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1
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Hajebi Khaniki S, Shokoohi F. Data-Driven Identification of Early Cancer-Associated Genes via Penalized Trans-Dimensional Hidden Markov Models. Biomolecules 2025; 15:294. [PMID: 40001597 PMCID: PMC11853217 DOI: 10.3390/biom15020294] [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: 01/16/2025] [Revised: 02/13/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Colorectal cancer (CRC) is a significant worldwide health problem due to its high prevalence, mortality rates, and frequent diagnosis at advanced stages. While diagnostic and therapeutic approaches have evolved, the underlying mechanisms driving CRC initiation and progression are not yet fully understood. Early detection is critical for improving patient survival, as initial cancer stages often exhibit epigenetic changes-such as DNA methylation-that regulate gene expression and tumor progression. Identifying DNA methylation patterns and key survival-related genes in CRC could thus enhance diagnostic accuracy and extend patient lifespans. In this study, we apply two of our recently developed methods for identifying differential methylation and analyzing survival using a sparse, finite mixture of accelerated failure time regression models, focusing on key genes and pathways in CRC datasets. Our approach outperforms two other leading methods, yielding robust findings and identifying novel differentially methylated cytosines. We found that CRC patient survival time follows a two-component mixture regression model, where genes CDH11, EPB41L3, and DOCK2 are active in the more aggressive form of CRC, whereas TMEM215, PPP1R14A, GPR158, and NAPSB are active in the less aggressive form.
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Affiliation(s)
- Saeedeh Hajebi Khaniki
- Department of Biostatistics, School of Health, Mashhad University of Medical Sciences, Mashhad 9137673119, Iran;
| | - Farhad Shokoohi
- Department of Mathematical Sciences, University of Nevada Las Vegas, Las Vegas, NV 89154, USA
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2
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Sabale P, Waghmare S, Potey L, Khedekar P, Sabale V, Rarokar N, Chikhale R, Palekar R. Novel targeting strategies on signaling pathways of colorectal cancer. COLORECTAL CANCER 2024:489-531. [DOI: 10.1016/b978-0-443-13870-6.00017-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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3
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Dong X, Zhang Y, Sun Y, Nan Q, Li M, Ma L, Zhang L, Luo J, Qi Y, Miao Y. Promoter hypermethylation and comprehensive regulation of ncRNA lead to the down-regulation of ZNF880, providing a new insight for the therapeutics and research of colorectal cancer. BMC Med Genomics 2023; 16:148. [PMID: 37370088 PMCID: PMC10294494 DOI: 10.1186/s12920-023-01571-2] [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: 06/02/2022] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
The human genome encodes more than 350 kinds of Krüppel-associated box (KRAB) domain-containing zinc-finger proteins (KZFPs), KRAB-type ZNF transcription factor family (KZNF) plays a vital role in gene regulatory networks. The KZNF family members include a large number of highly homologous genes, gene subtypes and pseudogenes, and their expression has a high degree of tissue specificity and precision. Due to the high complexity of its regulatory network, the KZNF gene family has not been researched in sufficient, and the role of its members in the occurrence of cancer is mostly unexplored. In this study, ZNF880 was significantly associated with overall survival (OS) and disease-free survival (DFS) in colorectal carcinoma (CRC) patients. Low ZNF880 expression resulted in shorter OS and DFS. Combined with Colon adenocarcinoma (COAD) and Rectum adenocarcinoma (READ) data collection in the TCGA database, we found that ZNF880 was significantly down-regulated in CRC. Further analysis of the sequence variation of ZNF880 in CRC showed that ZNF880 accumulated a large number of SNV in the C2H2 domain and KRAB domain, while promoter region of ZNF880 also showed high methylation in COAD and READ. Combined with the Cbioportal and TIMER databases, the expression of mutant ZNF880 was significantly lower in COAD compared to the wild type. Simultaneously, the lncRNA-miRNA-ZNF880 ceRNA regulatory network was constructed through co-expression and miRNAs target gene prediction, demonstrating the precision of the ZNF880 regulatory network. In addition, the decreased expression of ZNF880 caused the significant immune infiltration decreases of CD8 + cells in COAD. In contrast, the immune infiltration of CD4 + cells and macrophages in COAD is positively correlated with ZNF880. Finally, through protein-protein interaction (PPI) network analysis and transcription factor target gene prediction, we screened out the genes most likely to be related to the function of ZNF880. CENPK, IFNGR2, REC8 and ZBTB17 were identified as the most closely functioning genes with ZNF880, which may indicate that ZNF880 has important links with the formation of cell centromere, tumor immunity, cell cycle and other pathways closely related to the occurrence of CRC. These studies show that the down-regulation of ZNF880 gene is closely related to CRC, and the targeted change of the expression of its regulatory molecules (miRNA and lncRNA) may be a new perspective for CRC treatment.
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Affiliation(s)
- Xiangqian Dong
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China
| | - Yinghui Zhang
- Department of Gastroenterology, Affiliated Hospital of Yunnan University, Kunming, 650021, China
| | - Yang Sun
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China
| | - Qiong Nan
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China
| | - Maojuan Li
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China
| | - Lanqing Ma
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China
| | - Lei Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China
| | - Juan Luo
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China
| | - Yating Qi
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China
| | - Yinglei Miao
- Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, NO.295 Xichang Road, Kunming, 650032, P.R. China.
- Yunnan Province Clinical Research Center for Digestive Diseases, Kunming, 650032, China.
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Mokhtari K, Peymani M, Rashidi M, Hushmandi K, Ghaedi K, Taheriazam A, Hashemi M. Colon cancer transcriptome. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 180-181:49-82. [PMID: 37059270 DOI: 10.1016/j.pbiomolbio.2023.04.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/31/2023] [Accepted: 04/06/2023] [Indexed: 04/16/2023]
Abstract
Over the last four decades, methodological innovations have continuously changed transcriptome profiling. It is now feasible to sequence and quantify the transcriptional outputs of individual cells or thousands of samples using RNA sequencing (RNA-seq). These transcriptomes serve as a connection between cellular behaviors and their underlying molecular mechanisms, such as mutations. This relationship, in the context of cancer, provides a chance to unravel tumor complexity and heterogeneity and uncover novel biomarkers or treatment options. Since colon cancer is one of the most frequent malignancies, its prognosis and diagnosis seem to be critical. The transcriptome technology is developing for an earlier and more accurate diagnosis of cancer which can provide better protectivity and prognostic utility to medical teams and patients. A transcriptome is a whole set of expressed coding and non-coding RNAs in an individual or cell population. The cancer transcriptome includes RNA-based changes. The combined genome and transcriptome of a patient may provide a comprehensive picture of their cancer, and this information is beginning to affect treatment decision-making in real-time. A full assessment of the transcriptome of colon (colorectal) cancer has been assessed in this review paper based on risk factors such as age, obesity, gender, alcohol use, race, and also different stages of cancer, as well as non-coding RNAs like circRNAs, miRNAs, lncRNAs, and siRNAs. Similarly, they have been examined independently in the transcriptome study of colon cancer.
