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Wettergren Y, Rolny P, Lindegren H, Odin E, Rotter Sopasakis V, Keane S, Ejeskär K. Increased MLH1, MGMT, and p16INK4a methylation levels in colon mucosa potentially useful as early risk marker of colon cancer. Mol Cell Oncol 2025; 12:2503069. [PMID: 40357388 PMCID: PMC12068326 DOI: 10.1080/23723556.2025.2503069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/30/2025] [Accepted: 05/01/2025] [Indexed: 05/15/2025]
Abstract
The genes MutL Homolog 1 (MLH1), O6-methylguanine-DNA methyltransferase (MGMT), and cyclin-dependent kinase inhibitor p16INK4a are commonly downregulated by hypermethylation in colorectal cancer. Long interspersed nucleotide element 1 (LINE-1) can be used as marker for global hypomethylation. This study compared MLH1, MGMT, p16INK4a, and LINE-1 methylation with gene expression in colon tumors, matched non-cancerous mucosa, and control mucosa to identify signs of premalignancy. Tissues were obtained from 20 colon cancer patients and 40 controls. CpG site methylation was quantified by pyrosequencing, expression by qPCR, and MSI/KRAS status by fragment analysis and droplet digital PCR. MLH1, MGMT, and p16INK4a methylation was increasingly higher in control mucosa, non-cancerous mucosa, and tumors. MLH1 expression was lower in tumors compared to non-cancerous mucosa but higher compared to control mucosa. Tumoral LINE-1 methylation correlated negatively with MLH1 (r = -0.51, p = .021) and p16INK4a (r = -0.55, p = .012) methylation, but positively (r = 0.74, p = .0002) with MLH1 expression. A p16INK4a SNP (rs3814960 C>T) was associated with methylation, expression, and MSI/KRAS status. Aberrant methylation of tumor suppressor genes in colon mucosa could be an early cancer risk marker. Control mucosa is a more reliable reference than non-cancerous mucosa when identifying premalignant changes. Extended studies will evaluate the possible association between rs3814960 and cancer susceptibility. Trial registration: NCT03072641.
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Affiliation(s)
- Yvonne Wettergren
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Peter Rolny
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Medicine, Division of Gastroenterology and Hepatology, Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
| | - Helena Lindegren
- Department of Medicine, Division of Gastroenterology and Hepatology, Region Västra Götaland, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden
| | - Elisabeth Odin
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Victoria Rotter Sopasakis
- Department of Clinical Chemistry, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Simon Keane
- Translational Medicine, School of Health Sciences, University of Skövde, Skövde, Sweden
| | - Katarina Ejeskär
- Translational Medicine, School of Health Sciences, University of Skövde, Skövde, Sweden
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Lønning PE, Nikolaienko O, Knappskog S. Constitutional Epimutations: From Rare Events Toward Major Cancer Risk Factors? JCO Precis Oncol 2025; 9:e2400746. [PMID: 40179326 PMCID: PMC11995855 DOI: 10.1200/po-24-00746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 01/09/2025] [Accepted: 01/14/2025] [Indexed: 04/05/2025] Open
Abstract
Constitutional epimutations are epigenetic aberrations that arise in normal cells prenatally. Two major forms exist: secondary constitutional epimutations (SCEs), associated with cis-acting genetic aberrations, and primary constitutional epimutations (PCEs), for which no associated genetic aberrations were identified. Some SCEs have been associated with risk of cancer (MLH1 and MSH2 with colon or endometrial cancers, BRCA1 with familial breast and ovarian cancers), although such epimutations are rare, with a total of <100 cases reported. This contrasts recent findings for PCE, where low-level mosaic BRCA1 epimutations are recorded in 5%-10% of healthy females across all age groups, including newborns. BRCA1 PCEs predict an elevated risk of high-grade serous ovarian cancer and triple-negative breast cancer (TNBC) and are estimated to account for about 20% of all TNBCs. A similarly high population frequency is observed for mosaic constitutional epimutations in MGMT, occurring as PCE or SCE, but not in MLH1. Contrasting BRCA1 and MLH1, a potential association with cancer risk for MGMT epimutations is yet unclear. In this review, we provide a summary of findings linking constitutional epimutations to cancer risk with emphasis on PCE. We also highlight challenges in detection of PCE exemplified by low-level mosaic epimutations in BRCA1 and indicate the need for further studies, hypothesizing that improved knowledge about PCE may add significantly to our understanding of cancer risk, carcinogenesis, and potentially development of other diseases as well.
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Affiliation(s)
| | - Oleksii Nikolaienko
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Stian Knappskog
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
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Nikolaienko O, Anderson GL, Chlebowski RT, Jung SY, Harris HR, Knappskog S, Lønning PE. MGMT epimutations and risk of incident cancer of the colon, glioblastoma multiforme, and diffuse large B cell lymphomas. Clin Epigenetics 2025; 17:28. [PMID: 39980037 PMCID: PMC11841191 DOI: 10.1186/s13148-025-01835-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 02/06/2025] [Indexed: 02/22/2025] Open
Abstract
BACKGROUND Constitutional BRCA1 epimutations (promoter hypermethylation) are associated with an elevated risk of triple-negative breast cancer and high-grade serous ovarian cancer. While MGMT epimutations are frequent in colon cancer, glioblastoma, and B-cell lymphoma, it remains unknown whether constitutional MGMT epimutations are associated with risk of any of these malignancies. METHODS We designed a nested case-control study, assessing potential associations between MGMT epimutations in blood from healthy individuals and subsequent risk of incident cancer. The study cohort was drawn from postmenopausal women, participating in the Women's Health Initiative (WHI) study, who had not been diagnosed with either colon cancer, glioblastoma, or B-cell lymphoma prior to study entry. The protocol included n = 400 women developing incident left-sided and n = 400 women developing right-sided colon cancer, n = 400 women developing diffuse large B-cell lymphomas, all matched on a 1:2 basis with cancer-free controls, and n = 195 women developing incident glioblastoma multiforme, matched on a 1:4 basis. All cancers were confirmed in centralized medical record review. Blood samples, collected at entry, were analyzed for MGMT epimutations by massive parallel sequencing. Associations between MGMT methylation and incident cancers were analyzed by Cox proportional hazards regression. RESULTS Analyzing epimutations affecting the key regulatory area of the MGMT promoter, the hazard ratio (HR) was 1.07 (95% CI 0.79-1.45) and 0.80 (0.59-1.08) for right- and left-sided colon cancer, respectively, 1.13 (0.78-1.64) for glioblastoma, and 1.11 (0.83-1.48) for diffuse large B-cell lymphomas. Sensitivity analyses limited to subregions of the MGMT promoter and to individuals with different genotypes of a functional SNP in the MGMT promoter (rs16906252), revealed no significant effect on HR for any of the cancer forms. Neither did we observe any effect of rs16906252 status on HR for any of the cancer forms among individuals methylated or non-methylated at the MGMT promoter. CONCLUSIONS Constitutional MGMT promoter methylation in normal tissue is not associated with an increased risk of developing colon cancer, glioblastoma, or B-cell lymphoma.
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Affiliation(s)
- Oleksii Nikolaienko
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Garnet L Anderson
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, USA
| | | | - Su Yon Jung
- Department of Epidemiology, Fielding School of Public Health, Translational Sciences Section, Jonsson Comprehensive Cancer Center, School of Nursing, University of California, Los Angeles, USA
| | - Holly R Harris
- Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, USA
| | - Stian Knappskog
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Per E Lønning
- Department of Oncology, Haukeland University Hospital, Bergen, Norway.
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Kalra A, Meltzer SJ. The Role of DNA Methylation in Gastrointestinal Disease: An Expanded Review of Malignant and Nonmalignant Gastrointestinal Diseases. Gastroenterology 2025; 168:245-266. [PMID: 38971197 PMCID: PMC11698954 DOI: 10.1053/j.gastro.2024.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 06/20/2024] [Accepted: 07/01/2024] [Indexed: 07/08/2024]
Abstract
Esophageal, colorectal, pancreatic, hepatocellular, and gastric cancer together impact millions of patients worldwide each year, with high overall mortality rates, and are increasing in incidence. Additionally, premalignant gastrointestinal diseases, such as Barrett's esophagus and inflammatory bowel disease, are also increasing in incidence. However, involvement of aberrant DNA methylation in these diseases is incompletely understood, especially given recent research advancements in this field. Here, we review knowledge of this epigenetic mechanism in gastrointestinal preneoplasia and neoplasia, considering mechanisms of action, genetic and environmental factors, and 5'-C-phosphate-G-3' island methylator phenotype. We also highlight developments in translational research, focusing on genomic-wide data, methylation-based biomarkers and diagnostic tests, machine learning, and therapeutic epigenetic strategies.
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Affiliation(s)
- Andrew Kalra
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Stephen J Meltzer
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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He Y, Wu S, Chen L, Chen W, Zhan X, Li J, Wang B, Gao C, Wu J, Wang Q, Li M, Liu B. Constructing and validating pan-apoptosis-related features for predicting prognosis and immunotherapy response in hepatocellular carcinoma. Biochem Biophys Res Commun 2024; 734:150633. [PMID: 39243678 DOI: 10.1016/j.bbrc.2024.150633] [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: 05/06/2024] [Revised: 07/25/2024] [Accepted: 08/29/2024] [Indexed: 09/09/2024]
Abstract
The study aimed to develop a prognostic model for Hepatocellular Carcinoma (HCC) based on pan-apoptosis-related genes, a novel inflammatory programmed cell death form intricately linked to HCC progression. Utilizing transcriptome sequencing and clinical data from the TCGA database, we identified six crucial pan-apoptosis-related genes through statistical analyses. These genes were then employed to construct a prognostic model that accurately predicts overall survival rates in HCC patients. Our findings revealed a strong correlation between the model's risk scores and tumor microenvironment (TME) status, immune cell infiltration, and immune checkpoint expression. Furthermore, we screened for drugs with potential therapeutic efficacy in high- and low-risk HCC groups. Notably, PPP2R5B gene knockdown was found to inhibit HCC cell proliferation and clonogenic capacity, suggesting its role in HCC progression. In conclusion, this study presents a novel pan-apoptosis gene-based prognostic risk model for HCC, providing valuable insights into patient TME status and guiding the selection of targeted therapies and immunotherapies.
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Affiliation(s)
- Yuhong He
- Laboratory of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China; Hepatobiliary Related Diseases Key Laboratory of Zhanjiang, Zhanjiang, 524001, Guangdong, China.
| | - Shihao Wu
- Laboratory of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China; Hepatobiliary Related Diseases Key Laboratory of Zhanjiang, Zhanjiang, 524001, Guangdong, China.
| | - Lifan Chen
- Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China.
| | - Wenxia Chen
- Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China.
| | - Xiumei Zhan
- Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China.
| | - Jiaxing Li
- Laboratory of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China; Hepatobiliary Related Diseases Key Laboratory of Zhanjiang, Zhanjiang, 524001, Guangdong, China.
| | - Bingyuan Wang
- Laboratory of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China; Hepatobiliary Related Diseases Key Laboratory of Zhanjiang, Zhanjiang, 524001, Guangdong, China.
| | - Chenfeng Gao
- Laboratory of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China; Hepatobiliary Related Diseases Key Laboratory of Zhanjiang, Zhanjiang, 524001, Guangdong, China.
| | - Jiayuan Wu
- Clinical Research Service Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China.
| | - Qingwei Wang
- Laboratory of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China; Hepatobiliary Related Diseases Key Laboratory of Zhanjiang, Zhanjiang, 524001, Guangdong, China.
| | - Mingyi Li
- Laboratory of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China; Hepatobiliary Related Diseases Key Laboratory of Zhanjiang, Zhanjiang, 524001, Guangdong, China.
| | - Bin Liu
- Laboratory of Hepatobiliary Surgery, The Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong, China; Hepatobiliary Related Diseases Key Laboratory of Zhanjiang, Zhanjiang, 524001, Guangdong, China.
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Jiang J, Xu J, Ji S, Yu X, Chen J. Unraveling the mysteries of MGMT: Implications for neuroendocrine tumors. Biochim Biophys Acta Rev Cancer 2024; 1879:189184. [PMID: 39303858 DOI: 10.1016/j.bbcan.2024.189184] [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: 01/28/2024] [Revised: 07/15/2024] [Accepted: 09/16/2024] [Indexed: 09/22/2024]
Abstract
Neuroendocrine tumors (NETs) are a diverse group of tumors that arise from neuroendocrine cells and are commonly found in various organs. A considerable proportion of NET patients were diagnosed at an advanced or metastatic stage. Alkylating agents are the primary treatment for NET, and O6-methylguanine methyltransferase (MGMT) remains the first-line of defense against DNA damage caused by these agents. Clinical trials have indicated that MGMT promoter methylation or its low/lacked expression can predict a favorable outcome with Temozolomide in NETs. Its status could help select NET patients who can benefit from alkylating agents. Therefore, MGMT status serves as a biomarker to guide decisions on the efficacy of Temozolomide as a personalized treatment option. Additionally, delving into the regulatory mechanisms of MGMT status can lead to the development of MGMT-targeted therapies, benefiting individuals with high levels of MGMT expression. This review aims to explore the polymorphism of MGMT regulation and summarize its clinical implications in NETs, which would help establish the role of MGMT as a biomarker and its potential as a therapeutic target in NETs. Additionally, we explore the benefits of combining Temozolomide and immunotherapy in MGMT hypermethylated subgroups. Future studies can focus on optimizing Temozolomide administration to induce specific immunomodulatory changes.
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Affiliation(s)
- Jianyun Jiang
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
| | - Junfeng Xu
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Shunrong Ji
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Xianjun Yu
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Shanghai Pancreatic Cancer Institute, Shanghai 200032, China; Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China.
| | - Jie Chen
- Center for Neuroendocrine Tumors, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
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Wang Y, Liu H, Zhang M, Xu J, Zheng L, Liu P, Chen J, Liu H, Chen C. Epigenetic reprogramming in gastrointestinal cancer: biology and translational perspectives. MedComm (Beijing) 2024; 5:e670. [PMID: 39184862 PMCID: PMC11344282 DOI: 10.1002/mco2.670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 07/03/2024] [Accepted: 07/08/2024] [Indexed: 08/27/2024] Open
Abstract
Gastrointestinal tumors, the second leading cause of human mortality, are characterized by their association with inflammation. Currently, progress in the early diagnosis and effective treatment of gastrointestinal tumors is limited. Recent whole-genome analyses have underscored their profound heterogeneity and extensive genetic and epigenetic reprogramming. Epigenetic reprogramming pertains to dynamic and hereditable alterations in epigenetic patterns, devoid of concurrent modifications in the underlying DNA sequence. Common epigenetic modifications encompass DNA methylation, histone modifications, noncoding RNA, RNA modifications, and chromatin remodeling. These modifications possess the potential to invoke or suppress a multitude of genes associated with cancer, thereby governing the establishment of chromatin configurations characterized by diverse levels of accessibility. This intricate interplay assumes a pivotal and indispensable role in governing the commencement and advancement of gastrointestinal cancer. This article focuses on the impact of epigenetic reprogramming in the initiation and progression of gastric cancer, esophageal cancer, and colorectal cancer, as well as other uncommon gastrointestinal tumors. We elucidate the epigenetic landscape of gastrointestinal tumors, encompassing DNA methylation, histone modifications, chromatin remodeling, and their interrelationships. Besides, this review summarizes the potential diagnostic, therapeutic, and prognostic targets in epigenetic reprogramming, with the aim of assisting clinical treatment strategies.
