnan, China
| | - Yu Xu
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Disease, Kunming, 650032, Yunnan, China.,Yunnan Engineering Technology Center of Digestive Disease, Kunming, 650032, Yunnan, China.,Kunming Engineering Technology Center of Digestive Disease, Kunming, 650032, Yunnan, China
| | - Shuhua Zhao
- Department of Reproduction and Genetics, the First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China
| | - Rui Mao
- School of Stomatology, Kunming Medical University, Kunming, 650500, Yunnan, China
| | - Xiaolu Li
- Public Technical Service Center, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, 650032, Yunnan, China.,Kunming Biological Diversity Regional Center of Large Apparatus and Equipments, Chinese Academy of Sciences, Kunming, 650032, Yunnan, China
| | - Li Ren
- Department of Reproductive Gynecology, the First People's Hospital of Yunnan Province, Kunming, 650031, Yunnan, China
| | - Kunhua Wang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Disease, Kunming, 650032, Yunnan, China. .,Yunnan Engineering Technology Center of Digestive Disease, Kunming, 650032, Yunnan, China. .,Kunming Engineering Technology Center of Digestive Disease, Kunming, 650032, Yunnan, China.
| |
Collapse
|
|
21
|
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.
Collapse
|
|
22
|
Salama RH, Sayed ZEAA, Ashmawy AM, Elsewify WA, Ezzat GM, Mahmoud MA, Alsanory AA, Alsanory TA. Interrelations of Apoptotic and Cellular Senescence Genes Methylation in Inflammatory Bowel Disease Subtypes and Colorectal Carcinoma in Egyptians Patients. Appl Biochem Biotechnol 2019; 189:330-343. [PMID: 30989570 DOI: 10.1007/s12010-019-03017-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Accepted: 03/27/2019] [Indexed: 12/24/2022]
Abstract
Ras-related domain family member 1 transcript variant A (RASSF1A) controls apoptosis and cell proliferation while p14/ARF gene has a regulatory role in cellular senescence. Failure of apoptosis and cellular senescence occurs during inflammatory bowel disease (IBD) and colorectal cancer (CRC). To reveal the role of peripheral leukocyte promoter methylation of RASSF1A and p14/ARF in the pathogenesis of IBD subtypes and CRC we investigated the methylation state of the two genes by methylation-specific polymerase chain reaction (MSP-PCR) in 60 CRC patients, 60 patients with IBD; 27 with ulcerative colitis and 33 had Crohn's disease and also in 30 healthy subjects. Methylated RASSF1A and p14/ARF genes were detected in 55% and 60% of CRC, while the frequency of the methylated RASSF1A and p14/ARF genes was 23.3% and 43.3% in IBD patients and 3.3% and 13.3% in the control group (P = 0.000 each). Also, the frequency of methylated RASSF1A gene was significantly higher in ulcerative colitis than in Crohn's disease, while a non-significant frequency of methylated p14/ARF was detected between ulcerative colitis and Crohn's disease. Furthermore, methylated RASSF1A and p14/ARF were associated with the grade of CRC but not associated with the age of patients, family history, or tumor location. Results suggest that methylated RASSF1A and p14/ARF are related to CRC and IBD pathogenesis and may be used as molecular biomarkers for early detection of CRC and IBD.
Collapse
Affiliation(s)
- Ragaa H Salama
- Department of Medical Biochemistry, Faculty of Medicine, Assiut University, Assiut, Egypt
| | | | - Ahmed M Ashmawy
- Department of Internal Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Wael A Elsewify
- Department of Internal Medicine, Faculty of Medicine, Aswan University, Aswan, Egypt
| | - Ghada M Ezzat
- Department of Medical Biochemistry, Faculty of Medicine, Assiut University, Assiut, Egypt.
| | - Mahmoud A Mahmoud
- Department of Internal Medicine, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Aya A Alsanory
- Students at Faculty of Medicine, Faculty of Pharmacy, Assiut University, Assiut, Egypt
| | - Tasneem A Alsanory
- Students at Faculty of Medicine, Faculty of Pharmacy, Assiut University, Assiut, Egypt
| |
Collapse
|
|
23
|
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.
Collapse
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,
| |
Collapse
|
|
24
|
Diagnostic Assessment of septin9 DNA Methylation for Colorectal Cancer Using Blood Detection: A Meta-Analysis. Pathol Oncol Res 2018; 25:1525-1534. [PMID: 30488278 DOI: 10.1007/s12253-018-0559-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 11/20/2018] [Indexed: 02/08/2023]
Abstract
This meta-analysis aimed to assess the diagnostic efficiency of blood-based septin 9 (SEPT9) methylation assay for the detection of colorectal cancer (CRC). Studies were searched in the Springer, Wiley, Cochrane Library, PubMed, Ovid, Embase, Web of Science, China BioMedicine, Wanfang and China National Knowledge Infrastructure databases until July 2017. Methodological quality assessment was performed based on the guidelines of the Quality Assessment of Diagnostic Accuracy Studies. According to 1/3 and 2/3 algorithms, the meta-analyses for the diagnostic effect of SEPT9 in CRC were compared with healthy subjects and subjects with polyps, adenoma, and non-CRC, respectively. The random effects model was applied and publication bias was evaluated. The included 29 studies comprised 10,486 subjects (3202 patients with CRC and 7284 controls). In comparison with healthy subjects, the pooled sensitivity with 95% confidence intervals (CIs) of SEPT9 methylation for the diagnosis of CRC was 0.74 (95% CI: 0.61-0.84) in the 1/3 algorithm group, whereas the specificity was 0.96 (95% CI: 0.95-0.97) in the 2/3 algorithm group. Additionally, positive likelihood ratio was less than 10 and negative likelihood ratio more than 0.1 in the 2/3 algorithm group for patients with CRC vs. polyps and adenoma. The P value of Deeks' funnel plot was 0.36, suggesting that there was no publication bias. SEPT9 methylation can be used to diagnose CRC in healthy individuals under the 2/3 algorithm. The determination of SEPT9 methylation does not distinguish well between CRC and polyps or adenoma.
Collapse
|
|
25
|
Alhumaid A, AlYousef Z, Bakhsh HA, AlGhamdi S, Aziz MA. Emerging paradigms in the treatment of liver metastases in colorectal cancer. Crit Rev Oncol Hematol 2018; 132:39-50. [PMID: 30447926 DOI: 10.1016/j.critrevonc.2018.09.011] [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: 08/31/2017] [Revised: 08/29/2018] [Accepted: 09/19/2018] [Indexed: 12/15/2022] Open
Abstract
Efforts to combat colorectal cancer have benefited from improved screening and surveillance, which facilitates early detection. The survival rate associated with diagnosis at stage I is approximately 90%. However, progress in improving survival in metastatic colorectal cancer (mCRC) has been minimal. This review focuses on mCRC with special emphasis on the molecular aspects of liver metastases, which is one of the most frequently involved organ site. Better molecular evidence is required to guide the decisions for surgical and other interventions used in the clinical management of mCRC. Results from different treatment modalities have exposed significant gaps in the existing paradigms of the mCRC management. Indeed there is a critical need to better understand molecular events and pathways that lead to colorectal cancer liver metastasis. Such a focused approach may help identify biomarkers and drug targets that can be useful in the clinical applications. With this focus, we provide an account of the molecular pathways involved in the spread of CRC to the liver. Specifically, the molecular changes at the DNA and RNA levels that are associated with liver metastases are discussed. Similarly, we describe relevant microRNAs that are identified as regulators of gene expression and can also serve as biomarkers. Conventionally applied biomarkers are not yet specific and sensitive enough to be relied in routine clinical decision making. Hence search for novel biomarkers is critically needed especially if these can be utilized using liquid biopsies. This review provides a comprehensive analysis of current molecular evidence along with potential future directions that could reshape the diagnostic and management paradigms and thus mitigate the devastating impact of colorectal cancer metastasis to the liver.