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Affiliation(s)
- Khatere Mokhtari
- Department of Modern Biology, ACECR Institute of Higher Education (Isfahan Branch), Isfahan, Iran
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, 4815733971, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, 4815733971, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Gao SS, Zhang ZK, Wang XB, Ma Y, Yin GQ, Guo XB. Role of transcribed ultraconserved regions in gastric cancer and therapeutic perspectives. World J Gastroenterol 2022; 28:2900-2909. [PMID: 35978878 PMCID: PMC9280734 DOI: 10.3748/wjg.v28.i25.2900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 04/08/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is the fourth leading cause of cancer-related death. The occurrence and development of GC is a complex process involving multiple biological mechanisms. Although traditional regulation modulates molecular functions related to the occurrence and development of GC, the comprehensive mechanisms remain unclear. Ultraconserved region (UCR) refers to a genome sequence that is completely conserved in the homologous regions of the human, rat and mouse genomes, with 100% identity, without any insertions or deletions, and often located in fragile sites and tumour-related genes. The transcribed UCR (T-UCR) is transcribed from the UCR and is a new type of long noncoding RNA. Recent studies have found that the expression level of T-UCRs changes during the occurrence and development of GC, revealing a new mechanism underlying GC. Therefore, this article aims to review the relevant research on T-UCRs in GC, as well as the function of T-UCRs and their regulatory role in the occurrence and development of GC, to provide new strategies for GC diagnosis and treatment.
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Affiliation(s)
- Shen-Shuo Gao
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
| | - Zhi-Kai Zhang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
| | - Xu-Bin Wang
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Yan Ma
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Guo-Qing Yin
- Department of Anus and Intestine Surgery, Qingzhou Hospital Affiliated to Shandong First Medical University, Qingzhou 262500, Shandong Province, China
| | - Xiao-Bo Guo
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250021, Shandong Province, China
- Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
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Maity P, Halder A, Ghosh R, Chatterjee U, Barman S, Sarkar R. Immunohistochemistry as a Surrogate Marker of Underlying Molecular Derangements in Sporadic Colorectal Carcinoma in Children - A Series of Three Cases. Fetal Pediatr Pathol 2022; 41:98-106. [PMID: 32441577 DOI: 10.1080/15513815.2020.1765918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Background: Colorectal carcinomas (CRCs) are uncommon tumors in children. Here, we elucidate three cases of childhood CRCs with their underlying molecular derangements using immunohistochemistry (IHC) with emphasis on BRAF mutation. Case summary: All three CRCs were sporadic tumors involving the left colon with two of them having a mucinous phenotype. We performed IHC for BRAF, p53 and β-catenin along with markers of microsatellite instability (MSI) in all three tumors. All the tumors had diffuse strong cytoplasmic BRAF positivity, with focal p53 positivity in two cases and cytoplasmic β-catenin staining in one case. One case showed CpG island hypermethylation with isolated loss of PMS2 staining. None of the cases had any family history of CRC. Conclusions: IHC can be used as a surrogate marker for determining the underlying molecular derangements in CRC. Sporadic CRCs in children are a cumulative effect of multiple mutations, of which BRAF mutation is significant and critical for planning targeted therapy.
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Affiliation(s)
- Priyanka Maity
- Department of Pathology, Institute of Postgraduate Medical Education and Research, Kolkata, India
| | - Aniket Halder
- Department of GI Pathology, Institute of Postgraduate Medical Education and Research, Kolkata, India
| | - Ranajoy Ghosh
- Department of GI Pathology, Institute of Postgraduate Medical Education and Research, Kolkata, India
| | - Uttara Chatterjee
- Department of Pathology, Institute of Postgraduate Medical Education and Research, Kolkata, India
| | - Shibsankar Barman
- Department of Pediatric Surgery, Institute of Postgraduate Medical Education and Research, Kolkata, India
| | - Ruchirendra Sarkar
- Department of Pediatric Surgery, Institute of Postgraduate Medical Education and Research, Kolkata, India
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7
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Sun Y, Zhang Z, Zheng CQ, Sang LX. Mucosal lesions of the upper gastrointestinal tract in patients with ulcerative colitis: A review. World J Gastroenterol 2021; 27:2963-2978. [PMID: 34168401 PMCID: PMC8192286 DOI: 10.3748/wjg.v27.i22.2963] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/10/2021] [Accepted: 04/21/2021] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is a chronic, nonspecific, relapsing inflammatory bowel disease. The colorectum is considered the chief target organ of UC, whereas upper gastrointestinal (UGI) tract manifestations are infrequent. Recently, emerging evidence has suggested that UC presents complications in esophageal, stomachic, and duodenal mucosal injuries. However, UC-related UGI tract manifestations are varied and frequently silenced or concealed. Moreover, the endoscopic and microscopic characteristics of UGI tract complicated with UC are nonspecific. Therefore, UGI involvement may be ignored by many clinicians. In addition, no standard criteria have been established for patients with UC who should undergo fibrogastroduodenoscopy. Furthermore, specific treatment recommendations may be needed for patients with UC-associated UGI lesions. Herein, we review the esophageal, gastric, and duodenal mucosal lesions of the UC-associated UGI tract, as well as the potential pathogenesis and therapy.
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Affiliation(s)
- Yan Sun
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Zhe Zhang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Chang-Qing Zheng
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
| | - Li-Xuan Sang
- Department of Gastroenterology, Shengjing Hospital of China Medical University, Shenyang 110022, Liaoning Province, China
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8
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The Role of Polycomb Group Protein BMI1 in DNA Repair and Genomic Stability. Int J Mol Sci 2021; 22:ijms22062976. [PMID: 33804165 PMCID: PMC7998361 DOI: 10.3390/ijms22062976] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 03/09/2021] [Indexed: 12/31/2022] Open
Abstract
The polycomb group (PcG) proteins are a class of transcriptional repressors that mediate gene silencing through histone post-translational modifications. They are involved in the maintenance of stem cell self-renewal and proliferation, processes that are often dysregulated in cancer. Apart from their canonical functions in epigenetic gene silencing, several studies have uncovered a function for PcG proteins in DNA damage signaling and repair. In particular, members of the poly-comb group complexes (PRC) 1 and 2 have been shown to recruit to sites of DNA damage and mediate DNA double-strand break repair. Here, we review current understanding of the PRCs and their roles in cancer development. We then focus on the PRC1 member BMI1, discussing the current state of knowledge of its role in DNA repair and genome integrity, and outline how it can be targeted pharmacologically.