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Affiliation(s)
- Yingjie Wang
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Hongyu Liu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Mengsha Zhang
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Jing Xu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Liuxian Zheng
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Pengpeng Liu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Jingyao Chen
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Hongyu Liu
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
| | - Chong Chen
- State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduSichuanChina
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Ghimire B, Kurlberg G, Falk P, Singh Y, Wettergren Y. Epigenetic differences in the tumor suppressor genes MLH1 and p16INK4a between Nepalese and Swedish patients with colorectal cancer. Innov Surg Sci 2024; 9:153-163. [PMID: 39309195 PMCID: PMC11416036 DOI: 10.1515/iss-2023-0039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 06/02/2024] [Indexed: 09/25/2024] Open
Abstract
Objectives Colorectal cancer (CRC) is one of the most prevalent cancer types worldwide, exhibiting significant variance in incidence rates across different ethnicities and geographical regions. Notably, there is a rising incidence of CRC among younger adults, particularly evident in advanced stages, with a more pronounced trend observed in developing nations. Epigenetic alterations potentially play a role in the early onset of CRC and could elucidate interpopulation disparities. This study aimed to examine DNA methylation levels in the tumor suppressor genes MLH1 and p16INK4a, comparing Nepalese and Swedish patients with CRC. Methods Patients who underwent CRC surgery at Tribhuvan University Teaching Hospital, Nepal (n=39), and Sahlgrenska University Hospital, Sweden (n=39) were included. Demographic and clinicopathological data were analyzed, and pyrosequencing was employed to determine methylation levels in the MLH1 promoter region and the first exon of p16INK4a in tumor tissues and adjacent mucosa located 10 cm from the tumor site. Subsequently, methylation status was compared between Nepalese and Swedish patients and correlated with clinicopathological parameters. Results Nepalese and Swedish patients displayed equal levels of MLH1 and p16INK4a methylation in tumors, but Nepalese patients exhibited a significantly higher level of MLH1 methylation in mucosa compared to Swedish patients (p=0.0008). Moreover, a greater proportion of Nepalese patients showed MLH1 methylation in mucosa compared to Swedish patients (31 vs. 2.6 %). Aberrant methylation of p16INK4a was also observed in the mucosa of Nepalese patients, characterized by high methylation at specific sites rather than uniform methylation across CpG sites. There were no significant differences in methylation levels based on tumor location among Nepalese patients, whereas Swedish patients exhibited higher methylation in right- compared to left-sided colon tumors. Swedish patients showed an increase in p16INK4a methylation in tumors with advancing age. Conclusions Nepalese and Swedish patients displayed equal levels of MLH1 and p16INK4a methylation in tumors. In contrast, Nepalese patients had a higher level of MLH1 methylation as well as aberrant methylation of p16INK4a in mucosa compared to Swedish patients. These epigenetic differences may be linked to environmental and lifestyle factors. Ongoing research will further explore whether hypermethylation in the mucosa of Nepalese patients is associated with tumorigenesis and its potential utility in screening high-risk patients or predicting recurrence.
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Affiliation(s)
- Bikal Ghimire
- Department of GI and General Surgery, Maharajgung Medical Campus, Institute of Medicine, Tribhuvan University, Kathmandu, Nepal
| | - Göran Kurlberg
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Peter Falk
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Yogendra Singh
- Department of GI and General Surgery, Maharajgung Medical Campus, Institute of Medicine, Tribhuvan University, Kathmandu, Nepal
| | - Yvonne Wettergren
- Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Surgery, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden
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Jeddi F, Faghfuri E, Mehranfar S, Soozangar N. The common bisulfite-conversion-based techniques to analyze DNA methylation in human cancers. Cancer Cell Int 2024; 24:240. [PMID: 38982390 PMCID: PMC11234524 DOI: 10.1186/s12935-024-03405-2] [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: 01/29/2024] [Accepted: 06/11/2024] [Indexed: 07/11/2024] Open
Abstract
DNA methylation is an important molecular modification that plays a key role in the expression of cancer genes. Evaluation of epigenetic changes, hypomethylation and hypermethylation, in specific genes are applied for cancer diagnosis. Numerous studies have concentrated on describing DNA methylation patterns as biomarkers for cancer diagnosis monitoring and predicting response to cancer therapy. Various techniques for detecting DNA methylation status in cancers are based on sodium bisulfite treatment. According to the application of these methods in research and clinical studies, they have a number of advantages and disadvantages. The current review highlights sodium bisulfite treatment-based techniques, as well as, the advantages, drawbacks, and applications of these methods in the evaluation of human cancers.
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Affiliation(s)
- Farhad Jeddi
- Zoonoses Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
- Department of Genetics and Pathology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Elnaz Faghfuri
- Digestive Diseases Research Center, Ardabil University of Medical Sciences, Ardabil, Iran
| | - Sahar Mehranfar
- Department of Genetics and Immunology, Faculty of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Narges Soozangar
- Zoonoses Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
- Digestive Diseases Research Center, Ardabil University of Medical Sciences, Ardabil, Iran.
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Zhang S, Xiao X, Yi Y, Wang X, Zhu L, Shen Y, Lin D, Wu C. Tumor initiation and early tumorigenesis: molecular mechanisms and interventional targets. Signal Transduct Target Ther 2024; 9:149. [PMID: 38890350 PMCID: PMC11189549 DOI: 10.1038/s41392-024-01848-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2024] [Revised: 04/23/2024] [Accepted: 04/27/2024] [Indexed: 06/20/2024] Open
Abstract
Tumorigenesis is a multistep process, with oncogenic mutations in a normal cell conferring clonal advantage as the initial event. However, despite pervasive somatic mutations and clonal expansion in normal tissues, their transformation into cancer remains a rare event, indicating the presence of additional driver events for progression to an irreversible, highly heterogeneous, and invasive lesion. Recently, researchers are emphasizing the mechanisms of environmental tumor risk factors and epigenetic alterations that are profoundly influencing early clonal expansion and malignant evolution, independently of inducing mutations. Additionally, clonal evolution in tumorigenesis reflects a multifaceted interplay between cell-intrinsic identities and various cell-extrinsic factors that exert selective pressures to either restrain uncontrolled proliferation or allow specific clones to progress into tumors. However, the mechanisms by which driver events induce both intrinsic cellular competency and remodel environmental stress to facilitate malignant transformation are not fully understood. In this review, we summarize the genetic, epigenetic, and external driver events, and their effects on the co-evolution of the transformed cells and their ecosystem during tumor initiation and early malignant evolution. A deeper understanding of the earliest molecular events holds promise for translational applications, predicting individuals at high-risk of tumor and developing strategies to intercept malignant transformation.
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Affiliation(s)
- Shaosen Zhang
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Xinyi Xiao
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Yonglin Yi
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Xinyu Wang
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Lingxuan Zhu
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Changping Laboratory, 100021, Beijing, China
| | - Yanrong Shen
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China
| | - Dongxin Lin
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Changping Laboratory, 100021, Beijing, China.
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China.
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou, 510060, China.
| | - Chen Wu
- Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, 100021, Beijing, China.
- Changping Laboratory, 100021, Beijing, China.
- Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China.
- CAMS Oxford Institute, Chinese Academy of Medical Sciences, 100006, Beijing, China.
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11
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Ishidoya M, Fujita T, Tasaka S, Fujii H. Real-time MBDi-RPA using methyl-CpG binding protein 2: A real-time detection method for simple and rapid estimation of CpG methylation status. Anal Chim Acta 2024; 1302:342486. [PMID: 38580404 DOI: 10.1016/j.aca.2024.342486] [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: 11/17/2023] [Revised: 02/21/2024] [Accepted: 03/14/2024] [Indexed: 04/07/2024]
Abstract
BACKGROUND Analysis of CpG methylation is informative for cancer diagnosis. Previously, we developed a novel method to discriminate CpG methylation status in target DNA by blocking recombinase polymerase amplification (RPA), an isothermal DNA amplification technique, using methyl-CpG binding domain (MBD) protein 2 (MBD2). The method was named MBD protein interference-RPA (MBDi-RPA). In this study, MBDi-RPA was performed using methyl-CpG binding protein 2 (MeCP2), another MBD family protein, as the blocking agent. RESULTS MBDi-RPA using MeCP2 detected low levels of CpG methylation, showing that it had higher sensitivity than MBDi-RPA using MBD2. We also developed real-time RPA, which enabled rapid analysis of DNA amplification without the need for laborious agarose gel electrophoresis and used it in combination with MBDi-RPA. We termed this method real-time MBDi-RPA. The method using MeCP2 could determine the abundance ratio of CpG-methylated target DNA simply and rapidly, although highly sensitive detection was challenging. SIGNIFICANCE AND NOVELTY Real-time MBDi-RPA using MeCP2 could be potentially useful for estimating CpG methylation status in target DNA prior to more detailed analyses.
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Affiliation(s)
- Mina Ishidoya
- Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Toshitsugu Fujita
- Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan.
| | - Sadatomo Tasaka
- Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
| | - Hodaka Fujii
- Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori, 036-8562, Japan
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12
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Sardari A, Usefi H. Machine learning-based meta-analysis of colorectal cancer and inflammatory bowel disease. PLoS One 2023; 18:e0290192. [PMID: 38134011 PMCID: PMC10745176 DOI: 10.1371/journal.pone.0290192] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 11/30/2023] [Indexed: 12/24/2023] Open
Abstract
Colorectal cancer (CRC) is a major global health concern, resulting in numerous cancer-related deaths. CRC detection, treatment, and prevention can be improved by identifying genes and biomarkers. Despite extensive research, the underlying mechanisms of CRC remain elusive, and previously identified biomarkers have not yielded satisfactory insights. This shortfall may be attributed to the predominance of univariate analysis methods, which overlook potential combinations of variants and genes contributing to disease development. Here, we address this knowledge gap by presenting a novel multivariate machine-learning strategy to pinpoint genes associated with CRC. Additionally, we applied our analysis pipeline to Inflammatory Bowel Disease (IBD), as IBD patients face substantial CRC risk. The importance of the identified genes was substantiated by rigorous validation across numerous independent datasets. Several of the discovered genes have been previously linked to CRC, while others represent novel findings warranting further investigation. A Python implementation of our pipeline can be accessed publicly at https://github.com/AriaSar/CRCIBD-ML.
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Affiliation(s)
- Aria Sardari
- Department of Computer Science, Memorial University of Newfoundland, St. John’s, NL, Canada
| | - Hamid Usefi
- Department of Computer Science, Memorial University of Newfoundland, St. John’s, NL, Canada
- Department of Mathematics & Statistics, Memorial University of Newfoundland, St. John’s, NL, Canada
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13
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Hernández A, Miranda DA, Pertuz S. An in silico study on the detectability of field cancerization through parenchymal analysis of digital mammograms. Med Phys 2023; 50:6379-6389. [PMID: 36994613 DOI: 10.1002/mp.16401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 03/07/2023] [Accepted: 03/15/2023] [Indexed: 03/31/2023] Open
Abstract
BACKGROUND Parenchymal analysis has shown promising performance for the assessment of breast cancer risk through the characterization of the texture features of mammography images. However, the working principles behind this practice are yet not well understood. Field cancerization is a phenomenon associated with genetic and epigenetic alterations in large volumes of cells, putting them on a path of malignancy before the appearance of recognizable cancer signs. Evidence suggests that it can induce changes in the biochemical and optical properties of the tissue. PURPOSE The aim of this work was to study whether the extended genetic mutations and epigenetic changes due to field cancerization, and the impact they have on the biochemistry of breast tissues are detectable in the radiological patterns of mammography images. METHODS An in silico experiment was designed, which implied the development of a field cancerization model to modify the optical tissue properties of a cohort of 60 voxelized virtual breast phantoms. Mammography images from these phantoms were generated and compared with images obtained from their non-modified counterparts, that is, without field cancerization. We extracted 33 texture features from the breast area to quantitatively assess the impact of the field cancerization model. We analyzed the similarity and statistical equivalence of texture features with and without field cancerization using the t-test, Wilcoxon sign rank test and Kolmogorov-Smirnov test, and performed a discrimination test using multinomial logistic regression analysis with lasso regularization. RESULTS With modifications of the optical tissue properties on 3.9% of the breast volume, some texture features started to fail to show equivalence (p < 0.05). At 7.9% volume modification, a high percent of texture features showed statistically significant differences (p < 0.05) and non-equivalence. At this level, multinomial logistic regression analysis of texture features showed a statistically significant performance in the discrimination of mammograms from breasts with and without field cancerization (AUC = 0.89, 95% CI: 0.75-1.00). CONCLUSIONS These results support the idea that field cancerization is a feasible underlying working principle behind the distinctive performance of parenchymal analysis in breast cancer risk assessment.
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Affiliation(s)
- Angie Hernández
- Connectivity and Signal Processing group - CPS, Universidad Industrial de Santander, Bucaramanga, Colombia
| | - David A Miranda
- Biological and Semiconductor Materials Science - CIMBIOS, Universidad Industrial de Santander, Bucaramanga, Colombia
| | - Said Pertuz
- Connectivity and Signal Processing group - CPS, Universidad Industrial de Santander, Bucaramanga, Colombia
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14
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Ashouri A, Zhang C, Gaiti F. Decoding Cancer Evolution: Integrating Genetic and Non-Genetic Insights. Genes (Basel) 2023; 14:1856. [PMID: 37895205 PMCID: PMC10606072 DOI: 10.3390/genes14101856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 09/19/2023] [Accepted: 09/22/2023] [Indexed: 10/29/2023] Open
Abstract
The development of cancer begins with cells transitioning from their multicellular nature to a state akin to unicellular organisms. This shift leads to a breakdown in the crucial regulators inherent to multicellularity, resulting in the emergence of diverse cancer cell subpopulations that have enhanced adaptability. The presence of different cell subpopulations within a tumour, known as intratumoural heterogeneity (ITH), poses challenges for cancer treatment. In this review, we delve into the dynamics of the shift from multicellularity to unicellularity during cancer onset and progression. We highlight the role of genetic and non-genetic factors, as well as tumour microenvironment, in promoting ITH and cancer evolution. Additionally, we shed light on the latest advancements in omics technologies that allow for in-depth analysis of tumours at the single-cell level and their spatial organization within the tissue. Obtaining such detailed information is crucial for deepening our understanding of the diverse evolutionary paths of cancer, allowing for the development of effective therapies targeting the key drivers of cancer evolution.