Collapse
Affiliation(s)
- Abdulrahman Alhumaid
- King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, College of Medicine, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
| | - Zeyad AlYousef
- King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, Department of Surgery, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
| | - Haafiz A Bakhsh
- King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, Department of Hepatology, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
| | - Saleh AlGhamdi
- King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, Department of Medical Genomics, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
| | - Mohammad Azhar Aziz
- King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, Department of Medical Genomics, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia; King Abdullah International Medical Research Center [KAIMRC], King Saud Bin Abdulaziz University for Health Sciences, Colorectal Cancer Research Program, National Guard Health Affairs, P.O. Box 22490, Riyadh 11426, Saudi Arabia.
| |
Collapse
|
|
26
|
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: 42] [Impact Index Per Article: 6.0] [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.
Collapse
|
|
27
|
Schirripa M, Cohen SA, Battaglin F, Lenz HJ. Biomarker-driven and molecular targeted therapies for colorectal cancers. Semin Oncol 2018; 45:124-132. [PMID: 30262397 PMCID: PMC7496213 DOI: 10.1053/j.seminoncol.2017.06.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Accepted: 06/27/2017] [Indexed: 12/23/2022]
Abstract
Improved clinical selection and identification of new molecules and innovative strategies have widened treatment options and increased overall survival in metastatic colorectal cancer patients in recent years. Biomarker-driven therapies represent an emerging issue in this field and new targeted treatments are under investigation and probably will be soon adopted into daily clinical practice. In the present review, the role RAS, BRAF mutations, Her2 amplification, microsatellite instability, and CpG island methylator phenotype are discussed according to their possible roles as prognostic, predictive markers, as well as possible biomarker-driven treatment options.
Collapse
Affiliation(s)
- Marta Schirripa
- Division of Medical Oncology 1, Istituto Oncologico Veneto, IRCCS, Padova, Italy
| | - Stacey A Cohen
- Division of Medical Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Francesca Battaglin
- Division of Medical Oncology 1, Istituto Oncologico Veneto, IRCCS, Padova, Italy
| | - Heinz-Josef Lenz
- Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
| |
Collapse
|
|
28
|
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.
Collapse
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.
| |
Collapse
|
|
29
|
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.
Collapse
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
| |
Collapse
|
|
30
|
Overman MJ, Morris V, Moinova H, Manyam G, Ensor J, Lee MS, Eng C, Kee B, Fogelman D, Shroff RT, LaFramboise T, Mazard T, Feng T, Hamilton S, Broom B, Lutterbaugh J, Issa JP, Markowitz SD, Kopetz S. Phase I/II study of azacitidine and capecitabine/oxaliplatin (CAPOX) in refractory CIMP-high metastatic colorectal cancer: evaluation of circulating methylated vimentin. Oncotarget 2018; 7:67495-67506. [PMID: 27542211 PMCID: PMC5341892 DOI: 10.18632/oncotarget.11317] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 08/10/2016] [Indexed: 12/13/2022] Open
Abstract
Purpose Hypermethylation of promoter CpG islands (CIMP) has been strongly implicated in chemotherapy resistance and is implicated in the pathogenesis of a subset of colorectal cancers (CRCs) termed CIMP-high. Experimental Design This phase I/II study in CRC (phase II portion restricted to CIMP-high CRC), treated fluoropyrimidine/oxaliplatin refractory patients with azacitidine (75 mg/m2/day subcutaneously D1-5) and CAPOX (capecitibine and oxaliplatin) every three weeks. Results Twenty-six patients (pts) were enrolled in this study: 15 pts (12 treated at MTD) in phase I and 11 pts in phase II. No dose limiting toxicities were observed. A total of 14 pts were CIMP-high. No responses were seen. CIMP-high status did not correlate with efficacy endpoints [stable disease (SD) or progression-free survival (PFS)] or baseline vimentin methylation level. Changes in vimentin methylation over time did not correlate with efficacy outcomes. Baseline methylated vimentin correlated with tumor volume (P<0.001) and higher levels of baseline methylation correlated with the obtainment of stable disease (P=0.04). Conclusions Azacitidine and CAPOX were well tolerated with high rates of stable disease in CIMP-high pts, but no objective responses. Serum methylated vimentin may be associated with benefit from a regimen including a hypomethylation agent, although this study is not able to separate a potential prognostic or predictive role for the biomarker.
Collapse
Affiliation(s)
- Michael J Overman
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Van Morris
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Helen Moinova
- Department of Medicine and Case Comprehensive Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH, USA
| | - Ganiraju Manyam
- Department of Bioinformatics and Computational Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Joe Ensor
- Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX, USA
| | - Michael S Lee
- Division of Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Cathy Eng
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Bryan Kee
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - David Fogelman
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Rachna T Shroff
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Thomas LaFramboise
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Thibault Mazard
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Tian Feng
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Stanley Hamilton
- Division of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Bradley Broom
- Department of Bioinformatics and Computational Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - James Lutterbaugh
- Department of Medicine and Case Comprehensive Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH, USA
| | - Jean-Pierre Issa
- Fels Institute for Cancer and Molecular Biology, Temple University, Philadelphia, PA, USA
| | - Sanford D Markowitz
- Department of Medicine and Case Comprehensive Cancer Center, Case Western Reserve University and Case Medical Center, Cleveland, OH, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| |
Collapse
|
|
31
|
Zhou X, Zhao M, Duan X, Guo B, Cheng W, Ding S, Ju H. Collapse of DNA Tetrahedron Nanostructure for "Off-On" Fluorescence Detection of DNA Methyltransferase Activity. ACS APPLIED MATERIALS & INTERFACES 2017; 9:40087-40093. [PMID: 29111659 DOI: 10.1021/acsami.7b13551] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
As a potential detection technique, highly rigid and versatile functionality of DNA tetrahedron nanostructures is often used in biosensing systems. In this work, a novel multifunctional nanostructure has been developed as an "off-on" fluorescent probe for detection of target methyltransferase by integrating the elements of DNA tetrahedron, target recognition, and dual-labeled reporter. This sensing system is initially in an "OFF" state owing to the close proximity of fluorophores and quenchers. After the substrate is recognized by target methyltransferase, the DNA tetrahedron can be methylated to produce methylated DNA sites. These sites can be recognized and cut by the restriction endonuclease DpnI to bring about the collapse of the DNA tetrahedron, which leads to the separation of the dual-labeled reporters from the quenchers, and thus the recovery of fluorescence signal to produce an "ON" state. The proposed DNA tetrahedron-based sensing method can detect Dam methyltransferase in the range of 0.1-90 U mL-1 with a detection limit of 0.045 U mL-1 and shows good specificity and reproducibility for detection of Dam methyltransferase in a real sample. It has been successfully applied for screening various methylation inhibitors. Thus, this work possesses a promising prospect for detection of DNA methyltransfrase in the field of clinical diagnostics.