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Singh MP, Rai S, Pandey A, Singh NK, Srivastava S. Molecular subtypes of colorectal cancer: An emerging therapeutic opportunity for personalized medicine. Genes Dis 2021; 8:133-145. [PMID: 33997160 PMCID: PMC8099693 DOI: 10.1016/j.gendis.2019.10.013] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 10/16/2019] [Accepted: 10/17/2019] [Indexed: 02/07/2023] Open
Abstract
Molecular subtypes-based therapies offer new potential framework for desired and precise outcome in clinical settings. Current treatment strategies in colorectal cancer are largely 'one drug fit all' model for patients that display same pathological conditions. However, CRC is a very heterogenous set of malignancy that does not support for above criteria. Each subtype displays different pathological and genetic signatures. Based on these features, therapeutic stratification for individual patients may be designed, which may ultimately lead to improved therapeutic outcomes. In this comprehensive review, we have attempted to briefly outline major CRC pathways. A detailed overview of molecular subtypes and their clinical significance has been discussed. Present and future methods, governing CRC subtyping in the era of personalized therapy with a special emphasis on CMS subtypes of CRC has been reviewed. Together, discovery and validation of new CRC patient stratification methods, screening for novel therapeutic targets, and enhanced diagnosis of CRC may improve the treatment outcome.
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Affiliation(s)
- Manish Pratap Singh
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, UP, 211004, India
| | - Sandhya Rai
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, UP, 211004, India
| | - Ashutosh Pandey
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, UP, 211004, India
| | - Nand K. Singh
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, UP, 211004, India
| | - Sameer Srivastava
- Department of Biotechnology, Motilal Nehru National Institute of Technology, Allahabad, UP, 211004, India
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Gu M, Sun J, Zhang S, Chen J, Wang G, Ju S, Wang X. A novel methylation signature predicts inferior outcome of patients with PDAC. Aging (Albany NY) 2021; 13:2851-2863. [PMID: 33550277 PMCID: PMC7880369 DOI: 10.18632/aging.202347] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 11/10/2020] [Indexed: 04/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) will become the second most common cause of death in North America and Europe over the next 10 years owing to the lack of early diagnosis, poor treatment, and poor prognosis. This study evaluated the methylation array data of 184 patients with PDAC in The Cancer Genome Atlas database to explore methylation biomarkers related to patient outcome. Using Univariable Cox regression analysis and Lasso regression analysis method in the training dataset, it was found that the four DNA methylation markers (CCNT1, ITGB3, SDS, and HMOX2) were significantly correlated with the overall survival of patients with PDAC. Kaplan-Meier analysis showed that these four DNA methylation markers could significantly distinguish high-risk and low-risk patients. Receiver operating characteristic analysis further confirmed that the four DNA methylation markers had high sensitivity and specificity, which could predict the prognosis of patients. Moreover, there was a difference in the genetic mutations between high-risk and low-risk patients distinguished by the four-DNA methylation model, which can provide information for clinical treatment. Finally, compared with known biomarkers, the model was more accurate in predicting the prognosis of PDAC. This four-DNA methylation model has potential as a new independent prognostic indicator, and could be used for the diagnosis, monitoring, and precision medicine of pancreatic cancer.
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Affiliation(s)
- Minqi Gu
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Jing Sun
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Shunhao Zhang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Jing Chen
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
| | - Guihua Wang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- School of Public Health, Nantong University, Nantong, Jiangsu, China
| | - Shaoqing Ju
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- School of Public Health, Nantong University, Nantong, Jiangsu, China
| | - Xudong Wang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China
- School of Public Health, Nantong University, Nantong, Jiangsu, China
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11
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Xiang R, Fu T. Gastrointestinal adenocarcinoma analysis identifies promoter methylation-based cancer subtypes and signatures. Sci Rep 2020; 10:21234. [PMID: 33277583 PMCID: PMC7719188 DOI: 10.1038/s41598-020-78228-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 11/23/2020] [Indexed: 12/31/2022] Open
Abstract
Gastric adenocarcinoma (GAC) and colon adenocarcinoma (CAC) are the most common gastrointestinal cancer subtypes, with a high incidence and mortality. Numerous studies have shown that its occurrence and progression are significantly related to abnormal DNA methylation, especially CpG island methylation. However, little is known about the application of DNA methylation in GAC and CAC. The methylation profiles were accessed from the Cancer Genome Atlas database to identify promoter methylation-based cancer subtypes and signatures for GAC and CAC. Six hypo-methylated clusters for GAC and six hyper-methylated clusters for CAC were separately generated with different OS profiles, tumor progression became worse as the methylation level decreased in GAC or increased in CAC, and hypomethylation in GAC and hypermethylation in CAC were negatively correlated with microsatellite instability. Additionally, the hypo- and hyper-methylated site-based signatures with high accuracy, high efficiency and strong independence can separately predict the OS of GAC and CAC patients. By integrating the methylation-based signatures with prognosis-related clinicopathologic characteristics, two clinicopathologic-epigenetic nomograms were cautiously established with strong predictive performance and high accuracy. Our research indicates that methylation mechanisms differ between GAC and CAC, and provides novel clinical biomarkers for the diagnosis and treatment of GAC and CAC.
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Affiliation(s)
- Renshen Xiang
- Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China
- The Central Laboratory of the First Clinical College of Wuhan University, Wuhan, 430060, Hubei Province, China
| | - Tao Fu
- Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei Province, China.
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Value of Serum NEUROG1 Methylation for the Detection of Advanced Adenomas and Colorectal Cancer. Diagnostics (Basel) 2020; 10:diagnostics10070437. [PMID: 32605302 PMCID: PMC7399835 DOI: 10.3390/diagnostics10070437] [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: 05/27/2020] [Revised: 06/23/2020] [Accepted: 06/26/2020] [Indexed: 02/06/2023] Open
Abstract
Aberrant DNA methylation detected in liquid biopsies is a promising approach for colorectal cancer (CRC) detection, including premalignant advanced adenomas (AA). We evaluated the diagnostic capability of serum NEUROG1 methylation for the detection of AA and CRC. A CpG island in NEUROG1 promoter was assessed by bisulfite pyrosequencing in a case-control cohort to select optimal CpGs. Selected sites were evaluated through a nested methylation-specific qPCR custom assay in a screening cohort of 504 asymptomatic family-risk individuals. Individuals with no colorectal findings and benign pathologies showed low serum NEUROG1 methylation, similar to non-advanced adenomas. Contrarily, individuals bearing AA or CRC (advanced neoplasia—AN), exhibited increased NEUROG1 methylation. Using >1.3518% as NEUROG1 cut-off (90.60% specificity), 33.33% of AN and 32.08% of AA were identified, detecting 50% CRC cases. Nonetheless, the combination of NEUROG1 with fecal immunochemical test (FIT), together with age and gender through a multivariate logistic regression resulted in an AUC = 0.810 for AN, and 0.796 for AA, detecting all cancer cases and 35–47% AA (specificity 98–95%). The combination of NEUROG1 methylation with FIT, age and gender demonstrated a convenient performance for the detection of CRC and AA, providing a valuable tool for CRC screening programs in asymptomatic individuals.