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Affiliation(s)
- Arghavan Ashouri
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada
| | - Chufan Zhang
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Federico Gaiti
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
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15
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Liu R, Zhao E, Yu H, Yuan C, Abbas MN, Cui H. Methylation across the central dogma in health and diseases: new therapeutic strategies. Signal Transduct Target Ther 2023; 8:310. [PMID: 37620312 PMCID: PMC10449936 DOI: 10.1038/s41392-023-01528-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/23/2023] [Accepted: 05/25/2023] [Indexed: 08/26/2023] Open
Abstract
The proper transfer of genetic information from DNA to RNA to protein is essential for cell-fate control, development, and health. Methylation of DNA, RNAs, histones, and non-histone proteins is a reversible post-synthesis modification that finetunes gene expression and function in diverse physiological processes. Aberrant methylation caused by genetic mutations or environmental stimuli promotes various diseases and accelerates aging, necessitating the development of therapies to correct the disease-driver methylation imbalance. In this Review, we summarize the operating system of methylation across the central dogma, which includes writers, erasers, readers, and reader-independent outputs. We then discuss how dysregulation of the system contributes to neurological disorders, cancer, and aging. Current small-molecule compounds that target the modifiers show modest success in certain cancers. The methylome-wide action and lack of specificity lead to undesirable biological effects and cytotoxicity, limiting their therapeutic application, especially for diseases with a monogenic cause or different directions of methylation changes. Emerging tools capable of site-specific methylation manipulation hold great promise to solve this dilemma. With the refinement of delivery vehicles, these new tools are well positioned to advance the basic research and clinical translation of the methylation field.
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Affiliation(s)
- Ruochen Liu
- State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing, 400715, China
- Jinfeng Laboratory, Chongqing, 401329, China
- Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China
- Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400715, China
| | - Erhu Zhao
- State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing, 400715, China
- Jinfeng Laboratory, Chongqing, 401329, China
- Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China
- Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400715, China
| | - Huijuan Yu
- State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing, 400715, China
| | - Chaoyu Yuan
- State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing, 400715, China
| | - Muhammad Nadeem Abbas
- State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing, 400715, China
- Jinfeng Laboratory, Chongqing, 401329, China
- Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China
- Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400715, China
| | - Hongjuan Cui
- State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing, 400715, China.
- Jinfeng Laboratory, Chongqing, 401329, China.
- Chongqing Engineering and Technology Research Center for Silk Biomaterials and Regenerative Medicine, Chongqing, 400716, China.
- Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, 400715, China.
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16
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Fahrer J, Christmann M. DNA Alkylation Damage by Nitrosamines and Relevant DNA Repair Pathways. Int J Mol Sci 2023; 24:ijms24054684. [PMID: 36902118 PMCID: PMC10003415 DOI: 10.3390/ijms24054684] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 02/17/2023] [Accepted: 02/24/2023] [Indexed: 03/04/2023] Open
Abstract
Nitrosamines occur widespread in food, drinking water, cosmetics, as well as tobacco smoke and can arise endogenously. More recently, nitrosamines have been detected as impurities in various drugs. This is of particular concern as nitrosamines are alkylating agents that are genotoxic and carcinogenic. We first summarize the current knowledge on the different sources and chemical nature of alkylating agents with a focus on relevant nitrosamines. Subsequently, we present the major DNA alkylation adducts induced by nitrosamines upon their metabolic activation by CYP450 monooxygenases. We then describe the DNA repair pathways engaged by the various DNA alkylation adducts, which include base excision repair, direct damage reversal by MGMT and ALKBH, as well as nucleotide excision repair. Their roles in the protection against the genotoxic and carcinogenic effects of nitrosamines are highlighted. Finally, we address DNA translesion synthesis as a DNA damage tolerance mechanism relevant to DNA alkylation adducts.
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Affiliation(s)
- Jörg Fahrer
- Division of Food Chemistry and Toxicology, Department of Chemistry, RPTU Kaiserslautern-Landau, Erwin-Schrödinger Strasse 52, D-67663 Kaiserslautern, Germany
- Correspondence: (J.F.); (M.C.); Tel.: +496312052974 (J.F.); Tel: +496131179066 (M.C.)
| | - Markus Christmann
- Department of Toxicology, University Medical Center Mainz, Obere Zahlbacher Strasse 67, D-55131 Mainz, Germany
- Correspondence: (J.F.); (M.C.); Tel.: +496312052974 (J.F.); Tel: +496131179066 (M.C.)
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17
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Oh CR, Kim JE, Lee JS, Kim SY, Kim TW, Choi J, Kim J, Park IJ, Lim SB, Park JH, Kim JH, Choi MK, Cha Y, Baek JY, Beom SH, Hong YS. Preoperative Chemoradiotherapy With Capecitabine With or Without Temozolomide in Patients With Locally Advanced Rectal Cancer: A Prospective, Randomised Phase II Study Stratified by O 6-Methylguanine DNA Methyltransferase Status: KCSG-CO17-02. Clin Oncol (R Coll Radiol) 2023; 35:e143-e152. [PMID: 36376167 DOI: 10.1016/j.clon.2022.10.016] [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: 06/17/2022] [Revised: 09/03/2022] [Accepted: 10/20/2022] [Indexed: 11/13/2022]
Abstract
AIMS To evaluate the clinical efficacy of adding temozolomide (TMZ) to preoperative capecitabine (CAP)-based chemoradiotherapy in patients with locally advanced rectal cancer (LARC) and validate O6-methylguanine DNA methyltransferase (MGMT) methylation status as a predictive marker for TMZ combined regimens. MATERIALS AND METHODS LARC patients with clinical stage II (cT3-4N0) or III (cTanyN+) disease were enrolled. They were stratified into unmethylated MGMT (uMGMT) and methylated MGMT (mMGMT) groups by methylation-specific polymerase chain reaction before randomisation and were then randomly assigned (1:1) to one of four treatment arms: uMGMT/CAP (arm A), uMGMT/TMZ + CAP (arm B), mMGMT/CAP (arm C) and mMGMT/TMZ + CAP (arm D). The primary end point was the pathological complete response (pCR) rate. RESULTS Between November 2017 and July 2020, 64 patients were randomised. Slow accrual caused early study termination. After excluding four ineligible patients, 60 were included in the full analysis set. The pCR rate was 15.0% (9/60), 0%, 14.3%, 18.8% and 26.7% for the entire cohort, arms A, B, C and D, respectively (P = 0.0498 between arms A and D). The pCR rate was 9.7% in the CAP group (arms A + C), 20.7% in the TMZ + CAP group (arms B + D), 6.9% in the uMGMT group (arms A + B) and 22.6% in the mMGMT group (arms C + D). Grade 1-2 nausea or vomiting was significantly more frequent in the TMZ + CAP treatment groups (arms B + D) than in the CAP treatment groups (arms A + C, P < 0.001) with no difference in grade 3 adverse events. There were no grade 4 or 5 adverse events. CONCLUSION The addition of TMZ to CAP-based chemoradiotherapy tended to improve pCR rates, particularly in those with mMGMT LARC. MGMT status may warrant further investigation as a predictive biomarker for chemotherapeutic agents and radiotherapy.
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Affiliation(s)
- C R Oh
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea
| | - J E Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - J S Lee
- Clinical Research Center, Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - S Y Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - T W Kim
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - J Choi
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - J Kim
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - I J Park
- Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - S-B Lim
- Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - J-H Park
- Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - J H Kim
- Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - M K Choi
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea
| | - Y Cha
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea
| | - J Y Baek
- Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea
| | - S-H Beom
- Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Y S Hong
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
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18
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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]
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19
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Rafeeinia A, Asadikaram G, Moazed V, Darabi MK. Organochlorine pesticides may induce leukemia by methylation of CDKN2B and MGMT promoters and histone modifications. Gene 2023; 851:146976. [DOI: 10.1016/j.gene.2022.146976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/25/2022] [Accepted: 10/11/2022] [Indexed: 11/27/2022]
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20
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Gabel K, Fitzgibbon ML, Yazici C, Gann P, Sverdlov M, Guzman G, Chen Z, McLeod A, Hamm A, Varady KA, Tussing‐Humphreys L. The basis and design for time-restricted eating compared with daily calorie restriction for weight loss and colorectal cancer risk reduction trial (TRE-CRC trial). Obesity (Silver Spring) 2022; 30:2376-2385. [PMID: 36319597 PMCID: PMC9691536 DOI: 10.1002/oby.23579] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/11/2022] [Accepted: 07/20/2022] [Indexed: 11/07/2022]
Abstract
OBJECTIVE Approximately 42% of American adults are living with obesity, increasing their risk of colorectal cancer (CRC). Efficacious approaches to prevent and treat obesity may reduce CRC incidence. Daily calorie restriction (Cal-R) is the most common approach to treating obesity, yet clinically meaningful weight loss is elusive owing to waning adherence. Time-restricted eating (TRE) consists of consuming foods within a specified time frame, creating a natural calorie deficit. TRE in animals shows cancer protective effects. In humans, TRE is safe and acceptable among adults with obesity, producing ~3% to 5% weight loss and reductions in oxidative stress and insulin resistance. However, TRE has not been tested rigorously for CRC preventive effects. METHODS The authors describe a 12-month randomized controlled trial of 8-hour TRE (ad libitum 12 PM-8 PM), Cal-R (25% restriction daily), or Control among 255 adults at increased risk for CRC and with obesity. RESULTS Effects on the following will be examined: 1) body weight, body composition, and adherence; 2) circulating metabolic, inflammation, and oxidative stress biomarkers; 3) colonic mucosal gene expression profiles and tissue microenvironment; and 4) maintenance of benefits on body weight/composition and CRC risk markers. CONCLUSIONS This study will examine efficacious lifestyle strategies to treat obesity and reduce CRC risk among individuals with obesity.
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Affiliation(s)
- Kelsey Gabel
- Department of Kinesiology and NutritionUniversity of Illinois ChicagoChicagoIllinoisUSA
- University of Illinois Cancer CenterChicagoIllinoisUSA
| | - Marian L. Fitzgibbon
- University of Illinois Cancer CenterChicagoIllinoisUSA
- Institute for Health Research and PolicyChicagoIllinoisUSA
| | - Cemal Yazici
- University of Illinois Cancer CenterChicagoIllinoisUSA
- Department of MedicineUniversity of Illinois ChicagoChicagoIllinoisUSA
| | - Peter Gann
- University of Illinois Cancer CenterChicagoIllinoisUSA
- Department of Pathology, University of Illinois ChicagoChicagoIllinoisUSA
| | - Maria Sverdlov
- University of Illinois Cancer CenterChicagoIllinoisUSA
- Research Histology and Tissue Imaging CoreUniversity of Illinois ChicagoChicagoIllinoisUSA
| | - Grace Guzman
- University of Illinois Cancer CenterChicagoIllinoisUSA
- Department of Pathology, University of Illinois ChicagoChicagoIllinoisUSA
| | - Zhengjia Chen
- University of Illinois Cancer CenterChicagoIllinoisUSA
| | - Andrew McLeod
- University of Illinois Cancer CenterChicagoIllinoisUSA
- Institute for Health Research and PolicyChicagoIllinoisUSA
| | - Alyshia Hamm
- Department of Kinesiology and NutritionUniversity of Illinois ChicagoChicagoIllinoisUSA
- University of Illinois Cancer CenterChicagoIllinoisUSA
| | - Krista A. Varady
- Department of Kinesiology and NutritionUniversity of Illinois ChicagoChicagoIllinoisUSA
- University of Illinois Cancer CenterChicagoIllinoisUSA
| | - Lisa Tussing‐Humphreys
- Department of Kinesiology and NutritionUniversity of Illinois ChicagoChicagoIllinoisUSA
- University of Illinois Cancer CenterChicagoIllinoisUSA
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21
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Chen XQ, Tan BG, Xu M, Zhou HY, Ou J, Zhang XM, Yu ZY, Chen TW. Apparent diffusion coefficient derived from diffusion-weighted imaging to differentiate between tumor, tumor-adjacent and tumor-distant tissues in resectable rectal adenocarcinoma. Eur J Radiol 2022; 155:110506. [PMID: 36087424 DOI: 10.1016/j.ejrad.2022.110506] [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: 06/23/2022] [Revised: 08/04/2022] [Accepted: 08/28/2022] [Indexed: 11/18/2022]
Abstract
PURPOSE To evaluate feasibility of apparent diffusion coefficient (ADC) at different b-values to differentiate between tumor, tumor-adjacent and tumor-distant tissues in rectal adenocarcinoma (RA). MATERIALS AND METHODS Seventy consecutive patients with RA undergoing preoperative diffusion-weighted imaging were retrospectively enrolled. ADCs of tumor, proximal tumor-adjacent tissue (PTA) and tumor-distant tissue (PTD), and distal tumor-adjacent tissue (DTA) and tumor-distant tissue (DTD) were calculated with b-values of 0 and 800 sec/mm2, 0 and 1000 sec/mm2, 0 and 1500 sec/mm2, and multiple b-values of 0, 50, 100, 800, 1000 and 1500 sec/mm2. Statistical analysis was performed to determine feasibility of ADC to differentiate between pairwise tissues. RESULTS Mean ADC of tumor was lower than those of PTA, PTD, DTA and DTD; and mean ADCs of PTA and DTA were lower than those of PTD and DTD at all b-values, respectively (all P-values < 0.001). ADC cut-offs of 1.089 × 10-3 mm2/sec (b = 0, 1000 sec/mm2) or 1.215 × 10-3 mm2/sec (b = 0, 800 sec/mm2), and 1.142 × 10-3 mm2/sec (b = 0, 1000 sec/mm2) or 0.995 × 10-3 mm2/sec (b = 0, 1500 sec/mm2) achieved excellent performance in differentiating tumor from PTA or PTD, and tumor from DTA or DTD (area under receiver operating characteristic curves [AUCs]: 0.813 or 0.952, and 0.970 or 0.996), respectively. ADC cut-offs of 1.625 × 10-3 mm2/sec (b = 0, 800 sec/mm2), and 1.165 × 10-3 mm2/sec (b = 0, 1500 sec/mm2) could differentiate PTA from PTD, and DTA from DTD (AUCs: 0.709 and 0.673), respectively. CONCLUSION ADC can help differentiate between tumor, tumor-adjacent and tumor-distant tissues in RA.
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Affiliation(s)
- Xiao-Qian Chen
- Sichuan Key Laboratory of Medical Imaging, and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 1# Maoyuan South Road, Shunqing District, Nanchong 637000, Sichuan, China
| | - Bang-Guo Tan
- Sichuan Key Laboratory of Medical Imaging, and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 1# Maoyuan South Road, Shunqing District, Nanchong 637000, Sichuan, China; Department of Radiology, Panzhihua Central Hospital, 34# Yikang Street, East District, Panzhihua 617067, Sichuan, China
| | - Min Xu
- Sichuan Key Laboratory of Medical Imaging, and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 1# Maoyuan South Road, Shunqing District, Nanchong 637000, Sichuan, China
| | - Hai-Ying Zhou
- Sichuan Key Laboratory of Medical Imaging, and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 1# Maoyuan South Road, Shunqing District, Nanchong 637000, Sichuan, China.
| | - Jing Ou
- Sichuan Key Laboratory of Medical Imaging, and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 1# Maoyuan South Road, Shunqing District, Nanchong 637000, Sichuan, China
| | - Xiao-Ming Zhang
- Sichuan Key Laboratory of Medical Imaging, and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 1# Maoyuan South Road, Shunqing District, Nanchong 637000, Sichuan, China
| | - Zi-Yi Yu
- Sichuan Key Laboratory of Medical Imaging, and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 1# Maoyuan South Road, Shunqing District, Nanchong 637000, Sichuan, China
| | - Tian-Wu Chen
- Sichuan Key Laboratory of Medical Imaging, and Department of Radiology, Affiliated Hospital of North Sichuan Medical College, 1# Maoyuan South Road, Shunqing District, Nanchong 637000, Sichuan, China.