Collapse
Affiliation(s)
- Xiaoyan Zhou
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University , Chongqing 400016, China
- Department of Clinical Laboratory, The Affiliated Hospital of Medical College, Qingdao University , Qingdao 266101, China
| | - Min Zhao
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University , Chongqing 400016, China
| | - Xiaolei Duan
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University , Chongqing 400016, China
| | - Bin Guo
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University , Chongqing 400016, China
| | - Wei Cheng
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University , Chongqing 400016, China
| | - Shijia Ding
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University , Chongqing 400016, China
| | - Huangxian Ju
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University , Chongqing 400016, China
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University , Nanjing 210023, China
| |
Collapse
|
|
32
|
Boeckx N, Janssens K, Van Camp G, Rasschaert M, Papadimitriou K, Peeters M, Op de Beeck K. The predictive value of primary tumor location in patients with metastatic colorectal cancer: A systematic review. Crit Rev Oncol Hematol 2017; 121:1-10. [PMID: 29279095 DOI: 10.1016/j.critrevonc.2017.11.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 09/22/2017] [Accepted: 11/06/2017] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most frequently diagnosed cancers worldwide. It has been reported that left- and right-sided CRC harbor varying disease characteristics, which leads to a difference in prognosis and response to therapy. Recently, there have been retrospective studies about tumor location in metastatic CRC (mCRC) and its potential to predict the effect of anti-vascular endothelial growth factor and anti-epidermal growth factor receptor (anti-EGFR) therapies. In this review, we provide a comprehensive overview of the latest trials studying the predictive value of primary tumor location in mCRC and discuss biomarkers that might be associated with the differences in treatment response. Although data need to be interpreted with caution due to the absence of randomized trials stratified based on tumor location, patients with left-sided CRC seem to benefit more from anti-EGFR therapy than patients with right-sided CRC. Further clinical trials, stratified for tumor location, are warranted.
Collapse
Affiliation(s)
- Nele Boeckx
- Center of Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium; Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43/6, 2650 Edegem, Belgium.
| | - Katleen Janssens
- Center of Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
| | - Guy Van Camp
- Center of Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium; Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43/6, 2650 Edegem, Belgium.
| | - Marika Rasschaert
- Department of Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium.
| | | | - Marc Peeters
- Center of Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium; Department of Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium.
| | - Ken Op de Beeck
- Center of Oncological Research (CORE), University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium; Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43/6, 2650 Edegem, Belgium.
| |
Collapse
|
|
33
|
Puccini A, Berger MD, Naseem M, Tokunaga R, Battaglin F, Cao S, Hanna DL, McSkane M, Soni S, Zhang W, Lenz HJ. Colorectal cancer: epigenetic alterations and their clinical implications. Biochim Biophys Acta Rev Cancer 2017; 1868:439-448. [PMID: 28939182 DOI: 10.1016/j.bbcan.2017.09.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 09/16/2017] [Accepted: 09/17/2017] [Indexed: 12/20/2022]
Abstract
Colorectal cancer (CRC) is a heterogeneous disease with distinct molecular and clinical features, which reflects the wide range of prognostic outcomes and treatment responses observed among CRC patients worldwide. Our understanding of the CRC epigenome has been largely developed over the last decade and it is now believed that among thousands of epigenetic alterations present in each tumor, a small subgroup of these may be considered as a CRC driver event. DNA methylation profiles have been the most widely studied in CRC, which includes a subset of patients with distinct molecular and clinical features now categorized as CpG island methylator phenotype (CIMP). Major advances have been made in our capacity to detect epigenetic alterations, providing us with new potential biomarkers for diagnostic, prognostic and therapeutic purposes. This review aims to summarize our current knowledge about epigenetic alterations occurring in CRC, underlying their potential future clinical implications in terms of diagnosis, prognosis and therapeutic strategies for CRC patients.
Collapse
Affiliation(s)
- Alberto Puccini
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Martin D Berger
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Madiha Naseem
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Ryuma Tokunaga
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Shu Cao
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Diana L Hanna
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Michelle McSkane
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Shivani Soni
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
| |
Collapse
|
|
34
|
Cohen SA, Yu M, Baker K, Redman M, Wu C, Heinzerling TJ, Wirtz RM, Charalambous E, Pentheroudakis G, Kotoula V, Kalogeras KT, Fountzilas G, Grady WM. The CpG island methylator phenotype is concordant between primary colorectal carcinoma and matched distant metastases. Clin Epigenetics 2017; 9:46. [PMID: 28469732 PMCID: PMC5414304 DOI: 10.1186/s13148-017-0347-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 04/21/2017] [Indexed: 12/13/2022] Open
Abstract
Background The CpG island methylator phenotype (CIMP) in stage III colon cancer (CRC) has been associated with improved survival after treatment with adjuvant irinotecan-based chemotherapy. In this analysis, we determine whether CIMP status in the primary CRC is concordant with the CIMP status of matched metastases in order to determine if assessment of CIMP status in the primary tumor can be used to predict CIMP status of metastatic disease, which is relevant for patient management as well as for understanding the biology of CIMP CRCs. Methods We assessed the CIMP status of 70 pairs of primary CRC and matched metastases using a CRC-specific panel of five markers (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1) where CIMP positive was defined as 3/5 positive markers at a percent methylated reference threshold of ≥10%. Concordance was compared using the Fisher’s exact test and P < 0.05 was considered significant. Results Sixty-nine of the pairs (98.6%) showed concordant CIMP status in the primary tumor and matched metastasis; five (7.0%) of the pairs were concordantly CIMP positive. Only one pair (1.4%) had divergent CIMP status, demonstrating CIMP positivity (4/5 markers positive) in the primary tumor, while the matched metastasis was CIMP negative (0 markers positive). Conclusions CIMP status is generally concordant between primary CRCs and matched metastases. Thus, CIMP status in the primary tumor is maintained in matched metastases and can be used to inform CIMP-based therapy options for the metastases. Electronic supplementary material The online version of this article (doi:10.1186/s13148-017-0347-1) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Stacey A Cohen
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA.,Division of Oncology, University of Washington, Seattle, WA USA.,825 Eastlake Ave E, G4-830, Seattle, WA 98109 USA
| | - Ming Yu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA.,1100 Fairview Ave N, D4-100, Seattle, WA 98109 USA
| | - Kelsey Baker
- Clinical Statistics, Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA USA.,1100 Fairview Ave N, M2-B230, Seattle, WA 98109 USA
| | - Mary Redman
- Clinical Statistics, Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA USA.,1100 Fairview Ave N, M2-B230, Seattle, WA 98109 USA
| | - Chen Wu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA.,College of Life Sciences, Hebei University, Baoding, Hebei People's Republic of China.,1100 Fairview Ave N, D4-100, Seattle, WA 98109 USA
| | - Tai J Heinzerling
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA.,1100 Fairview Ave N, D4-100, Seattle, WA 98109 USA
| | - Ralph M Wirtz
- STRATIFYER Molecular Pathology GmbH, Cologne, Germany.,Werthmann Str. Str. 1c, D-50935 Cologne, Germany
| | - Elpida Charalambous
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.,University Campus, Building 17B, 540 06 Thessaloniki, Greece
| | - George Pentheroudakis
- Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece.,Niarchos Av, Ioannina, 455 00 Greece
| | - Vassiliki Kotoula
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.,Department of Pathology, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.,University Campus, Building 17B, 540 06 Thessaloniki, Greece
| | - Konstantine T Kalogeras
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.,Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece.,18 Hatzikonstanti Str, 115 24 Athens, Greece
| | - George Fountzilas
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.,Aristotle University of Thessaloniki, Thessaloniki, Greece.,30 Kapetan Kotta Str, 552 36 Panorama, Thessaloniki Greece
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109 USA.,Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA USA.,1100 Fairview Ave N, D4-100, Seattle, WA 98109 USA
| |
Collapse
|
|
35
|
Distinct clinical outcomes of two CIMP-positive colorectal cancer subtypes based on a revised CIMP classification system. Br J Cancer 2017; 116:1012-1020. [PMID: 28278514 PMCID: PMC5396110 DOI: 10.1038/bjc.2017.52] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 02/06/2017] [Accepted: 02/08/2017] [Indexed: 12/22/2022] Open
Abstract
Background: Colorectal cancer (CRC) is a heterogeneous disease in terms of molecular carcinogenic pathways. Based on recent findings regarding the multiple serrated neoplasia pathway, we revised an eight-marker panel for a new CIMP classification system. Methods: 1370 patients who received surgical resection for CRCs were classified into three CIMP subtypes (CIMP-N: 0–4 methylated markers, CIMP-P1: 5–6 methylated markers and CIMP-P2: 7–8 methylated markers). Our findings were validated in a separate set of high-risk stage II or stage III CRCs receiving adjuvant fluoropyrimidine plus oxaliplatin (n=950). Results: A total of 1287/62/21 CRCs cases were classified as CIMP-N/CIMP-P1/CIMP-P2, respectively. CIMP-N showed male predominance, distal location, lower T, N category and devoid of BRAF mutation, microsatellite instability (MSI) and MLH1 methylation. CIMP-P1 showed female predominance, proximal location, advanced TNM stage, mild decrease of CK20 and CDX2 expression, mild increase of CK7 expression, BRAF mutation, MSI and MLH1 methylation. CIMP-P2 showed older age, female predominance, proximal location, advanced T category, markedly reduced CK20 and CDX2 expression, rare KRAS mutation, high frequency of CK7 expression, BRAF mutation, MSI and MLH1 methylation. CIMP-N showed better 5-year cancer-specific survival (CSS; HR=0.47; 95% CI: 0.28–0.78) in discovery set and better 5-year relapse-free survival (RFS; HR=0.50; 95% CI: 0.29–0.88) in validation set compared with CIMP-P1. CIMP-P2 showed marginally better 5-year CSS (HR=0.28, 95% CI: 0.07–1.22) in discovery set and marginally better 5-year RFS (HR=0.21, 95% CI: 0.05–0.92) in validation set compared with CIMP-P1. Conclusions: CIMP subtypes classified using our revised system showed different clinical outcomes, demonstrating the heterogeneity of multiple serrated precursors of CIMP-positive CRCs.