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Siskova A, Cervena K, Kral J, Hucl T, Vodicka P, Vymetalkova V. Colorectal Adenomas-Genetics and Searching for New Molecular Screening Biomarkers. Int J Mol Sci 2020; 21:ijms21093260. [PMID: 32380676 PMCID: PMC7247353 DOI: 10.3390/ijms21093260] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 05/01/2020] [Accepted: 05/02/2020] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a malignant disease with an incidence of over 1.8 million new cases per year worldwide. CRC outcome is closely related to the respective stage of CRC and is more favorable at less advanced stages. Detection of early colorectal adenomas is the key to survival. In spite of implemented screening programs showing efficiency in the detection of early precancerous lesions and CRC in asymptomatic patients, a significant number of patients are still diagnosed in advanced stages. Research on CRC accomplished during the last decade has improved our understanding of the etiology and development of colorectal adenomas and revealed weaknesses in the general approach to their detection and elimination. Recent studies seek to find a reliable non-invasive biomarker detectable even in the blood. New candidate biomarkers could be selected on the basis of so-called liquid biopsy, such as long non-coding RNA, microRNA, circulating cell-free DNA, circulating tumor cells, and inflammatory factors released from the adenoma into circulation. In this work, we focused on both genetic and epigenetic changes associated with the development of colorectal adenomas into colorectal carcinoma and we also discuss new possible biomarkers that are detectable even in adenomas prior to cancer development.
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Affiliation(s)
- Anna Siskova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14200 Prague, Czech Republic; (K.C.); (J.K.); (V.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 12800 Prague, Czech Republic
- Correspondence: (A.S.); (P.V.); Tel.: +420-241062251 (A.S.); +420-241062694 (P.V.)
| | - Klara Cervena
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14200 Prague, Czech Republic; (K.C.); (J.K.); (V.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 12800 Prague, Czech Republic
| | - Jan Kral
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14200 Prague, Czech Republic; (K.C.); (J.K.); (V.V.)
- Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic;
| | - Tomas Hucl
- Institute for Clinical and Experimental Medicine, Videnska 1958/9, 14021 Prague, Czech Republic;
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14200 Prague, Czech Republic; (K.C.); (J.K.); (V.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 12800 Prague, Czech Republic
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 32300 Pilsen, Czech Republic
- Correspondence: (A.S.); (P.V.); Tel.: +420-241062251 (A.S.); +420-241062694 (P.V.)
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Videnska 1083, 14200 Prague, Czech Republic; (K.C.); (J.K.); (V.V.)
- Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Albertov 4, 12800 Prague, Czech Republic
- Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 76, 32300 Pilsen, Czech Republic
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14
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Functional Prediction of Candidate MicroRNAs for CRC Management Using in Silico Approach. Int J Mol Sci 2019; 20:ijms20205190. [PMID: 31635135 PMCID: PMC6834124 DOI: 10.3390/ijms20205190] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 09/13/2019] [Accepted: 09/14/2019] [Indexed: 02/07/2023] Open
Abstract
Approximately 30–50% of malignant growths can be prevented by avoiding risk factors and implementing evidence-based strategies. Colorectal cancer (CRC) accounted for the second most common cancer and the third most common cause of cancer death worldwide. This cancer subtype can be reduced by early detection and patients’ management. In this study, the functional roles of the identified microRNAs were determined using an in silico pipeline. Five microRNAs identified using an in silico approach alongside their seven target genes from our previous study were used as datasets in this study. Furthermore, the secondary structure and the thermodynamic energies of the microRNAs were revealed by Mfold algorithm. The triplex binding ability of the oligonucleotide with the target promoters were analyzed by Trident. Finally, evolutionary stage-specific somatic events and co-expression analysis of the target genes in CRC were analyzed by SEECancer and GeneMANIA plugin in Cytoscape. Four of the five microRNAs have the potential to form more than one secondary structure. The ranges of the observed/expected ratio of CpG dinucleotides of these genes range from 0.60 to 1.22. Three of the candidate microRNA were capable of forming multiple triplexes along with three of the target mRNAs. Four of the total targets were involved in either early or metastatic stage-specific events while three other genes were either a product of antecedent or subsequent events of the four genes implicated in CRC. The secondary structure of the candidate microRNAs can be used to explain the different degrees of genetic regulation in CRC due to their conformational role to modulate target interaction. Furthermore, due to the regulation of important genes in the CRC pathway and the enrichment of the microRNA with triplex binding sites, they may be a useful diagnostic biomarker for the disease subtype.
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15
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Keum N, Liu L, Hamada T, Qian ZR, Nowak JA, Cao Y, da Silva A, Kosumi K, Song M, Nevo D, Wang M, Chan AT, Meyerhardt JA, Fuchs CS, Wu K, Ogino S, Nishihara R, Zhang X. Calcium intake and colon cancer risk subtypes by tumor molecular characteristics. Cancer Causes Control 2019; 30:637-649. [PMID: 30963391 DOI: 10.1007/s10552-019-01165-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Accepted: 03/28/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND A preventive potential of high calcium intake against colorectal cancer has been indicated for distal colon cancer, which is inversely associated with high-level CpG island methylator phenotype (CIMP), high-level microsatellite instability (MSI), and BRAF and PIK3CA mutations. In addition, BRAF mutation is strongly inversely correlated with KRAS mutation. We hypothesized that the association between calcium intake and colon cancer risk might vary by these molecular features. METHODS We prospectively followed 88,506 women from the Nurses' Health Study and 47,733 men from the Health Professionals Follow-up Study for up to 30 years. Duplication-method Cox proportional cause-specific hazards regression was used to estimate multivariable hazard ratios (HRs), and 95% confidence intervals (95% CIs) for the associations between calcium intake and the risk of colon cancer subtypes. By Bonferroni correction, the α-level was adjusted to 0.01. RESULTS Based on 853 colon cancer cases, the inverse association between dietary calcium intake and colon cancer risk differed by CIMP status (pheterogeneity = 0.01). Per each 300 mg/day increase in intake, multivariable HRs were 0.84 (95% CI 0.76-0.94) for CIMP-negative/low and 1.12 (95% CI 0.93-1.34) for CIMP-high. Similar differential associations were suggested for MSI subtypes (pheterogeneity = 0.02), with the corresponding HR being 0.86 (95% CI 0.77-0.95) for non-MSI-high and 1.10 (95% CI 0.92-1.32) for MSI-high. No differential associations were observed by BRAF, KRAS, or PIK3CA mutations. CONCLUSION The inverse association between dietary calcium intake and colon cancer risk may be specific to CIMP-negative/low and possibly non-MSI-high subtypes.