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22
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Ishwar D, Haldavnekar R, Das S, Tan B, Venkatakrishnan K. Glioblastoma Associated Natural Killer Cell EVs Generating Tumour-Specific Signatures: Noninvasive GBM Liquid Biopsy with Self-Functionalized Quantum Probes. ACS NANO 2022; 16:10859-10877. [PMID: 35816089 DOI: 10.1021/acsnano.2c03055] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Diagnosis of glioblastoma (GBM) poses a recurring struggle due to many factors, including the presence of the blood-brain barrier (BBB) in addition to the significant tumor heterogeneity. Natural killer (NK) cells of the innate immune system are the primary immune surveillance mechanism for GBM and identify GBM tumors without any previous sensitization. The metabolic reprogramming of NK cells during GBM association is expected to be reflected in its extracellular vesicles. Therefore, tracking the activity of NK cell vesicles in circulation (circulating immune vesicles, CIVs) has great potential for accurate GBM diagnosis. However, identification GBM associated CIVs in circulation is immensely challenging as there is no availability of clinically validated GBM-specific circulating biomarkers. Here, we present GBM associated CIV profiling for noninvasive GBM diagnosis. We investigated the feasibility of using the signals derived from GBM associated CIVs as a de novo methodology for GBM diagnosis. An ultrasensitive sensor and a marker-free approach were essential for the detection of rare signals of GBM associated CIVs. For this purpose, we designed GBM ImmunoProfiler platform using scalable ultrafast laser multiphoton ionization mechanism and adopted surface enhanced Raman spectroscopy (SERS) ensuring simultaneous detection of multiple CIV signals to identify GBM. We experimentally demonstrated that GBM associated CIVs carry unique, tumor-specific signals. The features of GBM associated CIVs were explored through machine learning identifying its similarity with GBM patient blood (without cell isolation) using a very small amount of peripheral blood (5 μL) with 96.82% sensitivity and 100% specificity. In addition, we demonstrated that a tumor associated CIV profile can classify between multiple brain cancer types (astrocytoma, oligodendroglioma, and glioblastoma). We also experimentally demonstrated significant variation in the immune checkpoint protein expression (PDL-1 and CTLA-4) between GBM associated CIVs and uninteracted CIVs. Preclinical analysis with serum specimens of GBM patients showed the possibility of using our technology for minimally invasive GBM diagnosis. With clinical validation, our technology has potential to improve GBM diagnostics with a useful, minimally invasive GBM liquid biopsy.
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Affiliation(s)
- Deeptha Ishwar
- Institute for Biomedical Engineering, Science and Technology (iBEST), Partnership between Toronto Metropolitan University and St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada
- Ultrashort Laser Nanomanufacturing Research Facility, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, 350 Victoria Street, Toronto, ON M5B 2K3, Canada
- Nano Characterization Laboratory, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, 350 Victoria Street, Toronto, Ontario M5B 2K3, Canada
- Nano-Bio Interface Facility, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, 350 Victoria Street, Toronto, ON M5B 2K3, Canada
| | - Rupa Haldavnekar
- Institute for Biomedical Engineering, Science and Technology (iBEST), Partnership between Toronto Metropolitan University and St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada
- Ultrashort Laser Nanomanufacturing Research Facility, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, 350 Victoria Street, Toronto, ON M5B 2K3, Canada
- Nano Characterization Laboratory, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, 350 Victoria Street, Toronto, Ontario M5B 2K3, Canada
- Nano-Bio Interface Facility, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, 350 Victoria Street, Toronto, ON M5B 2K3, Canada
| | - Sunit Das
- Department of Surgery, Division of Neurosurgery, University of Toronto, 30 Bond Street, Toronto, M5B1W8, Canada
| | - Bo Tan
- Keenan Research Centre for Biomedical Science, Unity Health Toronto, Toronto, Ontario M5B 1W8, Canada
- Institute for Biomedical Engineering, Science and Technology (iBEST), Partnership between Toronto Metropolitan University and St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada
- Nano Characterization Laboratory, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, 350 Victoria Street, Toronto, Ontario M5B 2K3, Canada
- Nano-Bio Interface Facility, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, 350 Victoria Street, Toronto, ON M5B 2K3, Canada
| | - Krishnan Venkatakrishnan
- Keenan Research Centre for Biomedical Science, Unity Health Toronto, Toronto, Ontario M5B 1W8, Canada
- Institute for Biomedical Engineering, Science and Technology (iBEST), Partnership between Toronto Metropolitan University and St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada
- Ultrashort Laser Nanomanufacturing Research Facility, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, 350 Victoria Street, Toronto, ON M5B 2K3, Canada
- Nano-Bio Interface Facility, Faculty of Engineering and Architectural Sciences, Toronto Metropolitan University, 350 Victoria Street, Toronto, ON M5B 2K3, Canada
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23
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Pinto R, Hauge T, Jeanmougin M, Pharo HD, Kresse SH, Honne H, Winge SB, Five MB, Kumar T, Mala T, Hauge T, Johnson E, Lind GE. Targeted genetic and epigenetic profiling of esophageal adenocarcinomas and non-dysplastic Barrett's esophagus. Clin Epigenetics 2022; 14:77. [PMID: 35701814 PMCID: PMC9195284 DOI: 10.1186/s13148-022-01287-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 05/10/2022] [Indexed: 11/22/2022] Open
Abstract
Background Despite the efforts to describe the molecular landscape of esophageal adenocarcinoma (EAC) and its precursor lesion Barrett’s esophagus (BE), discrepant findings are reported. Here, we investigated the prevalence of selected genetic (TP53 mutations and microsatellite instability (MSI) status) and epigenetic (DNA promoter hypermethylation of APC, CDKN2A, MGMT, TIMP3 and MLH1) modifications in a series of 19 non-dysplastic BE and 145 EAC samples. Additional biopsies from adjacent normal tissue were also evaluated. State-of-the-art methodologies and well-defined scoring criteria were applied in all molecular analyses. Results Overall, we confirmed frequent TP53 mutations among EAC (28%) in contrast to BE, which harbored no mutations. We demonstrated that MSI and MLH1 promoter hypermethylation are rare events, both in EAC and in BE. Our findings further support that APC, CDKN2A, MGMT and TIMP3 promoter hypermethylation is frequently seen in both lesions (21–89%), as well as in a subset of adjacent normal samples (up to 12%). Conclusions Our study further enlightens the molecular background of BE and EAC. To the best of our knowledge, this is one of the largest studies addressing a targeted analysis of genetic and epigenetic modifications simultaneously across a combined series of non-dysplastic BE and EAC samples. Supplementary Information The online version contains supplementary material available at 10.1186/s13148-022-01287-7.
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Affiliation(s)
- Rita Pinto
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Montebello, 0379, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Tobias Hauge
- Department of Pediatric and Gastrointestinal Surgery, Oslo University Hospital, Ullevål, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Marine Jeanmougin
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Montebello, 0379, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Heidi D Pharo
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Montebello, 0379, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Stine H Kresse
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Montebello, 0379, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Hilde Honne
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Montebello, 0379, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Sara B Winge
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Montebello, 0379, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - May-Britt Five
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Montebello, 0379, Oslo, Norway.,K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway
| | - Theresa Kumar
- Department of Pathology, Oslo University Hospital, Ullevål, Oslo, Norway
| | - Tom Mala
- Department of Pediatric and Gastrointestinal Surgery, Oslo University Hospital, Ullevål, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Truls Hauge
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Gastroenterology, Oslo University Hospital, Ullevål, Oslo, Norway
| | - Egil Johnson
- Department of Pediatric and Gastrointestinal Surgery, Oslo University Hospital, Ullevål, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Guro E Lind
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Montebello, 0379, Oslo, Norway. .,K.G. Jebsen Colorectal Cancer Research Centre, Division for Cancer Medicine, Oslo University Hospital, Oslo, Norway. .,Department of Biosciences, The Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
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24
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Cancer stem cell marker expression and methylation status in patients with colorectal cancer. Oncol Lett 2022; 24:231. [PMID: 35720495 PMCID: PMC9185140 DOI: 10.3892/ol.2022.13352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 03/29/2022] [Indexed: 11/21/2022] Open
Abstract
The number of individuals diagnosed with colorectal cancer (CRC) has been on an alarming upward trajectory over the past decade. In some countries, this cancer represents one of the most frequently diagnosed types of neoplasia. Therefore, it is an important demand to study the pathology underlying this disease to gain insights into the mechanism of resistance to treatment. Resistance of tumors to chemotherapy and tumor aggressiveness have been associated with a minor population of neoplastic cells, which are considered to be responsible for tumor recurrence. These types of neoplastic cells are known as cancer stem cells, which have been previously reported to serve an important role in pathogenesis of this malignant disease. Slovakia has one of the highest incidence rates of CRC worldwide. In the present study, the aim was to classify the abundance of selected stem cell markers (CD133, CD166 and Lgr5) in CRC tumors using flow cytometry. In addition, the methylation status of selected genomic regions of CRC biomarkers (ADAMTS16, MGMT, PROM1 (CD133), LGR5 and ALCAM) was investigated by pyrosequencing in a cohort of patients from Martin University Hospital, Martin, Slovakia. Samples from both primary tumors and metastatic tumors were tested. Analysis of DNA methylation in the genomic regions of indicated five CRC biomarkers was also performed, which revealed the highest levels of methylation in the A disintegrin and metalloproteinase with thrombospondin motifs 16 and O6-methyguanine-DNA methyl transferase genes, whereas the lowest levels of methylation were found in genes expressing prominin-1, leucine-rich repeat-containing G-protein-coupled receptor 5 and activated leukocyte cell adhesion molecule. Furthermore, tumor tissues from metastases showed significantly higher levels of CD133+ cells compared with that in primary tumors. Higher levels of CD133+ cells correlated with TNM stage and the invasiveness of CRC into the lymphatic system. Although relatively small number of samples was processed, CD133 marker was consider to be important marker in pathology of CRC.
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25
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Feddersen UR, Hendel SK, Berner-Hansen MA, Jepps TA, Berner-Hansen M, Bindslev N. Nanomolar EP4 receptor potency and expression of eicosanoid-related enzymes in normal appearing colonic mucosa from patients with colorectal neoplasia. BMC Gastroenterol 2022; 22:234. [PMID: 35549670 PMCID: PMC9097415 DOI: 10.1186/s12876-022-02311-z] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 04/27/2022] [Indexed: 12/13/2022] Open
Abstract
Background Aberrations in cyclooxygenase and lipoxygenase (LOX) pathways in non-neoplastic, normal appearing mucosa from patients with colorectal neoplasia (CRN), could hypothetically qualify as predisposing CRN-markers. Methods To test this hypothesis, biopsies were obtained during colonoscopy from macroscopically normal colonic mucosa from patients with and without CRN. Prostaglandin E2 (PGE2) receptors, EP1-4, were examined in Ussing-chambers by exposing biopsies to selective EP receptor agonists, antagonists and PGE2. Furthermore, mRNA expression of EP receptors, prostanoid synthases and LOX enzymes were evaluated with qPCR. Results Data suggest that PGE2 binds to both high and low affinity EP receptors. In particular, PGE2 demonstrated EP4 receptor potency in the low nanomolar range. Similar results were detected using EP2 and EP4 agonists. In CRN patients, mRNA-levels were higher for EP1 and EP2 receptors and for enzymes prostaglandin-I synthase, 5-LOX, 12-LOX and 15-LOX. Conclusions In conclusion, normal appearing colonic mucosa from CRN patients demonstrates deviating expression in eicosanoid pathways, which might indicate a likely predisposition for early CRN development and furthermore that PGE2 potently activates high affinity EP4 receptor subtypes, supporting relevance of testing EP4 antagonists in colorectal neoplasia management. Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02311-z.
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Affiliation(s)
| | | | | | - Thomas Andrew Jepps
- Department of Biomedical Sciences, University of Copenhagen, 2200, Copenhagen N, Denmark
| | - Mark Berner-Hansen
- Digestive Disease Center, Bispebjerg Hospital, 2400, Copenhagen NV, Denmark
| | - Niels Bindslev
- Department of Biomedical Sciences, University of Copenhagen, 2200, Copenhagen N, Denmark
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26
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Byun YJ, Kang HW, Piao XM, Zheng CM, Moon SK, Choi YH, Kim WT, Lee SC, Yun SJ, Kim WJ. Expression of hsv1-miR-H18 and hsv2-miR-H9 as a field defect marker for detecting prostate cancer. Prostate Int 2022; 10:1-6. [PMID: 35155300 PMCID: PMC8804185 DOI: 10.1016/j.prnil.2021.11.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/24/2021] [Accepted: 11/29/2021] [Indexed: 11/29/2022] Open
Abstract
Background Prostate-specific antigen (PSA) is a marker of prostate cancer (PCa), although its efficacy as a diagnostic marker remains controversial. A high false-positive rate leads to repeat biopsy in approximately 70% of patients, which may not be necessary. Epigenetic biomarkers of field cancerization have been investigated widely as promising tools for the diagnosis of patients with suspected tumors. In the current study, we examined the diagnostic value of two microRNA (miRNA) candidates, hsv1-miR-H18 and hsv2-miR-H9, using formalin-fixed paraffin-embedded (FFPE) tissues from patients with PCa or benign prostate hyperplasia (BPH) (as controls) to determine the usefulness of these markers for detecting the presence of cancer. Methods Expression of hsv1-miR-H18 and hsv2-miR-H9 in 201 FFPE tissues, including 52 primary tumors, 73 surrounding noncancerous tissues, and 90 BPH nontumor controls was examined by real-time PCR. Results Expression of hsv1-miR-H18 and hsv2-miR-H9 was significantly higher in primary tumors from PCa patients than in BPH controls (P < 0.0001). In patients within the PSA gray zone, the two viral miRNAs could distinguish PCa from controls with appropriate sensitivity and specificity. Expression of the two miRNAs did not differ between primary tumors and noncancerous surrounding tissues. Conclusions The viral miRNAs hsv1-miR-H18 and hsv2-miR-H9 may be associated with field cancerization of PCa and could be promising supplemental biomarkers to the PSA assay to decrease the rate of unnecessary biopsy, particularly in patients within the PSA gray zone.
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Affiliation(s)
- Young Joon Byun
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Korea
| | - Ho Won Kang
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Korea
- Department of Urology, Chungbuk National University Hospital, Cheongju, Korea
| | - Xuan-Mei Piao
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Korea
| | - Chuang-Ming Zheng
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Korea
| | - Sung-Kwon Moon
- Department of Food Science and Technology, Chung-Ang University, Ansung, 456-756, Korea
| | - Yung Hyun Choi
- Department of Biochemistry, Dongeui University College of Oriental Medicine, Busan, Korea
| | - Won Tae Kim
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Korea
- Department of Urology, Chungbuk National University Hospital, Cheongju, Korea
| | - Sang-Cheol Lee
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Korea
- Department of Urology, Chungbuk National University Hospital, Cheongju, Korea
| | - Seok Joong Yun
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Korea
- Department of Urology, Chungbuk National University Hospital, Cheongju, Korea
- Corresponding author. Department of Urology, College of Medicine, Chungbuk National University, Chungdae-ro 1, Seowon-Gu, Cheongju, Chungbuk 28644, Korea.
| | - Wun-Jae Kim
- Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Korea
- Institute of Urotech, Cheongju, 28644, Korea
- Corresponding author. Department of Urology, College of Medicine, Chungbuk National University, Institute of Urotech, Chungdae-ro 1, Seowon-Gu, Cheongju, Chungbuk 28644, Korea.