Collapse
|
|
36
|
Herbst A, Vdovin N, Gacesa S, Ofner A, Philipp A, Nagel D, Holdt LM, Op den Winkel M, Heinemann V, Stieber P, Graeven U, Reinacher-Schick A, Arnold D, Ricard I, Mansmann U, Hegewisch-Becker S, Kolligs FT. Methylated free-circulating HPP1 DNA is an early response marker in patients with metastatic colorectal cancer. Int J Cancer 2017; 140:2134-2144. [PMID: 28124380 DOI: 10.1002/ijc.30625] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 12/14/2016] [Accepted: 12/22/2016] [Indexed: 01/06/2023]
Abstract
Detection of methylated free-circulating DNA (mfcDNA) for hyperplastic polyposis 1 (HPP1) in blood is correlated with a poor prognosis for patients with metastatic colorectal cancers (mCRC). Here, we analyzed the plasma levels of HPP1 mfcDNA in mCRC patients treated with a combination therapy containing a fluoropyrimidine, oxaliplatin and bevacizumab to test whether HPP1 mfcDNA is a suitable prognostic and response biomarker. From 467 patients of the prospective clinical study AIO-KRK-0207, mfcDNA was isolated from plasma samples at different time points and bisulfite-treated mfcDNA was quantified using methylation specific PCR. About 337 of 467 patients had detectable levels for HPP1 mfcDNA before start of treatment. The detection was significantly correlated with poorer overall survival (OS) (HR = 1.86; 95%CI 1.37-2.53). About 2-3 weeks after the first administration of combination chemotherapy, HPP1 mfcDNA was reduced to non-detectable levels in 167 of 337 patients. These patients showed a better OS compared with patients with continued detection of HPP1 mfcDNA (HR HPP1(sample 1: pos/ sample 2: neg) vs. HPP1(neg/neg) = 1.41; 95%CI 1.00-2.01, HPP1(neg,pos/pos) vs. HPP1(neg/neg) = 2.60; 95%CI 1.86-3.64). Receiver operating characteristic analysis demonstrated that HPP1 mfcDNA discriminates well between patients who do (not) respond to therapy according to the radiological staging after 12 or 24 weeks (AUC = 0.77 or 0.71, respectively). Detection of HPP1 mfcDNA can be used as a prognostic marker and an early marker for response (as early as 3-4 weeks after start of treatment compared with radiological staging after 12 or 24 weeks) to identify patients who will likely benefit from a combination chemotherapy with bevacizumab.
Collapse
Affiliation(s)
- Andreas Herbst
- Department of Medicine II, University of Munich, Munich, Germany.,Institute of Laboratory Medicine, University of Munich, Munich, Germany
| | - Nikolay Vdovin
- Department of Medicine II, University of Munich, Munich, Germany
| | - Sanja Gacesa
- Institute for Medical Informatics, Biometry and Epidemiology, University of Munich, Munich, Germany
| | - Andrea Ofner
- Department of Medicine II, University of Munich, Munich, Germany
| | | | - Dorothea Nagel
- Institute of Laboratory Medicine, University of Munich, Munich, Germany
| | - Lesca M Holdt
- Institute of Laboratory Medicine, University of Munich, Munich, Germany
| | | | - Volker Heinemann
- Department of Medicine III and The Comprehensive Cancer Center, University of Munich, Munich, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Petra Stieber
- Institute of Laboratory Medicine, University of Munich, Munich, Germany
| | - Ullrich Graeven
- Medizinische Klinik I, Kliniken Maria-Hilf GmbH, Mönchengladbach, Germany
| | - Anke Reinacher-Schick
- Department of Hematology and Oncology, Ruhr-University of Bochum, St. Josef Hospital, Bochum, Germany
| | - Dirk Arnold
- Instituto CUF de Oncologia (I.C.O.), Lisbon, Portugal
| | - Ingrid Ricard
- Institute for Medical Informatics, Biometry and Epidemiology, University of Munich, Munich, Germany
| | - Ulrich Mansmann
- Institute for Medical Informatics, Biometry and Epidemiology, University of Munich, Munich, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | | | - Frank T Kolligs
- Department of Medicine II, University of Munich, Munich, Germany.,German Cancer Consortium (DKTK), Heidelberg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany.,HELIOS Klinikum Berlin-Buch, Berlin, Germany
| |
Collapse
|
|
37
|
Abdelfatah E, Kerner Z, Nanda N, Ahuja N. Epigenetic therapy in gastrointestinal cancer: the right combination. Therap Adv Gastroenterol 2016; 9:560-79. [PMID: 27366224 PMCID: PMC4913338 DOI: 10.1177/1756283x16644247] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Epigenetics is a relatively recent field of molecular biology that has arisen over the past 25 years. Cancer is now understood to be a disease of widespread epigenetic dysregulation that interacts extensively with underlying genetic mutations. The development of drugs targeting these processes has rapidly progressed; with several drugs already FDA approved as first-line therapy in hematological malignancies. Gastrointestinal (GI) cancers possess high degrees of epigenetic dysregulation, exemplified by subtypes such as CpG island methylator phenotype (CIMP), and the potential benefit of epigenetic therapy in these cancers is evident. The application of epigenetic drugs in solid tumors, including GI cancers, is just emerging, with increased understanding of the cancer epigenome. In this review, we provide a brief overview of cancer epigenetics and the epigenetic targets of therapy including deoxyribonucleic acid (DNA) methylation, histone modifications, and chromatin remodeling. We discuss the epigenetic drugs currently in use, with a focus on DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and explain the pharmacokinetic and mechanistic challenges in their application. We present the strategies employed in incorporating these drugs into the treatment of GI cancers, and explain the concept of the cancer stem cell in epigenetic reprogramming and reversal of chemo resistance. We discuss the most promising combination strategies in GI cancers including: (1) epigenetic sensitization to radiotherapy, (2) epigenetic sensitization to cytotoxic chemotherapy, and (3) epigenetic immune modulation and priming for immune therapy. Finally, we present preclinical and clinical trial data employing these strategies thus far in various GI cancers including colorectal, esophageal, gastric, and pancreatic cancer.