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Affiliation(s)
- NaNa Keum
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Building 2, 3rd Floor, 665 Huntington Avenue, Boston, MA, 02115, USA. .,Department of Food Science and Biotechnology, Dongguk University, Goyang, South Korea.
| | - Li Liu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Building 2, 3rd Floor, 665 Huntington Avenue, Boston, MA, 02115, USA.,Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.,Department of Epidemiology and Biostatistics, and the Ministry of Education Key Lab of Environment and Health, School of Public Health, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Tsuyoshi Hamada
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Zhi Rong Qian
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Jonathan A Nowak
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Yin Cao
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Annacarolina da Silva
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Keisuke Kosumi
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Mingyang Song
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Building 2, 3rd Floor, 665 Huntington Avenue, Boston, MA, 02115, USA.,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.,Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - Daniel Nevo
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Molin Wang
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Andrew T Chan
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.,Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.,Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Jeffrey A Meyerhardt
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA
| | - Charles S Fuchs
- Yale Cancer Center, New Haven, CT, USA.,Department of Medicine, Yale School of Medicine, New Haven, CT, USA.,Smilow Cancer Hospital, New Haven, CT, USA
| | - Kana Wu
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Building 2, 3rd Floor, 665 Huntington Avenue, Boston, MA, 02115, USA
| | - Shuji Ogino
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Building 2, 3rd Floor, 665 Huntington Avenue, Boston, MA, 02115, USA.,Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.,Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Reiko Nishihara
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Building 2, 3rd Floor, 665 Huntington Avenue, Boston, MA, 02115, USA.,Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.,Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.,Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Xuehong Zhang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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16
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Hamada T, Nowak JA, Milner DA, Song M, Ogino S. Integration of microbiology, molecular pathology, and epidemiology: a new paradigm to explore the pathogenesis of microbiome-driven neoplasms. J Pathol 2019; 247:615-628. [PMID: 30632609 PMCID: PMC6509405 DOI: 10.1002/path.5236] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 12/24/2018] [Accepted: 01/06/2019] [Indexed: 02/06/2023]
Abstract
Molecular pathological epidemiology (MPE) is an integrative transdisciplinary field that addresses heterogeneous effects of exogenous and endogenous factors (collectively termed 'exposures'), including microorganisms, on disease occurrence and consequences, utilising molecular pathological signatures of the disease. In parallel with the paradigm of precision medicine, findings from MPE research can provide aetiological insights into tailored strategies of disease prevention and treatment. Due to the availability of molecular pathological tests on tumours, the MPE approach has been utilised predominantly in research on cancers including breast, lung, prostate, and colorectal carcinomas. Mounting evidence indicates that the microbiome (inclusive of viruses, bacteria, fungi, and parasites) plays an important role in a variety of human diseases including neoplasms. An alteration of the microbiome may be not only a cause of neoplasia but also an informative biomarker that indicates or mediates the association of an epidemiological exposure with health conditions and outcomes. To adequately educate and train investigators in this emerging area, we herein propose the integration of microbiology into the MPE model (termed 'microbiology-MPE'), which could improve our understanding of the complex interactions of environment, tumour cells, the immune system, and microbes in the tumour microenvironment during the carcinogenic process. Using this approach, we can examine how lifestyle factors, dietary patterns, medications, environmental exposures, and germline genetics influence cancer development and progression through impacting the microbial communities in the human body. Further integration of other disciplines (e.g. pharmacology, immunology, nutrition) into microbiology-MPE would expand this developing research frontier. With the advent of high-throughput next-generation sequencing technologies, researchers now have increasing access to large-scale metagenomics as well as other omics data (e.g. genomics, epigenomics, proteomics, and metabolomics) in population-based research. The integrative field of microbiology-MPE will open new opportunities for personalised medicine and public health. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Tsuyoshi Hamada
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Jonathan A Nowak
- Department of Pathology Program in MPE Molecular Pathological Epidemiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Danny A Milner
- American Society for Clinical Pathology, Chicago, Illinois, USA
| | - Mingyang Song
- Departments of Epidemiology and Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Shuji Ogino
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA
- Department of Pathology Program in MPE Molecular Pathological Epidemiology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA
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17
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Kamińska K, Nalejska E, Kubiak M, Wojtysiak J, Żołna Ł, Kowalewski J, Lewandowska MA. Prognostic and Predictive Epigenetic Biomarkers in Oncology. Mol Diagn Ther 2019; 23:83-95. [PMID: 30523565 PMCID: PMC6394434 DOI: 10.1007/s40291-018-0371-7] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Epigenetic patterns, such as DNA methylation, histone modifications, and non-coding RNAs, can be both driver factors and characteristic features of certain malignancies. Aberrant DNA methylation can lead to silencing of crucial tumor suppressor genes or upregulation of oncogene expression. Histone modifications and chromatin spatial organization, which affect transcription, regulation of gene expression, DNA repair, and replication, have been associated with multiple tumors. Certain microRNAs (miRNAs), mainly those that silence tumor suppressor genes and occur in a greater number of copies, have also been shown to promote oncogenesis. Multiple patterns of these epigenetic factors occur specifically in certain malignancies, which allows their potential use as biomarkers. This review presents examples of tests for each group of epigenetic factors that are currently available or in development for use in early cancer detection, prediction, prognosis, and response to treatment. The availability of blood-based biomarkers is noted, as they allow sampling invasiveness to be reduced and the sampling procedure to be simplified. The article stresses the role of epigenetics as a crucial element of future cancer diagnostics and therapy.
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Affiliation(s)
- Katarzyna Kamińska
- Molecular Oncology and Genetics Department, Innovative Medical Forum, The F. Lukaszczyk Oncology Center, Bydgoszcz, Poland
- Department of Thoracic Surgery and Tumors, L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Ewelina Nalejska
- Molecular Oncology and Genetics Department, Innovative Medical Forum, The F. Lukaszczyk Oncology Center, Bydgoszcz, Poland
- Department of Thoracic Surgery and Tumors, L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Marta Kubiak
- Molecular Oncology and Genetics Department, Innovative Medical Forum, The F. Lukaszczyk Oncology Center, Bydgoszcz, Poland
- Department of Thoracic Surgery and Tumors, L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Joanna Wojtysiak
- Molecular Oncology and Genetics Department, Innovative Medical Forum, The F. Lukaszczyk Oncology Center, Bydgoszcz, Poland
- Department of Thoracic Surgery and Tumors, L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Łukasz Żołna
- Department of Thoracic Surgery and Tumors, L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Janusz Kowalewski
- Department of Thoracic Surgery and Tumors, L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
| | - Marzena Anna Lewandowska
- Molecular Oncology and Genetics Department, Innovative Medical Forum, The F. Lukaszczyk Oncology Center, Bydgoszcz, Poland.
- Department of Thoracic Surgery and Tumors, L. Rydygier Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
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18
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Ogino S, Nowak JA, Hamada T, Milner DA, Nishihara R. Insights into Pathogenic Interactions Among Environment, Host, and Tumor at the Crossroads of Molecular Pathology and Epidemiology. ANNUAL REVIEW OF PATHOLOGY 2019; 14:83-103. [PMID: 30125150 PMCID: PMC6345592 DOI: 10.1146/annurev-pathmechdis-012418-012818] [Citation(s) in RCA: 168] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Evidence indicates that diet, nutrition, lifestyle, the environment, the microbiome, and other exogenous factors have pathogenic roles and also influence the genome, epigenome, transcriptome, proteome, and metabolome of tumor and nonneoplastic cells, including immune cells. With the need for big-data research, pathology must transform to integrate data science fields, including epidemiology, biostatistics, and bioinformatics. The research framework of molecular pathological epidemiology (MPE) demonstrates the strengths of such an interdisciplinary integration, having been used to study breast, lung, prostate, and colorectal cancers. The MPE research paradigm not only can provide novel insights into interactions among environment, tumor, and host but also opens new research frontiers. New developments-such as computational digital pathology, systems biology, artificial intelligence, and in vivo pathology technologies-will further transform pathology and MPE. Although it is necessary to address the rarity of transdisciplinary education and training programs, MPE provides an exemplary model of integrative scientific approaches and contributes to advancements in precision medicine, therapy, and prevention.