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27
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Servidei T, Lucchetti D, Navarra P, Sgambato A, Riccardi R, Ruggiero A. Cell-of-Origin and Genetic, Epigenetic, and Microenvironmental Factors Contribute to the Intra-Tumoral Heterogeneity of Pediatric Intracranial Ependymoma. Cancers (Basel) 2021; 13:6100. [PMID: 34885210 PMCID: PMC8657076 DOI: 10.3390/cancers13236100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/24/2021] [Accepted: 12/01/2021] [Indexed: 02/07/2023] Open
Abstract
Intra-tumoral heterogeneity (ITH) is a complex multifaceted phenomenon that posits major challenges for the clinical management of cancer patients. Genetic, epigenetic, and microenvironmental factors are concurrent drivers of diversity among the distinct populations of cancer cells. ITH may also be installed by cancer stem cells (CSCs), that foster unidirectional hierarchy of cellular phenotypes or, alternatively, shift dynamically between distinct cellular states. Ependymoma (EPN), a molecularly heterogeneous group of tumors, shows a specific spatiotemporal distribution that suggests a link between ependymomagenesis and alterations of the biological processes involved in embryonic brain development. In children, EPN most often arises intra-cranially and is associated with an adverse outcome. Emerging evidence shows that EPN displays large intra-patient heterogeneity. In this review, after touching on EPN inter-tumoral heterogeneity, we focus on the sources of ITH in pediatric intra-cranial EPN in the framework of the CSC paradigm. We also examine how single-cell technology has shed new light on the complexity and developmental origins of EPN and the potential impact that this understanding may have on the therapeutic strategies against this deadly pediatric malignancy.
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Affiliation(s)
- Tiziana Servidei
- Pediatric Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of the Sacred Hearth, 00168 Rome, Italy; (R.R.); (A.R.)
| | - Donatella Lucchetti
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.L.); (A.S.)
| | - Pierluigi Navarra
- Department of Healthcare Surveillance and Bioethics, Section of Pharmacology, Università Cattolica del Sacro Cuore-Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Rome, Italy;
| | - Alessandro Sgambato
- Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, 00168 Rome, Italy; (D.L.); (A.S.)
- Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 85028 Rionero in Vulture, PZ, Italy
| | - Riccardo Riccardi
- Pediatric Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of the Sacred Hearth, 00168 Rome, Italy; (R.R.); (A.R.)
| | - Antonio Ruggiero
- Pediatric Oncology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of the Sacred Hearth, 00168 Rome, Italy; (R.R.); (A.R.)
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28
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Duggan C, Yu M, Willbanks AR, Tapsoba JDD, Wang CY, Grady WM, McTiernan A. Exercise effects on DNA methylation in EVL, CDKN2A (p14, ARF), and ESR1 in colon tissue from healthy men and women. Epigenetics 2021; 17:1070-1079. [PMID: 34550860 DOI: 10.1080/15592294.2021.1982512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
Abstract
Physical activity reduces risk of colon cancer persons by 20-30%. Aberrant methylation patterns are common epigenetic alterations in colorectal adenomas and cancers, and play a role in cancer initiation and progression. Alterations have been identified in normal colon tissue potentially representing a "field cancerization" process, where the normal colon is primed for carcinogenesis. Here, we investigate methylation patterns in three genes -Ena/VASP-like (EVL), (CDKN2A (p14, ARF)), and Estrogen Receptor-1 (ESR1)-in normal colon tissue collected at baseline and 12-months from 202 sedentary men and women, 40-75 years, enrolled in a randomized controlled trial testing an exercise intervention vs. control (http://clinicaltrials.gov/show/NCT00668161). Participants were randomized to moderate-to-vigorous intensity exercise, 60 minutes/day, 6 days/week for 12 months, or usual lifestyle. Sigmoid colon biopsies were obtained at baseline and 12-months, DNA extracted, and bisulphite converted. Droplet digital methylation-specific PCR was performed for EVL, p14ARF, and ESR1. Generalized estimating equations modification of linear regression were used to model relationships between intervention effects and candidate gene methylation levels, adjusting for possible confounders.There were no statistically significant differences between methylation patterns at 12-months between exercisers and controls. ESR1 methylation patterns differed by sex: women -10.58% (exercisers) +11.10% (controls); men +5.54% (exercisers), -8.16% (controls); (P=0.05), adjusting for BMI and age. There were no statistically significant changes in methylation patterns in any gene stratified by change in VO2max, or by minutes/week of exercise.While no statistically significant differences were found in gene methylation patterns comparing exercises vs. controls, 12-month exercise effects on ESR1 methylation differed by sex, warranting further study.
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Affiliation(s)
- Catherine Duggan
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Ming Yu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Amber R Willbanks
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Jean de Dieu Tapsoba
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Ching-Yun Wang
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.,Department of Medicine, University of Washington School of Medicine, Seattle, Washington
| | - Anne McTiernan
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.,Department of Medicine, University of Washington School of Medicine, Seattle, Washington.,School of Public Health, Department of Epidemiology, University of Washington, Seattle, Washington
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Abstract
INTRODUCTION: Colorectal cancer arises in a multistep process of carcinogenesis from normal mucosa. The earliest precursor might be a morphologically inconspicuous precancerous field, harboring cancer-associated mutations. METHODS: We systematically analyzed genetic alterations in 77 tissue samples from 30 patients with sporadic colorectal neoplasms (18 large adenomas and 12 adenocarcinomas) and matched adjacent normal mucosa (N = 30), as well as normal rectal tissue (N = 17). We profiled mutations associated with colorectal cancer by targeted sequencing of 46 genetic loci using 157 custom amplicons and a median depth of 42,655 reads per loci. RESULTS: Multiple mutations were found in colorectal neoplasms, most frequently in APC, KRAS, and TP53. In a subgroup of 11 of 30 patients, alterations were also detected in non-neoplastic mucosa. These mutations were divergent from those in matched neoplasms. The total alteration count and the allele frequency of mutations were higher in neoplasms compared with those in adjacent tissues. We found that younger patients (≤70 years) are less likely affected by mutations in non-neoplastic mucosa than older patients (>70 years, P = 0.013), although no association was found for other variables, including type, location and differentiation of neoplasia, and previous history of polyps. DISCUSSION: Our data show that cancer-associated mutations can be found in non-neoplastic tissues in a subgroup of patients with colorectal neoplasms. Further studies are needed to specify the risk of occurrence and recurrence of neoplasia in this patient population.
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30
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Yalchin M, Baker AM, Graham TA, Hart A. Predicting Colorectal Cancer Occurrence in IBD. Cancers (Basel) 2021; 13:2908. [PMID: 34200768 PMCID: PMC8230430 DOI: 10.3390/cancers13122908] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 05/27/2021] [Accepted: 06/01/2021] [Indexed: 12/13/2022] Open
Abstract
Patients with colonic inflammatory bowel disease (IBD) are at an increased risk of developing colorectal cancer (CRC), and are therefore enrolled into a surveillance programme aimed at detecting dysplasia or early cancer. Current surveillance programmes are guided by clinical, endoscopic or histological predictors of colitis-associated CRC (CA-CRC). We have seen great progress in our understanding of these predictors of disease progression, and advances in endoscopic technique and management, along with improved medical care, has been mirrored by the falling incidence of CA-CRC over the last 50 years. However, more could be done to improve our molecular understanding of CA-CRC progression and enable better risk stratification for patients with IBD. This review summarises the known risk factors associated with CA-CRC and explores the molecular landscape that has the potential to complement and optimise the existing IBD surveillance programme.
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Affiliation(s)
- Mehmet Yalchin
- Inflammatory Bowel Disease Department, St. Mark’s Hospital, Watford R.d., Harrow HA1 3UJ, UK
- Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse S.q., London EC1M 6BQ, UK; (A.-M.B.); (T.A.G.)
| | - Ann-Marie Baker
- Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse S.q., London EC1M 6BQ, UK; (A.-M.B.); (T.A.G.)
| | - Trevor A. Graham
- Centre for Genomics and Computational Biology, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse S.q., London EC1M 6BQ, UK; (A.-M.B.); (T.A.G.)
| | - Ailsa Hart
- Inflammatory Bowel Disease Department, St. Mark’s Hospital, Watford R.d., Harrow HA1 3UJ, UK
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31
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Joo JE, Clendenning M, Wong EM, Rosty C, Mahmood K, Georgeson P, Winship IM, Preston SG, Win AK, Dugué PA, Jayasekara H, English D, Macrae FA, Hopper JL, Jenkins MA, Milne RL, Giles GG, Southey MC, Buchanan DD. DNA Methylation Signatures and the Contribution of Age-Associated Methylomic Drift to Carcinogenesis in Early-Onset Colorectal Cancer. Cancers (Basel) 2021; 13:2589. [PMID: 34070516 PMCID: PMC8199056 DOI: 10.3390/cancers13112589] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/14/2021] [Accepted: 05/19/2021] [Indexed: 12/12/2022] Open
Abstract
We investigated aberrant DNA methylation (DNAm) changes and the contribution of ageing-associated methylomic drift and age acceleration to early-onset colorectal cancer (EOCRC) carcinogenesis. Genome-wide DNAm profiling using the Infinium HM450K on 97 EOCRC tumour and 54 normal colonic mucosa samples was compared with: (1) intermediate-onset CRC (IOCRC; diagnosed between 50-70 years; 343 tumour and 35 normal); and (2) late-onset CRC (LOCRC; >70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC. DNAm-age was estimated using epiTOC2. Common to all three age-of-onset groups, 88,385 (20% of all CpGs) CpGs were differentially methylated between tumour and normal mucosa. We identified 234 differentially methylated genes that were unique to the EOCRC group; 13 of these DMRs/genes were replicated in EOCRC compared with LOCRCs from TCGA. In normal mucosa from people without CRC, we identified 28,154 CpGs that undergo ageing-related DNAm drift, and of those, 65% were aberrantly methylated in EOCRC tumours. Based on the mitotic-based DNAm clock epiTOC2, we identified age acceleration in normal mucosa of people with EOCRC compared with normal mucosa from the IOCRC, LOCRC groups (p = 3.7 × 10-16) and young people without CRC (p = 5.8 × 10-6). EOCRC acquires unique DNAm alterations at 234 loci. CpGs associated with ageing-associated drift were widely affected in EOCRC without needing the decades-long accrual of DNAm drift as commonly seen in intermediate- and late-onset CRCs. Accelerated ageing in normal mucosa from people with EOCRC potentially underlies the earlier age of diagnosis in CRC carcinogenesis.
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Affiliation(s)
- Jihoon E. Joo
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia; (J.E.J.); (M.C.); (C.R.); (K.M.); (P.G.); (S.G.P.); (H.J.)
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
| | - Mark Clendenning
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia; (J.E.J.); (M.C.); (C.R.); (K.M.); (P.G.); (S.G.P.); (H.J.)
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
| | - Ee Ming Wong
- Precision Medicine, Monash Health, Monash University, Clayton, Melbourne 3800, Australia; (E.M.W.); (P.-A.D.); (R.L.M.); (G.G.G.); (M.C.S.)
| | - Christophe Rosty
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia; (J.E.J.); (M.C.); (C.R.); (K.M.); (P.G.); (S.G.P.); (H.J.)
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
- School of Medicine, University of Queensland, Herston, Brisbane 4006, Australia
- Envoi Pathology, Brisbane 4059, Australia
| | - Khalid Mahmood
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia; (J.E.J.); (M.C.); (C.R.); (K.M.); (P.G.); (S.G.P.); (H.J.)
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
- Melbourne Bioinformatics, The University of Melbourne, Parkville, Melbourne 3010, Australia
| | - Peter Georgeson
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia; (J.E.J.); (M.C.); (C.R.); (K.M.); (P.G.); (S.G.P.); (H.J.)
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
| | - Ingrid M. Winship
- Department of Medicine, The Royal Melbourne Hospital, University of Melbourne, Parkville, Melbourne 3050, Australia; (I.M.W.); (F.A.M.)
- Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Melbourne 3050, Australia
| | - Susan G. Preston
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia; (J.E.J.); (M.C.); (C.R.); (K.M.); (P.G.); (S.G.P.); (H.J.)
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
| | - Aung Ko Win
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne 3010, Australia; (A.K.W.); (D.E.); (J.L.H.); (M.A.J.)
| | - Pierre-Antoine Dugué
- Precision Medicine, Monash Health, Monash University, Clayton, Melbourne 3800, Australia; (E.M.W.); (P.-A.D.); (R.L.M.); (G.G.G.); (M.C.S.)
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne 3010, Australia; (A.K.W.); (D.E.); (J.L.H.); (M.A.J.)
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne 3004, Australia
| | - Harindra Jayasekara
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia; (J.E.J.); (M.C.); (C.R.); (K.M.); (P.G.); (S.G.P.); (H.J.)
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne 3004, Australia
| | - Dallas English
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne 3010, Australia; (A.K.W.); (D.E.); (J.L.H.); (M.A.J.)
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne 3004, Australia
| | - Finlay A. Macrae
- Department of Medicine, The Royal Melbourne Hospital, University of Melbourne, Parkville, Melbourne 3050, Australia; (I.M.W.); (F.A.M.)
- Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Melbourne 3050, Australia
- Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Parkville, Melbourne 3050, Australia
| | - John L. Hopper
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne 3010, Australia; (A.K.W.); (D.E.); (J.L.H.); (M.A.J.)
| | - Mark A. Jenkins
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne 3010, Australia; (A.K.W.); (D.E.); (J.L.H.); (M.A.J.)
| | - Roger L. Milne
- Precision Medicine, Monash Health, Monash University, Clayton, Melbourne 3800, Australia; (E.M.W.); (P.-A.D.); (R.L.M.); (G.G.G.); (M.C.S.)
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne 3010, Australia; (A.K.W.); (D.E.); (J.L.H.); (M.A.J.)
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne 3004, Australia
| | - Graham G. Giles
- Precision Medicine, Monash Health, Monash University, Clayton, Melbourne 3800, Australia; (E.M.W.); (P.-A.D.); (R.L.M.); (G.G.G.); (M.C.S.)
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne 3010, Australia; (A.K.W.); (D.E.); (J.L.H.); (M.A.J.)
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne 3004, Australia
| | - Melissa C. Southey
- Precision Medicine, Monash Health, Monash University, Clayton, Melbourne 3800, Australia; (E.M.W.); (P.-A.D.); (R.L.M.); (G.G.G.); (M.C.S.)