Collapse
Affiliation(s)
- Eihab Abdelfatah
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Zachary Kerner
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nainika Nanda
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- West Virginia University School of Medicine, Morgantown, WV, USA
| | - Nita Ahuja
- Department of Surgery and Oncology, Johns Hopkins University, 1650 Orleans St. Room 342, Baltimore, MD 21231, USA
| |
Collapse
|
|
38
|
Cha Y, Kim KJ, Han SW, Rhee YY, Bae JM, Wen X, Cho NY, Lee DW, Lee KH, Kim TY, Oh DY, Im SA, Bang YJ, Jeong SY, Park KJ, Kang GH, Kim TY. Adverse prognostic impact of the CpG island methylator phenotype in metastatic colorectal cancer. Br J Cancer 2016; 115:164-71. [PMID: 27310704 PMCID: PMC4947699 DOI: 10.1038/bjc.2016.176] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Revised: 05/06/2016] [Accepted: 05/16/2016] [Indexed: 12/17/2022] Open
Abstract
Background: The association between the CpG island methylator phenotype (CIMP) and clinical outcomes in metastatic colorectal cancer remains unclear. We investigated the prognostic impact of CIMP in patients with metastatic colorectal cancer treated with systemic chemotherapy. Methods: Eight CIMP-specific promoters (CACNA1G, IGF2, NEUROG1, RUNX3, SOCS1, CDKN2A, CRABP1, and MLH1) were examined. The CIMP status was determined by the number of methylated promoters as high (⩾5), low (1–4), and negative (0). Results: A total of 153 patients were included (men/women, 103/50; median age, 61 years; range, 22–80 years). The CIMP status was negative/low/high in 77/ 69/7 patients, respectively. Overall survival (OS) was significantly different among the three CIMP groups, with median values of 35.7, 22.2, and 9.77 months for the negative, low, and high groups, respectively (P<0.001). For patients treated with fluoropyrimidine and oxaliplatin first-line chemotherapy (N=128), OS and progression-free survival (PFS) were significantly different among the three CIMP groups; the median OS was 37.9, 23.8, and 6.77 months for the negative, low, and high groups, respectively (P<0.001), while the median PFS was 9.97, 7.87, and 1.83 months, respectively (P=0.002). Response rates were marginally different among the three CIMP groups (53.4% vs 45.1% vs 16.7%, respectively; P=0.107). For patients treated with fluoropyrimidine and irinotecan second-line chemotherapy (N=86), only OS showed a difference according to the CIMP status, with median values of 20.4, 13.4, and 2.90 months for the negative, low, and high groups, respectively (P<0.001). Conclusions: The CIMP status is a negative prognostic factor for patients with metastatic colorectal cancer treated with chemotherapy.
Collapse
Affiliation(s)
- Yongjun Cha
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Kyung-Ju Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Sae-Won Han
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Ye Young Rhee
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Jeong Mo Bae
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Xianyu Wen
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Nam-Yun Cho
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Dae-Won Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Kyung-Hun Lee
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Tae-Yong Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea
| | - Do-Youn Oh
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Seock-Ah Im
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Yung-Jue Bang
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea
| | - Seung-Yong Jeong
- Department of Surgery, Seoul National University Hospital, Seoul, South Korea
| | - Kyu Joo Park
- Department of Surgery, Seoul National University Hospital, Seoul, South Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University College of Medicine, Seoul, South Korea
| | - Tae-You Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea.,Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.,Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, South Korea
| |
Collapse
|
|
39
|
Integrated genomic analysis of colorectal cancer progression reveals activation of EGFR through demethylation of the EREG promoter. Oncogene 2016; 35:6403-6415. [PMID: 27270421 PMCID: PMC5161754 DOI: 10.1038/onc.2016.170] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2015] [Revised: 02/26/2016] [Accepted: 04/12/2016] [Indexed: 12/15/2022]
Abstract
Key molecular drivers that underlie transformation of colonic epithelium into colorectal adenocarcinoma (CRC) are well described. However, the mechanisms through which clinically targeted pathways are activated during CRC progression have yet to be elucidated. Here, we used an integrative genomics approach to examine CRC progression. We used laser capture microdissection to isolate colonic crypt cells, differentiated surface epithelium, adenomas, carcinomas and metastases, and used gene expression profiling to identify pathways that were differentially expressed between the different cell types. We identified a number of potentially important transcriptional changes in developmental and oncogenic pathways, and noted a marked upregulation of EREG in primary and metastatic cancer cells. We confirmed this pattern of gene expression by in situ hybridization and observed staining consistent with autocrine expression in the tumor cells. Upregulation of EREG during the adenoma-carcinoma transition was associated with demethylation of two key sites within its promoter, and this was accompanied by an increase in the levels of epidermal growth factor receptor (EGFR) phosphorylation, as assessed by reverse-phase protein analysis. In CRC cell lines, we demonstrated that EREG demethylation led to its transcriptional upregulation, higher levels of EGFR phosphorylation, and sensitization to EGFR inhibitors. Low levels of EREG methylation in patients who received cetuximab as part of a phase II study were associated with high expression of the ligand and a favorable response to therapy. Conversely, high levels of promoter methylation and low levels of EREG expression were observed in tumors that progressed after treatment. We also noted an inverse correlation between EREG methylation and expression levels in several other cancers, including those of the head and neck, lung and bladder. Therefore, we propose that upregulation of EREG expression through promoter demethylation might be an important means of activating the EGFR pathway during the genesis of CRC and potentially other cancers.
Collapse
|
|
40
|
Zong L, Abe M, Ji J, Zhu WG, Yu D. Tracking the Correlation Between CpG Island Methylator Phenotype and Other Molecular Features and Clinicopathological Features in Human Colorectal Cancers: A Systematic Review and Meta-Analysis. Clin Transl Gastroenterol 2016; 7:e151. [PMID: 26963001 PMCID: PMC4822093 DOI: 10.1038/ctg.2016.14] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 01/21/2016] [Indexed: 01/08/2023] Open
Abstract
Objectives: The controversy of CpG island methylator phenotype (CIMP) in colorectal cancers (CRCs) persists, despite many studies that have been conducted on its correlation with molecular and clinicopathological features. To drive a more precise estimate of the strength of this postulated relationship, a meta-analysis was performed. Methods: A comprehensive search for studies reporting molecular and clinicopathological features of CRCs stratified by CIMP was performed within the PubMed, EMBASE, and Cochrane Library. CIMP was defined by either one of the three panels of gene-specific CIMP markers (Weisenberger panel, classic panel, or a mixture panel of the previous two) or the genome-wide DNA methylation profile. The associations of CIMP with outcome parameters were estimated using odds ratio (OR) or weighted mean difference (WMD) or hazard ratios (HRs) with 95% confidence interval (CI) for each study using a fixed effects or random effects model. Results: A total of 29 studies involving 9,393 CRC patients were included for analysis. We observed more BRAF mutations (OR 34.87; 95% CI, 22.49–54.06) and microsatellite instability (MSI) (OR 12.85 95% CI, 8.84–18.68) in CIMP-positive vs. -negative CRCs, whereas KRAS mutations were less frequent (OR 0.47; 95% CI, 0.30–0.75). Subgroup analysis showed that only the genome-wide methylation profile-defined CIMP subset encompassed all BRAF-mutated CRCs. As expected, CIMP-positive CRCs displayed significant associations with female (OR 0.64; 95% CI, 0.56–0.72), older age at diagnosis (WMD 2.77; 95% CI, 1.15–4.38), proximal location (OR 6.91; 95% CI, 5.17–9.23), mucinous histology (OR 3.81; 95% CI, 2.93–4.95), and poor differentiation (OR 4.22; 95% CI, 2.52–7.08). Although CIMP did not show a correlation with tumor stage (OR 1.10; 95% CI, 0.82–1.46), it was associated with shorter overall survival (HR 1.73; 95% CI, 1.27–2.37). Conclusions: The meta-analysis highlights that CIMP-positive CRCs take their own molecular feature, especially overlapping with BRAF mutations, and clinicopathological features and worse prognosis from CIMP-negative CRCs, suggesting CIMP could be used as an independent prognostic marker for CRCs.