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Affiliation(s)
- Shuji Ogino
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02215, USA; , ,
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, Massachusetts 02215, USA;
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA
| | - Jonathan A Nowak
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02215, USA; , ,
| | - Tsuyoshi Hamada
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, Massachusetts 02215, USA;
| | - Danny A Milner
- American Society for Clinical Pathology, Chicago, Illinois 60603, USA;
| | - Reiko Nishihara
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02215, USA; , ,
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts 02142, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA
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19
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Ogino S, Nowak JA, Hamada T, Phipps AI, Peters U, Milner DA, Giovannucci EL, Nishihara R, Giannakis M, Garrett WS, Song M. Integrative analysis of exogenous, endogenous, tumour and immune factors for precision medicine. Gut 2018; 67:1168-1180. [PMID: 29437869 PMCID: PMC5943183 DOI: 10.1136/gutjnl-2017-315537] [Citation(s) in RCA: 128] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Revised: 01/02/2018] [Accepted: 01/05/2018] [Indexed: 12/14/2022]
Abstract
Immunotherapy strategies targeting immune checkpoints such as the CTLA4 and CD274 (programmed cell death 1 ligand 1, PD-L1)/PDCD1 (programmed cell death 1, PD-1) T-cell coreceptor pathways are revolutionising oncology. The approval of pembrolizumab use for solid tumours with high-level microsatellite instability or mismatch repair deficiency by the US Food and Drug Administration highlights promise of precision immuno-oncology. However, despite evidence indicating influences of exogenous and endogenous factors such as diet, nutrients, alcohol, smoking, obesity, lifestyle, environmental exposures and microbiome on tumour-immune interactions, integrative analyses of those factors and immunity lag behind. Immune cell analyses in the tumour microenvironment have not adequately been integrated into large-scale studies. Addressing this gap, the transdisciplinary field of molecular pathological epidemiology (MPE) offers research frameworks to integrate tumour immunology into population health sciences, and link the exposures and germline genetics (eg, HLA genotypes) to tumour and immune characteristics. Multilevel research using bioinformatics, in vivo pathology and omics (genomics, epigenomics, transcriptomics, proteomics and metabolomics) technologies is possible with use of tissue, peripheral blood circulating cells, cell-free plasma, stool, sputum, urine and other body fluids. This immunology-MPE model can synergise with experimental immunology, microbiology and systems biology. GI neoplasms represent exemplary diseases for the immunology-MPE model, given rich microbiota and immune tissues of intestines, and the well-established carcinogenic role of intestinal inflammation. Proof-of-principle studies on colorectal cancer provided insights into immunomodulating effects of aspirin, vitamin D, inflammatory diets and omega-3 polyunsaturated fatty acids. The integrated immunology-MPE model can contribute to better understanding of environment-tumour-immune interactions, and effective immunoprevention and immunotherapy strategies for precision medicine.
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Affiliation(s)
- Shuji Ogino
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA,Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA,Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA
| | - Jonathan A Nowak
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Tsuyoshi Hamada
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA,Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA,Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Danny A Milner
- American Society for Clinical Pathology, Chicago, Illinois, USA
| | - Edward L Giovannucci
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA,Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Reiko Nishihara
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA,Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA,Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Marios Giannakis
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA,Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Wendy S Garrett
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts, USA,Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA,Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA
| | - Mingyang Song
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, Massachusetts, USA,Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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20
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Mandal P. Molecular mechanistic pathway of colorectal carcinogenesis associated with intestinal microbiota. Anaerobe 2018; 49:63-70. [DOI: 10.1016/j.anaerobe.2017.12.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 09/24/2017] [Accepted: 12/18/2017] [Indexed: 12/13/2022]
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21
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Review Article: The Role of Molecular Pathological Epidemiology in the Study of Neoplastic and Non-neoplastic Diseases in the Era of Precision Medicine. Epidemiology 2018; 27:602-11. [PMID: 26928707 DOI: 10.1097/ede.0000000000000471] [Citation(s) in RCA: 146] [Impact Index Per Article: 20.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Molecular pathology diagnostics to subclassify diseases based on pathogenesis are increasingly common in clinical translational medicine. Molecular pathological epidemiology (MPE) is an integrative transdisciplinary science based on the unique disease principle and the disease continuum theory. While it has been most commonly applied to research on breast, lung, and colorectal cancers, MPE can investigate etiologic heterogeneity in non-neoplastic diseases, such as cardiovascular diseases, obesity, diabetes mellitus, drug toxicity, and immunity-related and infectious diseases. This science can enhance causal inference by linking putative etiologic factors to specific molecular biomarkers as outcomes. Technological advances increasingly enable analyses of various -omics, including genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, microbiome, immunomics, interactomics, etc. Challenges in MPE include sample size limitations (depending on availability of biospecimens or biomedical/radiological imaging), need for rigorous validation of molecular assays and study findings, and paucities of interdisciplinary experts, education programs, international forums, and standardized guidelines. To address these challenges, there are ongoing efforts such as multidisciplinary consortium pooling projects, the International Molecular Pathological Epidemiology Meeting Series, and the Strengthening the Reporting of Observational Studies in Epidemiology-MPE guideline project. Efforts should be made to build biorepository and biobank networks, and worldwide population-based MPE databases. These activities match with the purposes of the Big Data to Knowledge (BD2K), Genetic Associations and Mechanisms in Oncology (GAME-ON), and Precision Medicine Initiatives of the United States National Institute of Health. Given advances in biotechnology, bioinformatics, and computational/systems biology, there are wide open opportunities in MPE to contribute to public health.
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Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science 2018; 357:357/6348/eaal2380. [PMID: 28729483 DOI: 10.1126/science.aal2380] [Citation(s) in RCA: 894] [Impact Index Per Article: 127.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Chromatin and associated epigenetic mechanisms stabilize gene expression and cellular states while also facilitating appropriate responses to developmental or environmental cues. Genetic, environmental, or metabolic insults can induce overly restrictive or overly permissive epigenetic landscapes that contribute to pathogenesis of cancer and other diseases. Restrictive chromatin states may prevent appropriate induction of tumor suppressor programs or block differentiation. By contrast, permissive or "plastic" states may allow stochastic oncogene activation or nonphysiologic cell fate transitions. Whereas many stochastic events will be inconsequential "passengers," some will confer a fitness advantage to a cell and be selected as "drivers." We review the broad roles played by epigenetic aberrations in tumor initiation and evolution and their potential to give rise to all classic hallmarks of cancer.