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne 3004, Australia
- Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia
| | - Daniel D. Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia; (J.E.J.); (M.C.); (C.R.); (K.M.); (P.G.); (S.G.P.); (H.J.)
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
- Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Melbourne 3050, Australia
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32
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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: 26] [Impact Index Per Article: 6.5] [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.
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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.
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33
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Bacon ER, Brinton RD. Epigenetics of the developing and aging brain: Mechanisms that regulate onset and outcomes of brain reorganization. Neurosci Biobehav Rev 2021; 125:503-516. [PMID: 33657435 DOI: 10.1016/j.neubiorev.2021.02.040] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 02/17/2021] [Accepted: 02/23/2021] [Indexed: 12/11/2022]
Abstract
Brain development is a life-long process that encompasses several critical periods of transition, during which significant cognitive changes occur. Embryonic development, puberty, and reproductive senescence are all periods of transition that are hypersensitive to environmental factors. Rather than isolated episodes, each transition builds upon the last and is influenced by consequential changes that occur in the transition before it. Epigenetic marks, such as DNA methylation and histone modifications, provide mechanisms by which early events can influence development, cognition, and health outcomes. For example, parental environment influences imprinting patterns in gamete cells, which ultimately impacts gene expression in the embryo which may result in hypersensitivity to poor maternal nutrition during pregnancy, raising the risks for cognitive impairment later in life. This review explores how epigenetics induce and regulate critical periods, and also discusses how early environmental interactions prime a system towards a particular health outcome and influence susceptibility to disease or cognitive impairment throughout life.
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Affiliation(s)
- Eliza R Bacon
- Department of Neuroscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA; The Center for Precision Medicine, Beckman Research Institute, City of Hope, Duarte, CA, 91010, USA
| | - Roberta Diaz Brinton
- Department of Neuroscience, Dornsife College of Letters, Arts and Sciences, University of Southern California, Los Angeles, CA, 90089, USA; Center for Innovation in Brain Science, School of Medicine, University of Arizona, Tucson, AZ, 85721, USA.
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34
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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: 147] [Impact Index Per Article: 36.8] [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.
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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
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35
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Perea J, García JL, Corchete L, Tapial S, Olmedillas-López S, Vivas A, García-Olmo D, Urioste M, Goel A, González-Sarmiento R. A clinico-pathological and molecular analysis reveals differences between solitary (early and late-onset) and synchronous rectal cancer. Sci Rep 2021; 11:2202. [PMID: 33500439 PMCID: PMC7838158 DOI: 10.1038/s41598-020-79118-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Accepted: 11/30/2020] [Indexed: 02/06/2023] Open
Abstract
Rectal cancer (RC) appears to behave differently compared with colon cancer. We aimed to analyze existence of different subtypes of RC depending on distinct features (age of onset and the presence of synchronous primary malignant neoplasms). We compared the clinicopathological, familial and molecular features of three different populations diagnosed with RC (early-onset RC [EORC], late-onset RC, and synchronous RC [SRC]). Eighty-five RCs were identified and were evaluated according to their microsatellite instability, CpG Island Methylator Phenotype (CIMP) and chromosomal instability, as assessed by Next Generation Sequencing and microarray-based comparative genomic hybridization approaches. The results were subjected to cluster analysis. SRCs displayed the most specific characteristics including a trend for the development of multiple malignant neoplasms, a greater proportion of CIMP-High tumors (75%) and more frequent genomic alterations. These findings were confirmed by a clustering analysis that stratified RCs according to their genomic alterations. We also found that EORCs exhibited their own features including an important familial cancer component and a remarkable rate of mutations in TP53 (53%). Together, heterogeneity in RC characteristics by age of disease-onset and SRC warrants further study to optimize tailored prevention, detection and intervention strategies-particularly among young adults.
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Affiliation(s)
- José Perea
- Surgery Department, Fundación Jiménez Díaz University Hospital, 28040, Madrid, Spain.
- Health Research Institute, Fundación Jiménez Díaz University Hospital, 28040, Madrid, Spain.
| | - Juan L García
- Molecular Medicine Unit, Department of Medicine, Biomedical Research Institute of Salamanca (IBSAL), Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-SACYL-CSIC, 37007, Salamanca, Spain
| | - Luis Corchete
- Molecular Medicine Unit, Department of Medicine, Biomedical Research Institute of Salamanca (IBSAL), Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-SACYL-CSIC, 37007, Salamanca, Spain
| | - Sandra Tapial
- Digestive Cancer Research Group, 12 de Octubre Research Institute, 28041, Madrid, Spain
| | | | - Alfredo Vivas
- Department of Surgery, 12 de Octubre University Hospital, 28041, Madrid, Spain
| | - Damián García-Olmo
- Surgery Department, Fundación Jiménez Díaz University Hospital, 28040, Madrid, Spain
- Health Research Institute, Fundación Jiménez Díaz University Hospital, 28040, Madrid, Spain
| | - Miguel Urioste
- Familial Cancer Clinical Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute at City of Hope Comprehensive Cancer Center, Monrovia, CA, 91016, USA
| | - Rogelio González-Sarmiento
- Molecular Medicine Unit, Department of Medicine, Biomedical Research Institute of Salamanca (IBSAL), Institute of Molecular and Cellular Biology of Cancer (IBMCC), University of Salamanca-SACYL-CSIC, 37007, Salamanca, Spain
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36
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Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/p38 signaling. Epigenetics Chromatin 2021; 14:7. [PMID: 33436083 PMCID: PMC7805211 DOI: 10.1186/s13072-020-00380-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 12/17/2020] [Indexed: 11/18/2022] Open
Abstract
Benign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity and mortality in NF1. Cutaneous (CNF) and plexiform neurofibromas (PNF) share nearly identical histology, but maintain different growth rates and risk of malignant conversion. The reasons for this disparate clinical behavior are not well explained by recent genome or transcriptome profiling studies. We hypothesized that CNFs and PNFs are epigenetically distinct tumor types that exhibit differential signaling due to genome-wide and site-specific methylation events. We interrogated the methylation profiles of 45 CNFs and 17 PNFs from NF1 subjects with the Illumina EPIC 850K methylation array. Based on these profiles, we confirm that CNFs and PNFs are epigenetically distinct tumors with broad differences in higher-order chromatin states and specific methylation events altering genes involved in key biological and cellular processes, such as inflammation, RAS/MAPK signaling, actin cytoskeleton rearrangement, and oxytocin signaling. Based on our identification of two separate DMRs associated with alternative leading exons in MAP2K3, we demonstrate differential RAS/MKK3/p38 signaling between CNFs and PNFs. Epigenetic reinforcement of RAS/MKK/p38 was a defining characteristic of CNFs leading to pro-inflammatory signaling and chromatin conformational changes, whereas PNFs signaled predominantly through RAS/MEK. Tumor size also correlated with specific CpG methylation events. Taken together, these findings confirm that NF1 deficiency influences the epigenetic regulation of RAS signaling fates, accounting for observed differences in CNF and PNF clinical behavior. The extension of these findings is that CNFs may respond differently than PNFs to RAS-targeted therapeutics raising the possibility of targeting p38-mediated inflammation for CNF treatment.
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Oleksiewicz U, Machnik M. Causes, effects, and clinical implications of perturbed patterns within the cancer epigenome. Semin Cancer Biol 2020; 83:15-35. [PMID: 33359485 DOI: 10.1016/j.semcancer.2020.12.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 12/18/2020] [Accepted: 12/18/2020] [Indexed: 02/06/2023]
Abstract
Somatic mutations accumulating over a patient's lifetime are well-defined causative factors that fuel carcinogenesis. It is now clear, however, that epigenomic signature is also largely perturbed in many malignancies. These alterations support the transcriptional program crucial for the acquisition and maintenance of cancer hallmarks. Epigenetic instability may arise due to the genetic mutations or transcriptional deregulation of the proteins implicated in epigenetic signaling. Moreover, external stimulation and physiological aging may also participate in this phenomenon. The epigenomic signature is frequently associated with a cell of origin, as well as with tumor stage and differentiation, which all reflect its high heterogeneity across and within various tumors. Here, we will overview the current understanding of the causes and effects of the altered and heterogeneous epigenomic landscape in cancer. We will focus mainly on DNA methylation and post-translational histone modifications as the key regulatory epigenetic signaling marks. In addition, we will describe how this knowledge is translated into the clinic. We will particularly concentrate on the applicability of epigenetic alterations as biomarkers for improved diagnosis, prognosis, and prediction. Finally, we will also review current developments regarding epi-drug usage in clinical and experimental settings.
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Affiliation(s)
- Urszula Oleksiewicz
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznan, Poland; Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, Poznan, Poland.
| | - Marta Machnik
- Department of Cancer Immunology, Poznan University of Medical Sciences, Poznan, Poland; Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, Poznan, Poland
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Chiara F, Indraccolo S, Trevisan A. Filling the gap between risk assessment and molecular determinants of tumor onset. Carcinogenesis 2020; 42:507-516. [PMID: 33319226 DOI: 10.1093/carcin/bgaa135] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 11/22/2020] [Accepted: 12/11/2020] [Indexed: 12/30/2022] Open
Abstract
In the past two decades, a ponderous epidemiological literature has causally linked tumor onset to environmental exposure to carcinogens. As consequence, risk assessment studies have been carried out with the aim to identify both predictive models of estimating cancer risks within exposed populations and establishing rules for minimizing hazard when handling carcinogenic compounds. The central assumption of these works is that neoplastic transformation is directly related to the mutational burden of the cell without providing further mechanistic clues to explain increased cancer onset after carcinogen exposure. Nevertheless, in the last few years, a growing number of studies have implemented the traditional models of cancer etiology, proposing that neoplastic transformation is a complex process in which several parameters and crosstalk between tumor and microenvironmental cells must be taken into account and integrated with mutagenesis. In this conceptual framework, the current strategies of risk assessment that are solely based on the 'mutator model' require an urgent update and revision to keep pace with advances in our understanding of cancer biology. We will approach this topic revising the most recent theories on the biological mechanisms involved in tumor formation in order to envision a roadmap leading to a future regulatory framework for a new, protective policy of risk assessment.
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Affiliation(s)
- Federica Chiara
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Via Giustiniani, Padua, Italy
| | | | - Andrea Trevisan
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, Via Giustiniani, Padua, Italy
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Sugiyama T, Iwaizumi M, Kaneko M, Tani S, Yamade M, Hamaya Y, Furuta T, Miyajima H, Osawa S, Baba S, Maekawa M, Sugimoto K. DNA mismatch repair is not disrupted in stage 0 colorectal cancer resected using endoscopic submucosal dissection. Oncol Lett 2020; 20:2435-2441. [PMID: 32782560 PMCID: PMC7399995 DOI: 10.3892/ol.2020.11799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 06/15/2020] [Indexed: 12/17/2022] Open
Abstract
The frequency of deficient mismatch repair (dMMR) or microsatellite instability-high colorectal cancer (CRC) is estimated to be ~15% of all patients with CRC; however, the patients reported are limited to surgical cases, and the frequency of patients exhibiting stage 0 disease is not considered, despite the currently increasing use of endoscopic techniques to cure a number of these patients. In the present study, the DNA MMR status for stage 0 patients with CRC treated using endoscopic submucosal dissection or endoscopic mucosal resection was analyzed via immunohistochemical staining of four types of proteins, namely MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MSH6 and PMS1 homolog 2 MMR system component, in adenocarcinoma specimens. Notably, none of the endoscopically resected specimens exhibited dMMR among the 41 patients diagnosed with stage 0 CRC. Since tumors harboring dMMR progress more rapidly than tumors with chromosomal instability, the present results highlight the importance of tumor resection during very early phases that exist before the promoter region of MLH1 becomes hypermethylated, resulting in a loss of DNA MMR function.
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Affiliation(s)
- Tomohiro Sugiyama
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Moriya Iwaizumi
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Masanao Kaneko
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Shinya Tani
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Mihoko Yamade
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Yasushi Hamaya
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Hiroaki Miyajima
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Satoshi Baba
- Department of Diagnostic Pathology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Masato Maekawa
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan
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40
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Poduval DB, Ognedal E, Sichmanova Z, Valen E, Iversen GT, Minsaas L, Lønning PE, Knappskog S. Assessment of tumor suppressor promoter methylation in healthy individuals. Clin Epigenetics 2020; 12:131. [PMID: 32859265 PMCID: PMC7455917 DOI: 10.1186/s13148-020-00920-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 08/17/2020] [Indexed: 12/21/2022] Open
Abstract
Background The number of tumor suppressor genes for which germline mutations have been linked to cancer risk is steadily increasing. However, while recent reports have linked constitutional normal tissue promoter methylation of BRCA1 and MLH1 to ovarian and colon cancer risk, the role of epigenetic alterations as cancer risk factors remains largely unknown, presenting an important area for future research. Currently, we lack fast and sensitive methods for assessment of promoter methylation status across known tumor suppressor genes. Results In this paper, we present a novel NGS-based approach assessing promoter methylation status across a large panel of defined tumor suppressor genes to base-pair resolution. The method omits the limitations related to commonly used array-approaches. Our panel includes 565 target regions covering the promoters of 283 defined tumor suppressors, selected by pre-specified criteria, and was applied for rapid targeted methylation-specific NGS. The feasibility of the method was assessed by analyzing normal tissue DNA (white blood cells, WBC) samples from 34 healthy postmenopausal women and by performing preliminary assessment of the methylation landscape of tumor suppressors in these individuals. The mean target coverage was 189.6x providing a sensitivity of 0.53%, sufficient for promoter methylation assessment of low-level methylated genes like BRCA1. Within this limited test-set, we detected 206 regions located in the promoters of 149 genes to be differentially methylated (hyper- or hypo-) at > 99% confidence level. Seven target regions in gene promoters (CIITA, RASSF1, CHN1, PDCD1LG2, GSTP1, XPA, and ZNF668) were found to be hyper-methylated in a minority of individuals, with a > 20 percent point difference in mean methylation across the region between individuals. In an exploratory hierarchical clustering analysis, we found that the individuals analyzed may be grouped into two main groups based on their WBC methylation profile across the 283 tumor suppressor gene promoters. Conclusions Methylation-specific NGS of our tumor suppressor panel, with detailed assessment of differential methylation in healthy individuals, presents a feasible method for identification of novel epigenetic risk factors for cancer.
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Affiliation(s)
- Deepak B Poduval
- K.G. Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Elisabet Ognedal
- K.G. Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Oncology, Haukeland University Hospital, Bergen, Norway.,Present address: Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
| | - Zuzana Sichmanova
- K.G. Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Eivind Valen
- Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway.,Sars International Centre for Marine Molecular Biology, University of Bergen, Bergen, Norway
| | - Gjertrud T Iversen
- K.G. Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Laura Minsaas
- K.G. Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Per E Lønning
- K.G. Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Stian Knappskog
- K.G. Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway. .,Department of Oncology, Haukeland University Hospital, Bergen, Norway.