Collapse
Affiliation(s)
- Liang Zong
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.,Department of Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.,Department of Gastrointestinal Surgery, Su Bei People's Hospital of Jiangsu Province, Yangzhou University, Yangzhou, China
| | - Masanobu Abe
- Division for Health Service Promotion, University of Tokyo Hospital, Tokyo, Japan
| | - Jiafu Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, China
| | - Wei-Guo Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China.,Peking-Tsinghua University Center for Life Sciences, Peking University, Beijing, China
| | - Duonan Yu
- Non-coding RNA Center, Yangzhou University, Yangzhou, China.,Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Disease, Yangzhou, China.,Institute of Comparative Medicine, Yangzhou University, Yangzhou, China.,Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou, China
| |
Collapse
|
|
41
|
Jia M, Gao X, Zhang Y, Hoffmeister M, Brenner H. Different definitions of CpG island methylator phenotype and outcomes of colorectal cancer: a systematic review. Clin Epigenetics 2016; 8:25. [PMID: 26941852 PMCID: PMC4776403 DOI: 10.1186/s13148-016-0191-8] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Accepted: 02/23/2016] [Indexed: 12/26/2022] Open
Abstract
Contradictory results were reported for the prognostic role of CpG island methylator phenotype (CIMP) among colorectal cancer (CRC) patients. Differences in the definitions of CIMP were the most common explanation for these discrepancies. The aim of this systematic review was to give an overview of the published studies on CRC prognosis according to the different definitions of CIMP. A systematic literature search was performed in MEDLINE and ISI Web of Science for articles published until 3 April 2015. Data extraction included information about the study population, the definition of CIMP, and investigated outcomes. Thirty-six studies were included in this systematic review. Among them, 30 studies reported the association of CIMP and CRC prognosis and 11 studies reported the association of CIMP with survival after CRC therapy. Overall, 16 different definitions of CIMP were identified. The majority of studies reported a poorer prognosis for patients with CIMP-positive (CIMP+)/CIMP-high (CIMP-H) CRC than with CIMP-negative (CIMP-)/CIMP-low (CIMP-L) CRC. Inconsistent results or varying effect strengths could not be explained by different CIMP definitions used. No consistent variation in response to specific therapies according to CIMP status was found. Comparative analyses of different CIMP panels in the same large study populations are needed to further clarify the role of CIMP definitions and to find out how methylation information can best be used to predict CRC prognosis and response to specific CRC therapies.
Collapse
Affiliation(s)
- Min Jia
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Xu Gao
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Yan Zhang
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany ; German Cancer Consortium (DKTK), Heidelberg, Germany
| |
Collapse
|
|
42
|
Savio AJ, Daftary D, Dicks E, Buchanan DD, Parfrey PS, Young JP, Weisenberger D, Green RC, Gallinger S, McLaughlin JR, Knight JA, Bapat B. Promoter methylation of ITF2, but not APC, is associated with microsatellite instability in two populations of colorectal cancer patients. BMC Cancer 2016; 16:113. [PMID: 26884349 PMCID: PMC4756469 DOI: 10.1186/s12885-016-2149-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Accepted: 02/08/2016] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Aberrant Wnt signaling activation occurs commonly in colorectal carcinogenesis, leading to upregulation of many target genes. APC (adenomatous polyposis coli) is an important component of the β-catenin destruction complex, which regulates Wnt signaling, and is often mutated in colorectal cancer (CRC). In addition to mutational events, epigenetic changes arise frequently in CRC, specifically, promoter hypermethylation which silences tumor suppressor genes. APC and the Wnt signaling target gene ITF2 (immunoglobulin transcription factor 2) incur hypermethylation in various cancers, however, methylation-dependent regulation of these genes in CRC has not been studied in large, well-characterized patient cohorts. The microsatellite instability (MSI) subtype of CRC, featuring DNA mismatch repair deficiency and often promoter hypermethylation of MutL homolog 1 (MLH1), has a favorable outcome and is characterized by different chemotherapeutic responses than microsatellite stable (MSS) tumors. Other epigenetic events distinguishing these subtypes have not yet been fully elucidated. METHODS Here, we quantify promoter methylation of ITF2 and APC by MethyLight in two case-case studies nested in population-based CRC cohorts from the Ontario Familial Colorectal Cancer Registry (n = 330) and the Newfoundland Familial Colorectal Cancer Registry (n = 102) comparing MSI status groups. RESULTS ITF2 and APC methylation are significantly associated with tumor versus normal state (both P < 1.0 × 10(-6)). ITF2 is methylated in 45.8% of MSI cases and 26.9% of MSS cases and is significantly associated with MSI in Ontario (P = 0.002) and Newfoundland (P = 0.005) as well as the MSI-associated feature of MLH1 promoter hypermethylation (P = 6.72 × 10(-4)). APC methylation, although tumor-specific, does not show a significant association with tumor subtype, age, gender, or stage, indicating it is a general tumor-specific CRC biomarker. CONCLUSIONS This study demonstrates, for the first time, MSI-associated ITF2 methylation, and further reveals the subtype-specific epigenetic events modulating Wnt signaling in CRC.
Collapse
Affiliation(s)
- Andrea J Savio
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
- Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
| | - Darshana Daftary
- Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
- Ontario Familial Colorectal Cancer Registry, Toronto, ON, Canada.
| | - Elizabeth Dicks
- Faculty of Medicine, Memorial University of Newfoundland, St John's, Newfoundland, Canada.
| | - Daniel D Buchanan
- Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Parkville, VIC, Australia.
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, Australia.
| | - Patrick S Parfrey
- Faculty of Medicine, Memorial University of Newfoundland, St John's, Newfoundland, Canada.
| | - Joanne P Young
- Department of Haematology and Oncology, The Queen Elizabeth Hospital, Woodville, South Australia, Australia.
| | - Daniel Weisenberger
- USC Epigenome Center, University of Southern California, Los Angeles, CA, USA.
| | - Roger C Green
- Faculty of Medicine, Memorial University of Newfoundland, St John's, Newfoundland, Canada.
| | - Steven Gallinger
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
- Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
- Ontario Familial Colorectal Cancer Registry, Toronto, ON, Canada.
- Department of Surgery, University of Toronto, Toronto, ON, Canada.
| | - John R McLaughlin
- Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
- Ontario Familial Colorectal Cancer Registry, Toronto, ON, Canada.
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
| | - Julia A Knight
- Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada.
| | - Bharati Bapat
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
- Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
- Department of Pathology, University Health Network, Toronto, ON, Canada.
| |
Collapse
|
|
43
|
Bejarano PA, Garcia-Buitrago MT, Berho M, Allende D. Biologic and molecular markers for staging colon carcinoma. COLORECTAL CANCER 2016. [DOI: 10.2217/crc.15.27] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Biomarkers in the field of pathology and oncology may allow for the detection of disease, assessment of prognosis or to predict response to certain therapy. Molecular abnormalities in colorectal cancer genesis may occur due to chromosome instability, microsatellite instability and DNA methylation (CpG island methylator phenotype). These alterations are associated in some cases to sporadic carcinomas whereas in others are seen in syndrome-related tumors and are the basis for the use of different biomarkers in the clinical setting. These may include mismatched repair gene/proteins, RAS, BRAF, PIK3CA, which help to determine tumor prognosis and predict response to certain drugs.