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Affiliation(s)
- William A Flavahan
- Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, and Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Elizabeth Gaskell
- Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, and Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
| | - Bradley E Bernstein
- Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA, and Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
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23
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Matos P, Jordan P. Targeting Colon Cancers with Mutated BRAF and Microsatellite Instability. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1110:7-21. [PMID: 30623363 DOI: 10.1007/978-3-030-02771-1_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The subgroup of colon cancer (CRC) characterized by mutation in the BRAF gene and high mutation rate in the genomic DNA sequence, known as the microsatellite instability (MSI) phenotype, accounts for roughly 10% of the patients and derives from polyps with a serrated morphology. In this review, both features are discussed with regard to therapeutic opportunities. The most prevalent cancer-associated BRAF mutation is BRAF V600E that causes constitutive activation of the pro-proliferative MAPK pathway. Unfortunately, the available BRAF-specific inhibitors had little clinical benefit for metastatic CRC patients due to adaptive MAPK reactivation. Recent contributions for the development of new combination therapy approaches to pathway inhibition will be highlighted. In addition, we review the promising role of the recently developed immune checkpoint therapy for the treatment of this CRC subtype. The MSI phenotype of this subgroup results from an inactivated DNA mismatch repair system and leads to frameshift mutations with translation of new amino acid stretches and the generation of neo-antigens. This most likely explains the observed high degree of infiltration by tumour-associated lymphocytes. As cytotoxic lymphocytes are already part of the tumour environment, their activation by immune checkpoint therapy approaches is highly promising.
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Affiliation(s)
- Paulo Matos
- Department of Chemistry and Biochemistry, Faculty of Sciences, University of Lisbon, Lisbon, Portugal.,BioISI - Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal.,Department of Human Genetics, National Health Institute 'Dr. Ricardo Jorge', Lisbon, Portugal
| | - Peter Jordan
- BioISI - Biosystems & Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, Lisbon, Portugal. .,Department of Human Genetics, National Health Institute 'Dr. Ricardo Jorge', Lisbon, Portugal.
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24
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Ogino S, Jhun I, Mata DA, Soong TR, Hamada T, Liu L, Nishihara R, Giannakis M, Cao Y, Manson JE, Nowak JA, Chan AT. Integration of pharmacology, molecular pathology, and population data science to support precision gastrointestinal oncology. NPJ Precis Oncol 2017; 1. [PMID: 29552640 PMCID: PMC5856171 DOI: 10.1038/s41698-017-0042-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Precision medicine has a goal of customizing disease prevention and treatment strategies. Under the precision medicine paradigm, each patient has unique pathologic processes resulting from cellular genomic, epigenomic, proteomic, and metabolomic alterations, which are influenced by pharmacological, environmental, microbial, dietary, and lifestyle factors. Hence, to realize the promise of precision medicine, multi-level research methods that can comprehensively analyze many of these variables are needed. In order to address this gap, the integrative field of molecular pathology and population data science (i.e., molecular pathological epidemiology) has been developed to enable such multi-level analyses, especially in gastrointestinal cancer research. Further integration of pharmacology can improve our understanding of drug effects, and inform decision-making of drug use at both the individual and population levels. Such integrative research demonstrated potential benefits of aspirin in colorectal carcinoma with PIK3CA mutations, providing the basis for new clinical trials. Evidence also suggests that HPGD (15-PDGH) expression levels in normal colon and the germline rs6983267 polymorphism that relates to tumor CTNNB1 (β-catenin)/WNT signaling status may predict the efficacy of aspirin for cancer chemoprevention. As immune checkpoint blockade targeting the CD274 (PD-L1)/PDCD1 (PD-1) pathway for microsatellite instability-high (or mismatch repair-deficient) metastatic gastrointestinal or other tumors has become standard of care, potential modifying effects of dietary, lifestyle, microbial, and environmental factors on immunotherapy need to be studied to further optimize treatment strategies. With its broad applicability, our integrative approach can provide insights into the interactive role of medications, exposures, and molecular pathology, and guide the development of precision medicine.
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Affiliation(s)
- Shuji Ogino
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Iny Jhun
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Douglas A Mata
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Thing Rinda Soong
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Tsuyoshi Hamada
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Li Liu
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Reiko Nishihara
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.,Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Marios Giannakis
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.,Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Yin Cao
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.,Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - JoAnn E Manson
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.,Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jonathan A Nowak
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.,Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Andrew T Chan
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.,Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Boston, MA, USA.,Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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25
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Wang Y, He T, Herman JG, Linghu E, Yang Y, Fuks F, Zhou F, Song L, Guo M. Methylation of ZNF331 is an independent prognostic marker of colorectal cancer and promotes colorectal cancer growth. Clin Epigenetics 2017; 9:115. [PMID: 29075358 PMCID: PMC5648453 DOI: 10.1186/s13148-017-0417-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 10/05/2017] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND ZNF331 was reported to be a transcriptional repressor. Methylation of the promoter region of ZNF331 has been found frequently in human esophageal and gastric cancers. The function and methylation status of ZNF331 remain to be elucidated in human colorectal cancer (CRC). METHODS Six colorectal cancer cell lines, 146 cases of primary colorectal cancer samples, and 10 cases of noncancerous colorectal mucosa were analyzed in this study using the following techniques: methylation specific PCR (MSP), qRT-PCR, siRNA, flow cytometry, xenograft mice, MTT, colony formation, and transfection assays. RESULTS Loss of ZNF331 expression was found in DLD1 and SW48 cells, reduced expression was found in SW480, SW620, and HCT116 cells, and high level expression was detected in DKO cells. Complete methylation of the ZNF331 in the promoter region was found in DLD1 and SW48 cells, partial methylation was found in SW480, SW620, and HCT116 cells, and unmethylation was detected in DKO cells. Loss of/reduced expression of ZNF331 is correlated with promoter region methylation. Restoration of ZNF331 expression was induced by 5-aza-2'-deoxycytidine (DAC) in DLD1 and SW48 cells. These results suggest that ZNF331 expression is regulated by promoter region methylation in CRC cells. ZNF331 was methylated in 67.1% (98/146) of human primary colorectal cancer samples. Methylation of ZNF331 was significantly associated with tumor size, overall survival (OS), and disease-free survival (DFS) (p < 0.01, p < 0.01, p < 0.05). Methylation of ZNF331 was an independent poor prognostic marker for 5-year OS and 5-year DFS (both p < 0.05). ZNF331 suppressed cell proliferation and colony formation in CRC cells and suppressed human CRC cell xenograft growth in mice. CONCLUSIONS ZNF331 is frequently methylated in human colorectal cancer, and the expression of ZNF331 is regulated by promoter region methylation. Methylation of ZNF331 is a poor prognostic marker of CRC.