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Oncogenic Features in Histologically Normal Mucosa: Novel Insights Into Field Effect From a Mega-Analysis of Colorectal Transcriptomes. Clin Transl Gastroenterol 2020; 11:e00210. [PMID: 32764205 PMCID: PMC7386360 DOI: 10.14309/ctg.0000000000000210] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
INTRODUCTION: Colorectal cancer is a common malignancy that can be cured when detected early, but recurrence among survivors is a persistent risk. A field effect of cancer in the colon has been reported and could have implications for surveillance, but studies to date have been limited. A joint analysis of pooled transcriptomic data from all available bulk RNA-sequencing data sets of healthy, histologically normal tumor-adjacent, and tumor tissues was performed to provide an unbiased assessment of field effect. METHODS: A novel bulk RNA-sequencing data set from biopsies of nondiseased colon from screening colonoscopy along with published data sets from the Genomic Data Commons and Sequence Read Archive were considered for inclusion. Analyses were limited to samples with a quantified read depth of at least 10 million reads. Transcript abundance was estimated with Salmon, and downstream analysis was performed in R. RESULTS: A total of 1,139 samples were analyzed in 3 cohorts. The primary cohort consisted of 834 independent samples from 8 independent data sets, including 462 healthy, 61 tumor-adjacent, and 311 tumor samples. Tumor-adjacent gene expression was found to represent an intermediate state between healthy and tumor expression. Among differentially expressed genes in tumor-adjacent samples, 1,143 were expressed in patterns similar to tumor samples, and these genes were enriched for cancer-associated pathways. DISCUSSION: Novel insights into the field effect in colorectal cancer were generated in this mega-analysis of the colorectal transcriptome. Oncogenic features that might help explain metachronous lesions in cancer survivors and could be used for surveillance and risk stratification were identified.
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Terradas M, Capellá G, Valle L. Dominantly Inherited Hereditary Nonpolyposis Colorectal Cancer Not Caused by MMR Genes. J Clin Med 2020; 9:jcm9061954. [PMID: 32585810 PMCID: PMC7355797 DOI: 10.3390/jcm9061954] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 06/16/2020] [Accepted: 06/18/2020] [Indexed: 12/30/2022] Open
Abstract
In the past two decades, multiple studies have been undertaken to elucidate the genetic cause of the predisposition to mismatch repair (MMR)-proficient nonpolyposis colorectal cancer (CRC). Here, we present the proposed candidate genes according to their involvement in specific pathways considered relevant in hereditary CRC and/or colorectal carcinogenesis. To date, only pathogenic variants in RPS20 may be convincedly linked to hereditary CRC. Nevertheless, accumulated evidence supports the involvement in the CRC predisposition of other genes, including MRE11, BARD1, POT1, BUB1B, POLE2, BRF1, IL12RB1, PTPN12, or the epigenetic alteration of PTPRJ. The contribution of the identified candidate genes to familial/early onset MMR-proficient nonpolyposis CRC, if any, is extremely small, suggesting that other factors, such as the accumulation of low risk CRC alleles, shared environmental exposures, and/or gene-environmental interactions, may explain the missing heritability in CRC.
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Affiliation(s)
- Mariona Terradas
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.T.); (G.C.)
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain
| | - Gabriel Capellá
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.T.); (G.C.)
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
| | - Laura Valle
- Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (M.T.); (G.C.)
- Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-93-260-7145
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Yang L, Zhang J, Yang G, Xu H, Lin J, Shao L, Li J, Guo C, Du Y, Guo L, Li X, Han-Zhang H, Wang C, Chuai S, Ye J, Kang Q, Liu H, Ying J, Wang Y. The prognostic value of a Methylome-based Malignancy Density Scoring System to predict recurrence risk in early-stage Lung Adenocarcinoma. Theranostics 2020; 10:7635-7644. [PMID: 32685009 PMCID: PMC7359091 DOI: 10.7150/thno.44229] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 06/01/2020] [Indexed: 12/11/2022] Open
Abstract
Current NCCN guidelines do not recommend the use of adjuvant chemotherapy for stage IA lung adenocarcinoma patients with R0 surgery. However, 25% to 40% of patients with stage IA disease experience recurrence. Stratifying patients according to the recurrence risk may tailor adjuvant therapy and surveillance imaging for those with a higher risk. However, prognostic markers are often identified by comparing high-risk and low-risk cases which might introduce bias due to the widespread interpatient heterogeneity. Here, we developed a scoring system quantifying the degree of field cancerization in adjacent normal tissues and revealed its association with disease-free survival (DFS). Methods: We recruited a cohort of 44 patients with resected stage IA lung adenocarcinoma who did not receive adjuvant therapy. Both tumor and adjacent normal tissues were obtained from each patient and subjected to capture-based targeted genomic and epigenomic profiling. A novel methylome-based scoring system namely malignancy density ratio (MD ratio) was developed based on 39 patients by comparing tumor and corresponding adjacent normal tissues of each patient. A MD score was then obtained by Wald statistics. The correlations of MD ratio, MD score, and genomic features with clinical outcome were investigated. Results: Patients with a high-risk MD ratio showed a significantly shorter postsurgical DFS compared with those with a low-risk MD ratio (HR=4.47, P=0.01). The MD ratio was not associated with T stage (P=1), tumor cell fraction (P=0.748) nor inflammatory status (p=0.548). Patients with a high-risk MD score also demonstrated an inferior DFS (HR=4.69, P=0.039). In addition, multivariate analysis revealed EGFR 19 del (HR=5.39, P=0.012) and MD score (HR= 7.90, P=0.01) were independent prognostic markers. Conclusion: The novel methylome-based scoring system, developed by comparing the signatures between tumor and corresponding adjacent normal tissues of individual patients, largely minimizes the bias of interpatient heterogeneity and reveals a robust prognostic value in patients with resected lung adenocarcinoma.
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Povedano E, Ruiz-Valdepeñas Montiel V, Gamella M, Pedrero M, Barderas R, Peláez-García A, Mendiola M, Hardisson D, Feliú J, Yáñez-Sedeño P, Campuzano S, Pingarrón JM. Amperometric Bioplatforms To Detect Regional DNA Methylation with Single-Base Sensitivity. Anal Chem 2020; 92:5604-5612. [PMID: 32073832 DOI: 10.1021/acs.analchem.0c00628] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
This work reports the first bioplatform able to determine electrochemically 5-hydroxymethylcytosine (5-hmC) methylation events at localized sites and single-base sensitivity. The described bioplatform relies on a specific antibody (anti-5-hmC), further conjugated with commercial bioreagents loaded with multiple horseradish peroxidase (HRP) molecules, recognizing the epimark in a target DNA, captured through hybridization onto streptavidin-magnetic microbeads (Strep-MBs) modified with a complementary DNA capture probe. The electrochemical detection is performed by amperometry (-0.20 V vs Ag pseudoreference electrode) at disposable screen-printed carbon electrodes (SPCEs) in the presence of H2O2/hydroquinone (HQ) upon magnetic capture of the modified MBs onto the SPCE. The use of the commercial bioreagents ProtA-polyHRP80 and Histostar, very scarcely explored so far in electrochemical biosensors, provides high sensitivities for a synthetic target DNA sequence with a unique 5-hmC in the promoter region of MGMT tumor suppressor gene. Amplification factors of 43.6 and 55.2 were achieved using ProtA-polyHRP80 or Histostar, respectively, compared to the conventional secondary antibody labeling. This amplification was crucial to detect methylation events at single-nucleotide resolution achieving limits of detection (LODs) of 23.0 and 13.2 pM, respectively, without any target DNA amplification. The ProtA-polyHRP80-based bioplatform, selected as a compromise between sensitivity and cost per determination, exhibited full discrimination toward the target 5-hmC against the closely related 5-mC. In addition, the bioplatform detected 5-hmC at the regional level (MGMT promoter region) in just 10 ng of genomic DNA (gDNA, ∼2700 genomes) extracted from cancer cells and tissues from colorectal cancer (CRC) patients within 60 min.
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Affiliation(s)
- Eloy Povedano
- Departamento de Quı́mica Analı́tica, Facultad de CC. Quı́micas, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | | | - Maria Gamella
- Departamento de Quı́mica Analı́tica, Facultad de CC. Quı́micas, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - María Pedrero
- Departamento de Quı́mica Analı́tica, Facultad de CC. Quı́micas, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Rodrigo Barderas
- Chronic Disease Programme, UFIEC, Instituto de Salud Carlos III, 28220 Majadahonda, Madrid, Spain
| | - Alberto Peláez-García
- Molecular Pathology and Therapeutic Targets Group, IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Marta Mendiola
- Molecular Pathology and Therapeutic Targets Group, IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain.,Translational Oncology Group, IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - David Hardisson
- Molecular Pathology and Therapeutic Targets Group, IdiPAZ, Hospital Universitario La Paz, 28046 Madrid, Spain
| | - Jaime Feliú
- Center for Biomedical Research in the Cancer Network, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Paloma Yáñez-Sedeño
- Departamento de Quı́mica Analı́tica, Facultad de CC. Quı́micas, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Susana Campuzano
- Departamento de Quı́mica Analı́tica, Facultad de CC. Quı́micas, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - José M Pingarrón
- Departamento de Quı́mica Analı́tica, Facultad de CC. Quı́micas, Universidad Complutense de Madrid, 28040 Madrid, Spain
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45
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Ta TV, Nguyen QN, Chu HH, Truong VL, Vuong LD. RAS/RAF mutations and their associations with epigenetic alterations for distinct pathways in Vietnamese colorectal cancer. Pathol Res Pract 2020; 216:152898. [PMID: 32089414 DOI: 10.1016/j.prp.2020.152898] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Revised: 01/27/2020] [Accepted: 02/16/2020] [Indexed: 02/07/2023]
Abstract
KRAS, NRAS, and BRAF are potential tumor-driven genes that are involved in the RAS/RAF/MAPK signaling pathway. RAS/RAF mutations importantly contribute to colorectal tumorigenesis since they remain the activated status of downstream pathways without regulation of the upstream EGFR signal. However, it has not been unclear how epigenetic alterations involved in colorectal tumorigenesis mediated by KRAS, NRAS, or BRAF mutations. Therefore, in this study, we investigated the frequency and distribution of KRAS/NRAS/BRAF mutations in Vietnamese colorectal cancer (CRC) and explored the relationship between genetic and epigenetic abnormalities in 156 tumors of CRC. Somatic mutations of KRAS (exon 2, codon 12/13; exon 3, codon 61), NRAS (exon 2, codon 12/13; exon 3, codon 61), and BRAF (exon 15, codon 600) was determined by Cobas® KRAS Mutation Test, Therascreen NRAS Pyro Kit and Cobas® 4800 BRAF V600 Mutation Test, respectively. Methylation status of BRCA1, MLH1, MGMT, p16, RASSF1A, and APC was detected by methylation-specific PCR. Distribution of each abnormality in clinicopathological features was also analyzed. Results showed the mutation rates of KRAS, NRAS, and BRAF were 41.0 %, 9.6 %, 8.3 % respectively, while the methylation rates of BRCA1, MLH1, MGMT, p16, RASSF1A, and APC were 16.7 %, 16.7 %, 32.7 %, 30.1 %, 30.1 %, and 37.2 % respectively. The distribution of KRAS mutation was mutually exclusive against that of NRAS (p < 0.001) and BRAF (p < 0.001) mutations in CRC. RAS/RAF mutations were more common in adenocarcinoma subtype (p = 0.020), whereas RASSF1A methylation was more frequent in mucinous adenocarcinoma subtype (p = 0.007). In addition, the frequency of having KRAS mutations was significantly higher in MGMT (p = 0.035) or RASSF1A (p = 0.043) methylated cases than in those without methylation. BRAF mutations were positively associated with MLH1 hypermethylation (p = 0.028) but were inversely associated with APC hypermethylation (p = 0.032). Overall, our results show specific interactions of genetic and epigenetic alterations and suggest the presence of independent oncogenic pathways in tumorigenesis of CRC.
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Affiliation(s)
- To Van Ta
- Pathology and Molecular Biology Center, National Cancer Hospital K, 30 Cau Buou Street, Thanh Tri, Hanoi, Viet Nam
| | - Quang Ngoc Nguyen
- Pathology and Molecular Biology Center, National Cancer Hospital K, 30 Cau Buou Street, Thanh Tri, Hanoi, Viet Nam
| | - Ha Hoang Chu
- National Key Laboratory of Gene Technology, Institute of Biotechnology, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Street, Cau Giay, Hanoi, Viet Nam
| | - Van-Long Truong
- Department of Smart Food and Drug, College of BNIT, Inje University, Gimhae 50834, South Korea.
| | - Linh Dieu Vuong
- Pathology and Molecular Biology Center, National Cancer Hospital K, 30 Cau Buou Street, Thanh Tri, Hanoi, Viet Nam.
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Pardini B, Corrado A, Paolicchi E, Cugliari G, Berndt SI, Bezieau S, Bien SA, Brenner H, Caan BJ, Campbell PT, Casey G, Chan AT, Chang-Claude J, Cotterchio M, Gala M, Gallinger SJ, Haile RW, Harrison TA, Hayes RB, Hoffmeister M, Hopper JL, Hsu L, Huyghe J, Jenkins MA, Le Marchand L, Lin Y, Lindor NM, Nan H, Newcomb PA, Ogino S, Potter JD, Schoen RE, Slattery ML, White E, Vodickova L, Vymetalkova V, Vodicka P, Gemignani F, Peters U, Naccarati A, Landi S. DNA repair and cancer in colon and rectum: Novel players in genetic susceptibility. Int J Cancer 2020; 146:363-372. [PMID: 31209889 PMCID: PMC7301215 DOI: 10.1002/ijc.32516] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 05/27/2019] [Indexed: 01/07/2023]
Abstract
Interindividual differences in DNA repair systems may play a role in modulating the individual risk of developing colorectal cancer. To better ascertain the role of DNA repair gene polymorphisms on colon and rectal cancer risk individually, we evaluated 15,419 single nucleotide polymorphisms (SNPs) within 185 DNA repair genes using GWAS data from the Colon Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), which included 8,178 colon cancer, 2,936 rectum cancer cases and 14,659 controls. Rs1800734 (in MLH1 gene) was associated with colon cancer risk (p-value = 3.5 × 10-6 ) and rs2189517 (in RAD51B) with rectal cancer risk (p-value = 5.7 × 10-6 ). The results had statistical significance close to the Bonferroni corrected p-value of 5.8 × 10-6 . Ninety-four SNPs were significantly associated with colorectal cancer risk after Binomial Sequential Goodness of Fit (BSGoF) procedure and confirmed the relevance of DNA mismatch repair (MMR) and homologous recombination pathways for colon and rectum cancer, respectively. Defects in MMR genes are known to be crucial for familial form of colorectal cancer but our findings suggest that specific genetic variations in MLH1 are important also in the individual predisposition to sporadic colon cancer. Other SNPs associated with the risk of colon cancer (e.g., rs16906252 in MGMT) were found to affect mRNA expression levels in colon transverse and therefore working as possible cis-eQTL suggesting possible mechanisms of carcinogenesis.