Collapse
Affiliation(s)
- Pablo A Bejarano
- Department of Pathology Cleveland Clinic Florida, 2900 Weston Road, Weston, FL 33331, USA
| | - Monica T Garcia-Buitrago
- Department of Pathology, University of Miami School of Medicine, 1611 NW 12 Ave. Holtz Bldg, Miami, FL 33136, USA
| | - Mariana Berho
- Department of Pathology Cleveland Clinic Florida, 2900 Weston Road, Weston, FL 33331, USA
| | - Daniela Allende
- Department of Pathology Cleveland Clinic, Cleveland, OH 9500 Euclid Avenue Cleveland, OH 44195, USA
| |
Collapse
|
|
44
|
Jesinghaus M, Pfarr N, Kloor M, Endris V, Tavernar L, Muckenhuber A, von Knebel Doeberitz M, Penzel R, Weichert W, Stenzinger A. Genetic heterogeneity in synchronous colorectal cancers impacts genotyping approaches and therapeutic strategies. Genes Chromosomes Cancer 2015; 55:268-77. [DOI: 10.1002/gcc.22330] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 10/21/2015] [Accepted: 10/21/2015] [Indexed: 12/23/2022] Open
Affiliation(s)
- Moritz Jesinghaus
- Institute of Pathology, Technical University Munich (TUM); Munich Germany
- Institute of Pathology, University Hospital Heidelberg; Heidelberg Germany
| | - Nicole Pfarr
- Institute of Pathology, Technical University Munich (TUM); Munich Germany
- Institute of Pathology, University Hospital Heidelberg; Heidelberg Germany
| | - Matthias Kloor
- Applied Tumor Biology; Institute of Pathology, University Hospital Heidelberg; Heidelberg Germany
| | - Volker Endris
- Institute of Pathology, University Hospital Heidelberg; Heidelberg Germany
| | - Luca Tavernar
- Institute of Pathology, University Hospital Heidelberg; Heidelberg Germany
| | | | | | - Roland Penzel
- Institute of Pathology, University Hospital Heidelberg; Heidelberg Germany
| | - Wilko Weichert
- Institute of Pathology, Technical University Munich (TUM); Munich Germany
- Institute of Pathology, University Hospital Heidelberg; Heidelberg Germany
- National Center for Tumor Diseases; Heidelberg Germany
- Member of the German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Albrecht Stenzinger
- Institute of Pathology, University Hospital Heidelberg; Heidelberg Germany
- National Center for Tumor Diseases; Heidelberg Germany
- National Center for Tumor Diseases, Heidelberg School of Oncology (NCT-HSO); Heidelberg Germany
| |
Collapse
|
|
45
|
Gallois C, Laurent-Puig P, Taieb J. Methylator phenotype in colorectal cancer: A prognostic factor or not? Crit Rev Oncol Hematol 2015; 99:74-80. [PMID: 26702883 DOI: 10.1016/j.critrevonc.2015.11.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Accepted: 11/04/2015] [Indexed: 12/18/2022] Open
Abstract
Colorectal cancer (CRC) is due to different types of genetic alterations that are translated into different phenotypes. Among them, CpG island methylator phenotype (CIMP+) is the most recently involved in carcinogenesis of some CRC. The malignant transformation in this case is mainly due to the transcriptional inactivation of tumor suppressor genes. CIMP+ are reported to be more frequently found in the elderly and in women. The tumors are more frequently located in the proximal part of the colon, BRAF mutated and are associated with microsatellite instability (MSI) phenotype. All sporadic MSI CRC belong to the methylator phenotype, however some non MSI CRC may also harbor a methylator phenotype. The prognostic value of CIMP is not well known. Most studies show a worse prognosis in CIMP+ CRC, and adjuvant treatments seem to be more efficient. We review here the current knowledge on prognostic and predictive values in CIMP+ CRC.
Collapse
Affiliation(s)
- C Gallois
- Georges Pompidou European Hospital, Department of Hepatogastroenterology and GI Oncology, Paris Descartes University, Paris, France
| | - P Laurent-Puig
- UMRS 1147 Paris Descartes University, Personalized medicine; Pharmacogenetic; Therapeutic optimization, Paris, France
| | - J Taieb
- Georges Pompidou European Hospital, Department of Hepatogastroenterology and GI Oncology, Paris Descartes University, Paris, France.
| |
Collapse
|
|
46
|
Kang KJ, Min BH, Ryu KJ, Kim KM, Chang DK, Kim JJ, Rhee JC, Kim YH. The role of the CpG island methylator phenotype on survival outcome in colon cancer. Gut Liver 2015; 9:202-7. [PMID: 25167802 PMCID: PMC4351027 DOI: 10.5009/gnl13352] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background/Aims CpG island methylator phenotype (CIMP)- high colorectal cancers (CRCs) have distinct clinicopathological features from their CIMP-low/negative CRC counterparts. However, controversy exists regarding the prognosis of CRC according to the CIMP status. Therefore, this study examined the prognosis of Korean patients with colon cancer according to the CIMP status. Methods Among a previous cohort population with CRC, a total of 154 patients with colon cancer who had available tissue for DNA extraction were included in the study. CIMP-high was defined as 3/5 methylated markers using the five-marker panel (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1). Results CIMP-high and CIMP-low/negative cancers were observed in 27 patients (17.5%) and 127 patients (82.5%), respectively. Multivariate analysis adjusting for age, gender, tumor location, tumor stage and CIMP and microsatellite instability (MSI) statuses indicated that CIMP-high colon cancers were associated with a significant increase in colon cancer-specific mortality (hazard ratio [HR], 3.23; 95% confidence interval [CI], 1.20 to 8.69; p=0.02). In microsatellite stable cancers, CIMP-high cancer had a poor survival outcome compared to CIMP-low/negative cancer (HR, 2.91; 95% CI, 1.02 to 8.27; p=0.04). Conclusions Regardless of the MSI status, CIMP-high cancers had poor survival outcomes in Korean patients.
Collapse
Affiliation(s)
- Ki Joo Kang
- Department of Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea
| | - Byung Hoon Min
- Departments of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyung Ju Ryu
- Departments of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Kyoung Mee Kim
- Departments of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dong Kyung Chang
- Departments of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae J Kim
- Departments of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong Chul Rhee
- Departments of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Ho Kim
- Departments of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| |
Collapse
|
|
47
|
Cohen SA, Wu C, Yu M, Gourgioti G, Wirtz R, Raptou G, Gkakou C, Kotoula V, Pentheroudakis G, Papaxoinis G, Karavasilis V, Pectasides D, Kalogeras KT, Fountzilas G, Grady WM. Evaluation of CpG Island Methylator Phenotype as a Biomarker in Colorectal Cancer Treated With Adjuvant Oxaliplatin. Clin Colorectal Cancer 2015; 15:164-9. [PMID: 26702772 DOI: 10.1016/j.clcc.2015.10.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 10/21/2015] [Indexed: 01/28/2023]
Abstract
BACKGROUND The CpG island methylator phenotype (CIMP) is a promising biomarker for irinotecan/5-fluorouracil/leucovorin chemotherapy for stage III colon cancer. In the present study, we evaluated whether CIMP is a prognostic biomarker for standard-of-care oxaliplatin-based adjuvant therapy. MATERIALS AND METHODS The HE6C/05 trial randomized 441 patients with stage II-III colorectal adenocarcinoma to adjuvant XELOX (capecitabine, oxaliplatin) or modified FOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin). The primary and secondary objectives were disease-free and overall survival, respectively. CIMP status was determined using the DNA methylation status of CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1. Cox models were used to assess the association of CIMP with survival. RESULTS Of the 293 available tumors, 28 (9.6%) were CIMP(+). On univariate Cox regression analysis, no significant differences in survival were observed between individuals with CIMP(+) versus CIMP(-) tumors. CIMP(+) tumors were more likely to be right-sided and BRAF mutant (χ(2), P < .001). In the multivariate model, TNM stage II (vs. stage III) was associated with a reduced risk of relapse (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.11-0.55; Wald's P < .001), and a colon primary located on the left side and earlier TNM stage were associated with a reduced risk of death (HR, 0.48; 95% CI, 0.28-0.81; P = .006; and HR, 0.22; 95% CI, 0.10-0.49; P < .001, respectively). CONCLUSION In the present exploratory analysis, CIMP did not appear to be a prognostic biomarker in oxaliplatin-treated patients with resected colorectal cancer.