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Affiliation(s)
- Barbara Pardini
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Alda Corrado
- Department of Biology, University of Pisa, Pisa, Italy
| | | | - Giovanni Cugliari
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Sonja I. Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD. USA
| | - Stephane Bezieau
- Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, France
| | - Stephanie A. Bien
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- School of Public Health, University of Washington, Seattle, WA, USA
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Germany
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Bette J. Caan
- Kaiser Permanente Medical Care Program of Northern California, Oakland, CA, USA
| | - Peter T. Campbell
- Epidemiology Research Program, American Cancer Society, Atlanta, GA, USA
| | - Graham Casey
- Public Health Sciences, University of Virginia, VA, USA
| | - Andrew T. Chan
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ) Heidelberg, Germany
| | | | - Manish Gala
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | | | | | - Tabitha A. Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Richard B. Hayes
- Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY, USA
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ) Heidelberg, Germany
| | - John L. Hopper
- Melborne School of Population Health, The University of Melborne, Melborne, Australia
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Jeroen Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Mark A. Jenkins
- Melborne School of Population Health, The University of Melborne, Melborne, Australia
| | - Loic Le Marchand
- Epidemiology Program, Research Cancer Center of Hawaii, University of Hawaii, Honolulu, HI, USA
| | - Yi Lin
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Noralane M. Lindor
- Department of Health Sciences Research, Mayo Clinic Arizona, Scottsdale, AZ, USA
| | - Hongmei Nan
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN, USA
| | - Polly A. Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Shuji Ogino
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School
- Department of Oncologic Pathology, Dana-Farber Cancer Institute
- Department of Epidemiology, Harvard T.H. Chan School of Public Health; all in, Boston, MA, USA
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - John D. Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Robert E. Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Martha L. Slattery
- Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City, UT, USA
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Ludmila Vodickova
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Prague, Czech Republic
| | - Veronika Vymetalkova
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Prague, Czech Republic
| | - Pavel Vodicka
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic
- Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Prague, Czech Republic
| | | | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Alessio Naccarati
- Italian Institute for Genomic Medicine (IIGM), Turin, Italy
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, The Czech Academy of Sciences, Prague, Czech Republic
| | - Stefano Landi
- Department of Biology, University of Pisa, Pisa, Italy
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Wang T, Maden SK, Luebeck GE, Li CI, Newcomb PA, Ulrich CM, Joo JHE, Buchanan DD, Milne RL, Southey MC, Carter KT, Willbanks AR, Luo Y, Yu M, Grady WM. Dysfunctional epigenetic aging of the normal colon and colorectal cancer risk. Clin Epigenetics 2020; 12:5. [PMID: 31900199 PMCID: PMC6942339 DOI: 10.1186/s13148-019-0801-3] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 12/23/2019] [Indexed: 12/12/2022] Open
Abstract
Background Chronological age is a prominent risk factor for many types of cancers including colorectal cancer (CRC). Yet, the risk of CRC varies substantially between individuals, even within the same age group, which may reflect heterogeneity in biological tissue aging between people. Epigenetic clocks based on DNA methylation are a useful measure of the biological aging process with the potential to serve as a biomarker of an individual’s susceptibility to age-related diseases such as CRC. Methods We conducted a genome-wide DNA methylation study on samples of normal colon mucosa (N = 334). Subjects were assigned to three cancer risk groups (low, medium, and high) based on their personal adenoma or cancer history. Using previously established epigenetic clocks (Hannum, Horvath, PhenoAge, and EpiTOC), we estimated the biological age of each sample and assessed for epigenetic age acceleration in the samples by regressing the estimated biological age on the individual’s chronological age. We compared the epigenetic age acceleration between different risk groups using a multivariate linear regression model with the adjustment for gender and cell-type fractions for each epigenetic clock. An epigenome-wide association study (EWAS) was performed to identify differential methylation changes associated with CRC risk. Results Each epigenetic clock was significantly correlated with the chronological age of the subjects, and the Horvath clock exhibited the strongest correlation in all risk groups (r > 0.8, p < 1 × 10−30). The PhenoAge clock (p = 0.0012) revealed epigenetic age deceleration in the high-risk group compared to the low-risk group. Conclusions Among the four DNA methylation-based measures of biological age, the Horvath clock is the most accurate for estimating the chronological age of individuals. Individuals with a high risk for CRC have epigenetic age deceleration in their normal colons measured by the PhenoAge clock, which may reflect a dysfunctional epigenetic aging process.
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Affiliation(s)
- Ting Wang
- Clinical Research Division, Fred Hutchinson Cancer Research Center, D4-100, 1100 Fairview Ave N, Seattle, WA, 98109, USA
| | - Sean K Maden
- Clinical Research Division, Fred Hutchinson Cancer Research Center, D4-100, 1100 Fairview Ave N, Seattle, WA, 98109, USA.,Computational Biology Program, Oregon Health & Science University, Portland, OR, USA.,Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, USA
| | - Georg E Luebeck
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Christopher I Li
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Cornelia M Ulrich
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.,Huntsman Cancer Institute and Department of Population Health Sciences, Salt Lake City, UT, USA
| | - Ji-Hoon E Joo
- Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia
| | - Daniel D Buchanan
- Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia
| | - Roger L Milne
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.,Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.,Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Melissa C Southey
- Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia.,Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.,Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Kelly T Carter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, D4-100, 1100 Fairview Ave N, Seattle, WA, 98109, USA
| | - Amber R Willbanks
- Clinical Research Division, Fred Hutchinson Cancer Research Center, D4-100, 1100 Fairview Ave N, Seattle, WA, 98109, USA
| | - Yanxin Luo
- Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.,Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Ming Yu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, D4-100, 1100 Fairview Ave N, Seattle, WA, 98109, USA.
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, D4-100, 1100 Fairview Ave N, Seattle, WA, 98109, USA. .,Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. .,Department of Internal Medicine, University of Washington School of Medicine, Seattle, WA, USA.
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48
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Guo M, Peng Y, Gao A, Du C, Herman JG. Epigenetic heterogeneity in cancer. Biomark Res 2019; 7:23. [PMID: 31695915 PMCID: PMC6824025 DOI: 10.1186/s40364-019-0174-y] [Citation(s) in RCA: 145] [Impact Index Per Article: 24.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 10/10/2019] [Indexed: 12/15/2022] Open
Abstract
Phenotypic and functional heterogeneity is one of the hallmarks of human cancers. Tumor genotype variations among tumors within different patients are known as interpatient heterogeneity, and variability among multiple tumors of the same type arising in the same patient is referred to as intra-patient heterogeneity. Subpopulations of cancer cells with distinct phenotypic and molecular features within a tumor are called intratumor heterogeneity (ITH). Since Nowell proposed the clonal evolution of tumor cell populations in 1976, tumor heterogeneity, especially ITH, was actively studied. Research has focused on the genetic basis of cancer, particularly mutational activation of oncogenes or inactivation of tumor-suppressor genes (TSGs). The phenomenon of ITH is commonly explained by Darwinian-like clonal evolution of a single tumor. Despite the monoclonal origin of most cancers, new clones arise during tumor progression due to the continuous acquisition of mutations. It is clear that disruption of the "epigenetic machinery" plays an important role in cancer development. Aberrant epigenetic changes occur more frequently than gene mutations in human cancers. The epigenome is at the intersection of the environment and genome. Epigenetic dysregulation occurs in the earliest stage of cancer. The current trend of epigenetic therapy is to use epigenetic drugs to reverse and/or delay future resistance to cancer therapies. A majority of cancer therapies fail to achieve durable responses, which is often attributed to ITH. Epigenetic therapy may reverse drug resistance in heterogeneous cancer. Complete understanding of genetic and epigenetic heterogeneity may assist in designing combinations of targeted therapies based on molecular information extracted from individual tumors.
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Affiliation(s)
- Mingzhou Guo
- 1Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China.,State Key Laboratory of Esophageal Cancer Prevention and Treatment, 40 Daxue Road, Zhengzhou, Henan 450052 China
| | - Yaojun Peng
- 1Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - Aiai Gao
- 1Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - Chen Du
- 1Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - James G Herman
- 3The Hillman Cancer Center, University of Pittsburgh Cancer Institute, 5117 Centre Ave., Pittsburgh, PA 15213 USA
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Perea J, García JL, Corchete L, Lumbreras E, Arriba M, Rueda D, Tapial S, Pérez J, Vieiro V, Rodríguez Y, Brandáriz L, García-Arranz M, García-Olmo D, Goel A, Urioste M, Sarmiento RG. Redefining synchronous colorectal cancers based on tumor clonality. Int J Cancer 2019; 144:1596-1608. [PMID: 30151896 PMCID: PMC6361712 DOI: 10.1002/ijc.31761] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 06/14/2018] [Accepted: 07/13/2018] [Indexed: 12/19/2022]
Abstract
To analyze the possible clonal origin of a part of Synchronous colorectal cancer (SCRC), we studied 104 paired-SCRCs from 52 consecutive patients without hereditary forms of CRC. We used a Single-Nucleotide Polymorphism array to characterize the genomic profiles, and subsequently used a statistical application to define them according to clonality within the same individual. We categorized the ensuing groups according to colonic location to identify differential phenotypes. The SCRC Monoclonal group (M) (19 cases) was divided into Monosegmental (MM) and Pancolonic (MP) groups. The SCRC Polyclonal group (P) (33 cases) was also divided into Monosegmental (PM) and Pancolonic (PP), the first exhibiting preference for left colon. The MM group showed a high rate of mucinous tumors, the lowest mean-number of tumors and associated-polyps, and the worst prognosis. The MP group included the largest mean-number of associated-polyps, best prognosis and familial cancer component. The PM group seemed to be a "frontier" group. Finally, the PP group also exhibited a mucin component, the highest mean-number of tumors (4.6) compared with the mean-number of polyps (7.7), poor prognosis and sporadic cases. Most relevant differential genomic regions within M groups were gains on 1q24 and 8q24, and deletions on 1p21 and 1p23 for MM, while within P were the gains on 7q36 and deletions on 1p36 for PM. The statistical application employed seems to define clonality more accurately in SCRC -more likely to be polyclonal in origin-, and together with the tumor locations, helped us to configure a classification with prognostic and clinical value.
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Affiliation(s)
- José Perea
- Surgery Department, Fundación Jiménez Díaz University Hospital. Madrid, Spain
- Health Research Institute Fundación Jiménez Díaz. Madrid, Spain
| | - Juan L. García
- Biomedical Research Institute of Salamanca (IBSAL). University Hospital of Salamanca-USAL-CSIC. Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC). University of Salamanca-CSIC. Salamanca, Spain
| | - Luis Corchete
- Biomedical Research Institute of Salamanca (IBSAL). University Hospital of Salamanca-USAL-CSIC. Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC). University of Salamanca-CSIC. Salamanca, Spain
| | - Eva Lumbreras
- Biomedical Research Institute of Salamanca (IBSAL). University Hospital of Salamanca-USAL-CSIC. Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC). University of Salamanca-CSIC. Salamanca, Spain
| | - María Arriba
- Biochemistry Department, Gregorio Marañón University Hospital. Madrid, Spain
| | - Daniel Rueda
- Centre for Biomedical Research of the 12 de Octubre University Hospital. Madrid, Spain
- Molecular Biology Laboratory, 12 de Octubre University Hospital. Madrid, Spain
| | - Sandra Tapial
- Centre for Biomedical Research of the 12 de Octubre University Hospital. Madrid, Spain
| | - Jessica Pérez
- Biomedical Research Institute of Salamanca (IBSAL). University Hospital of Salamanca-USAL-CSIC. Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC). University of Salamanca-CSIC. Salamanca, Spain
| | - Victoria Vieiro
- Surgery Department, 12 de Octubre University Hospital. Madrid, Spain
| | - Yolanda Rodríguez
- Department of Pathology, 12 de Octubre University Hospital. Madrid, Spain
| | - Lorena Brandáriz
- Surgery Department, Fundación Jiménez Díaz University Hospital. Madrid, Spain
- Health Research Institute Fundación Jiménez Díaz. Madrid, Spain
| | | | - Damián García-Olmo
- Surgery Department, Fundación Jiménez Díaz University Hospital. Madrid, Spain
- Health Research Institute Fundación Jiménez Díaz. Madrid, Spain
| | - Ajay Goel
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute, Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX. USA
| | - Miguel Urioste
- Familial Cancer Clinical Unit, Human Cancer Genetics Program. Spanish National Cancer Research Centre (CNIO). Madrid, Spain
- Center for Biomedical Network Research on Rare Diseases (CIBERER). Institute of Health Carlos III. Madrid, Spain
| | - Rogelio González Sarmiento
- Biomedical Research Institute of Salamanca (IBSAL). University Hospital of Salamanca-USAL-CSIC. Salamanca, Spain
- Institute of Molecular and Cellular Biology of Cancer (IBMCC). University of Salamanca-CSIC. Salamanca, Spain
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50
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Lønning PE, Eikesdal HP, Løes IM, Knappskog S. Constitutional Mosaic Epimutations - a hidden cause of cancer? Cell Stress 2019; 3:118-135. [PMID: 31225507 PMCID: PMC6551830 DOI: 10.15698/cst2019.04.183] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 03/04/2019] [Accepted: 03/05/2019] [Indexed: 12/11/2022] Open
Abstract
Silencing of tumor suppressor genes by promoter hypermethylation is a key mechanism to facilitate cancer progression in many malignancies. While promoter hypermethylation can occur at later stages of the carcinogenesis process, constitutional methylation of key tumor suppressors may be an initiating event whereby cancer is started. Constitutional BRCA1 methylation due to cis-acting germline genetic variants is associated with a high risk of breast and ovarian cancer. However, this seems to be a rare event, restricted to a very limited number of families. In contrast, mosaic constitutional BRCA1 methylation is detected in 4-7% of newborn females without germline BRCA1 mutations. While the cause of such methylation is poorly understood, mosaic normal tissue BRCA1 methylation is associated with a 2-3 fold increased risk of high-grade serous ovarian cancer (HGSOC). As such, BRCA1 methylation may be the cause of a significant number of ovarian cancers. Given the molecular similarities between HGSOC and basal-like breast cancer, the findings with respect to HGSOC suggest that constitutional BRCA1 methylation could be a risk factor for basal-like breast cancer as well. Similar to BRCA1, some specific germline variants in MLH1 and MSH2 are associated with promoter methylation and a high risk of colorectal cancers in rare hereditary cases of the disease. However, as many as 15% of all colorectal cancers are of the microsatellite instability (MSI) "high" subtype, in which commonly the tumors harbor MLH1 hypermethylation. Constitutional mosaic methylation of MLH1 in normal tissues has been detected but not formally evaluated as a potential risk factor for incidental colorectal cancers. However, the findings with respect to BRCA1 in breast and ovarian cancer raises the question whether mosaic MLH1 methylation is a risk factor for MSI positive colorectal cancer as well. As for MGMT, a promoter variant is associated with elevated methylation across a panel of solid cancers, and MGMT promoter methylation may contribute to an elevated cancer risk in several of these malignancies. We hypothesize that constitutional mosaic promoter methylation of crucial tumor suppressors may trigger certain types of cancer, similar to germline mutations inactivating the same particular genes. Such constitutional methylation events may be a spark to ignite cancer development, and if associated with a significant cancer risk, screening for such epigenetic alterations could be part of cancer prevention programs to reduce cancer mortality in the future.
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Affiliation(s)
- Per E. Lønning
- K.G.Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Hans P. Eikesdal
- K.G.Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Inger M. Løes
- K.G.Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
| | - Stian Knappskog
- K.G.Jebsen Center for Genome Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Norway
- Department of Oncology, Haukeland University Hospital, Bergen, Norway
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