Collapse
Affiliation(s)
- Stacey A Cohen
- Division of Oncology, University of Washington, Seattle, WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
| | - Chen Wu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; College of Life Sciences, Hebei University, Baoding, Hebei, People's Republic of China
| | - Ming Yu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Georgia Gourgioti
- Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece
| | - Ralph Wirtz
- Stratifyer Molecular Pathology GmbH, Cologne, Germany
| | - Georgia Raptou
- Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
| | - Chryssa Gkakou
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
| | - Vassiliki Kotoula
- Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
| | | | - George Papaxoinis
- Oncology Section, Second Department of Internal Medicine, "Hippokration" Hospital, Athens, Greece
| | - Vasilios Karavasilis
- Department of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
| | - Dimitrios Pectasides
- Oncology Section, Second Department of Internal Medicine, "Hippokration" Hospital, Athens, Greece
| | - Konstantine T Kalogeras
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece
| | - George Fountzilas
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Division of Gastroenterology, University of Washington, Seattle, WA
| |
Collapse
|
|
48
|
Cleven AHG, Derks S, Draht MXG, Smits KM, Melotte V, Van Neste L, Tournier B, Jooste V, Chapusot C, Weijenberg MP, Herman JG, de Bruïne AP, van Engeland M. CHFR promoter methylation indicates poor prognosis in stage II microsatellite stable colorectal cancer. Clin Cancer Res 2015; 20:3261-71. [PMID: 24928946 DOI: 10.1158/1078-0432.ccr-12-3734] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Data on the prognostic significance of promoter CpG island methylation in colorectal cancer (CRC) are conflicting, possibly due to associations between methylation and other factors affecting survival such as genetic alterations and use of adjuvant therapy. Here, we examine the prognostic impact of promoter methylation in patients with CRC treated with surgery alone in the context of microsatellite instability (MSI), BRAF and KRAS mutations. EXPERIMENTAL METHODS One hundred and seventy-three CRCs were analyzed for promoter methylation of 19 tumor suppressor and DNA repair genes, the CpG island methylator phenotype (CIMP), MSI, the exon 15 V600E BRAF mutation and KRAS codon 12 and 13 mutations. RESULTS Unsupervised hierarchical clustering based on methylation status of 19 genes revealed three subgroups: cluster 1 [CL1, 57% (98/173) of CRCs], cluster 2 [CL2, 25% (43/173) of CRCs], and cluster 3 [CL3, 18% (32/173) of CRCs]. CL3 had the highest methylation index (0.25, 0.49, and 0.69, respectively, P = <0.01) and was strongly associated with CIMP (P < 0.01). Subgroup analysis for tumor stage, MSI, and BRAF status showed no statistically significant differences in survival between CL1, CL2, and CL3 nor between CIMP and non-CIMP CRCs. Analyzing genes separately revealed that CHFR promoter methylation was associated with a poor prognosis in stage II, microsatellite stability (MSS), BRAF wild-type (WT) CRCs: multivariate Cox proportional HR = 3.89 [95% confidence interval (CI), 1.58-9.60, P < 0.01; n = 66] and HR = 2.11 (95% CI, 0.95-4.69, P = 0.068, n = 136) in a second independent population-based study. CONCLUSIONS CHFR promoter CpG island methylation, which is associated with MSI, also occurs frequently in MSS CRCs and is a promising prognostic marker in stage II, MSS, BRAF WT CRCs.
Collapse
Affiliation(s)
- Arjen H G Cleven
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Sarah Derks
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Muriel X G Draht
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kim M Smits
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, MarylandAuthors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Veerle Melotte
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Leander Van Neste
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Benjamin Tournier
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Valerie Jooste
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Caroline Chapusot
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Matty P Weijenberg
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - James G Herman
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Adriaan P de Bruïne
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Manon van Engeland
- Authors' Affiliations: Departments of Pathology, Radiation Oncology (MAASTRO) and Epidemiology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands; Service de Pathologie; Registre des cancers digestifs, Université de Bourgogne, Centre Hospitalier Universitaire de Dijon, Dijon, France; and The Sidney Kimmel Comprehensive Cancer Center at the Johns Hopkins University School of Medicine, Baltimore, Maryland
| |
Collapse
|
|
49
|
Okugawa Y, Grady WM, Goel A. Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers. Gastroenterology 2015; 149:1204-1225.e12. [PMID: 26216839 PMCID: PMC4589488 DOI: 10.1053/j.gastro.2015.07.011] [Citation(s) in RCA: 536] [Impact Index Per Article: 53.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 07/13/2015] [Accepted: 07/20/2015] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. One of the fundamental processes driving the initiation and progression of CRC is the accumulation of a variety of genetic and epigenetic changes in colonic epithelial cells. Over the past decade, major advances have been made in our understanding of cancer epigenetics, particularly regarding aberrant DNA methylation, microRNA (miRNA) and noncoding RNA deregulation, and alterations in histone modification states. Assessment of the colon cancer "epigenome" has revealed that virtually all CRCs have aberrantly methylated genes and altered miRNA expression. The average CRC methylome has hundreds to thousands of abnormally methylated genes and dozens of altered miRNAs. As with gene mutations in the cancer genome, a subset of these epigenetic alterations, called driver events, are presumed to have a functional role in CRC. In addition, the advances in our understanding of epigenetic alterations in CRC have led to these alterations being developed as clinical biomarkers for diagnostic, prognostic, and therapeutic applications. Progress in this field suggests that these epigenetic alterations will be commonly used in the near future to direct the prevention and treatment of CRC.
Collapse
Affiliation(s)
- Yoshinaga Okugawa
- Gastrointestinal Cancer Research Laboratory, Division of Gastroenterology, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, Texas
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Gastroenterology, University of Washington School of Medicine, Seattle, Washington.
| | - Ajay Goel
- Gastrointestinal Cancer Research Laboratory, Division of Gastroenterology, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
| |
Collapse
|
|
50
|
Puerta-García E, Cañadas-Garre M, Calleja-Hernández MÁ. Molecular biomarkers in colorectal carcinoma. Pharmacogenomics 2015; 16:1189-222. [PMID: 26237292 DOI: 10.2217/pgs.15.63] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer is a tumor with increasing incidence which represents one of the first leading causes of death worldwide. Gene alterations described for colorectal cancer include genome instability (microsatellite and chromosomal instability), CpG islands methylator phenotype, microRNA, histone modification, protein biomarkers, gene mutations (RAS, BRAF, PI3K, TP53, PTEN) and polymorphisms (APC, CTNNB1, DCC). In this article, biomarkers with prognostic value commonly found in colorectal cancer will be reviewed.
Collapse
Affiliation(s)
- Elena Puerta-García
- Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, 18014 Granada, Spain
| | - Marisa Cañadas-Garre
- Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, 18014 Granada, Spain
| | - Miguel Ángel Calleja-Hernández
- Pharmacogenetics Unit, UGC Provincial de Farmacia de Granada, Instituto de Investigación Biosanitaria de Granada, Complejo Hospitalario Universitario de Granada, Avda. Fuerzas Armadas, 2, 18014 Granada, Spain
| |
Collapse
|