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Affiliation(s)
- Yuzhu Wang
- Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853 China
- Department of Geriatric Digestive System, Chinese PLA Navy General Hospital, 6 Fucheng Road, Beijing, 100048 China
| | - Tao He
- Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853 China
| | - James G. Herman
- The Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213 USA
| | - Enqiang Linghu
- Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853 China
| | - Yunsheng Yang
- Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853 China
| | - François Fuks
- Laboratory of Cancer Epigenetics, Free University of Brussels (U.L.B.), 1070 Brussels, Belgium
| | - Fuyou Zhou
- Department of Thoracic Surgery, Anyang Tumor Hospital, Anyang, 455000 China
| | - Linjie Song
- Department of General Surgery, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853 China
- Medical College of NanKai University, Tianjin, 300071 China
| | - Mingzhou Guo
- Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853 China
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26
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Heterogeneity Aware Random Forest for Drug Sensitivity Prediction. Sci Rep 2017; 7:11347. [PMID: 28900181 PMCID: PMC5595802 DOI: 10.1038/s41598-017-11665-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Accepted: 08/29/2017] [Indexed: 12/26/2022] Open
Abstract
Samples collected in pharmacogenomics databases typically belong to various cancer types. For designing a drug sensitivity predictive model from such a database, a natural question arises whether a model trained on diverse inter-tumor heterogeneous samples will perform similar to a predictive model that takes into consideration the heterogeneity of the samples in model training and prediction. We explore this hypothesis and observe that ensemble model predictions obtained when cancer type is known out-perform predictions when that information is withheld even when the samples sizes for the former is considerably lower than the combined sample size. To incorporate the heterogeneity idea in the commonly used ensemble based predictive model of Random Forests, we propose Heterogeneity Aware Random Forests (HARF) that assigns weights to the trees based on the category of the sample. We treat heterogeneity as a latent class allocation problem and present a covariate free class allocation approach based on the distribution of leaf nodes of the model ensemble. Applications on CCLE and GDSC databases show that HARF outperforms traditional Random Forest when the average drug responses of cancer types are different.
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27
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Houshmand M, Abbaszadegan MR, Kerachian MA. Assessment of Bone Morphogenetic Protein 3 Methylation in Iranian Patients with Colorectal Cancer. Middle East J Dig Dis 2017; 9:158-163. [PMID: 28894518 PMCID: PMC5585908 DOI: 10.15171/mejdd.2017.67] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
BACKGROUND
Colorectal cancer (CRC) is a common cancer that results in outstanding morbidity and mortality
worldwide. DNA methylation is one of the most important epigenetic events that is thought to occur
during the early stages of oncogenic transformation especially in CRC. The aim of this study was to
investigate whether hypermethylation of bone morphogenetic protein 3 (BMP3) in tissue samples is
implicated in Iranian patients with CRC.
METHODS
From fresh frozen tissue samples of 30 patients with CRC, the DNA was isolated, treated with
sodium bisulfite and analyzed by methylation-specific polymerase chain reaction with primers specific
for methylated or unmethylated promoter sequences of the BMP3 gene. Demographic characteristics of
the patients including age, sex, tumor grade, location, stage, and TNM classification were evaluated and
the relationship between hypermethylation of the gene and clinicopathological features was analyzed.
RESULTS
Methylation of the BMP3 promoter was often present in the DNA extracted from the tumoral
tissues. A sensitivity of 56.66% and specificity of 93.3% were attained in the detection of colorectal
neoplasia.
CONCLUSION
We assumed that solely BMP3 methylation analysis in our population is not sufficient to select
the gene as a screening biomarker and it should be considered in combination with other markers
to screen for detection of colorectal cancer.
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Affiliation(s)
- Massoud Houshmand
- Department of Medical Genetics, National Institute for Genetic Engineering and Biotechnology, Tehran, Iran.,Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Abbaszadegan
- Department of Biology, Nour Danesh Institute of Higher Education, Meyme, Isfahan, Iran.,Division of Human Genetics, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Medical Genetics, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Amin Kerachian
- Department of Biology, Nour Danesh Institute of Higher Education, Meyme, Isfahan, Iran.,Department of Medical Genetics, Mashhad University of Medical Sciences, Mashhad, Iran.,Cancer Genetics Research Unit, Reza Radiation Oncology Center, Mashhad, Iran
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Abstract
Length of the telomere (TL), a structure at the tip of chromosome that protects and ensures stability, is determined by multi-protein complexes such as telosome/shelterin and telomerase. Earlier studies from our laboratory show that longer TL has potential to be positive predictive biomarker of clinical outcome to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy in patients with KRAS WT metastatic colorectal cancer. Although there is extensive literature suggesting the role of shelterin and telomerase, not much literature exists that describes the role of EGFR and KRAS pathway in regulating TL. This detailed review focuses on an insight into various components, including proteins, enzymes and transcription factors, interlinking between EGFR pathways and telomerase that regulate TL.
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29
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Sánchez-Vega F, Gotea V, Chen YC, Elnitski L. CpG island methylator phenotype in adenocarcinomas from the digestive tract: Methods, conclusions, and controversies. World J Gastrointest Oncol 2017; 9:105-120. [PMID: 28344746 PMCID: PMC5348626 DOI: 10.4251/wjgo.v9.i3.105] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 10/01/2016] [Accepted: 01/03/2017] [Indexed: 02/05/2023] Open
Abstract
Over the last two decades, cancer-related alterations in DNA methylation that regulate transcription have been reported for a variety of tumors of the gastrointestinal tract. Due to its relevance for translational research, great emphasis has been placed on the analysis and molecular characterization of the CpG island methylator phenotype (CIMP), defined as widespread hypermethylation of CpG islands in clinically distinct subsets of cancer patients. Here, we present an overview of previous work in this field and also explore some open questions using cross-platform data for esophageal, gastric, and colorectal adenocarcinomas from The Cancer Genome Atlas. We provide a data-driven, pan-gastrointestinal stratification of individual samples based on CIMP status and we investigate correlations with oncogenic alterations, including somatic mutations and epigenetic silencing of tumor suppressor genes. Besides known events in CIMP such as BRAF V600E mutation, CDKN2A silencing or MLH1 inactivation, we discuss the potential role of emerging actors such as Wnt pathway deregulation through truncating mutations in RNF43 and epigenetic silencing of WIF1. Our results highlight the existence of molecular similarities that are superimposed over a larger backbone of tissue-specific features and can be exploited to reduce heterogeneity of response in clinical trials.
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30
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Hamada T, Keum N, Nishihara R, Ogino S. Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis. J Gastroenterol 2017; 52:265-275. [PMID: 27738762 PMCID: PMC5325774 DOI: 10.1007/s00535-016-1272-3] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 09/22/2016] [Indexed: 02/07/2023]
Abstract
Molecular pathological epidemiology (MPE) is an integrative field that utilizes molecular pathology to incorporate interpersonal heterogeneity of a disease process into epidemiology. In each individual, the development and progression of a disease are determined by a unique combination of exogenous and endogenous factors, resulting in different molecular and pathological subtypes of the disease. Based on "the unique disease principle," the primary aim of MPE is to uncover an interactive relationship between a specific environmental exposure and disease subtypes in determining disease incidence and mortality. This MPE approach can provide etiologic and pathogenic insights, potentially contributing to precision medicine for personalized prevention and treatment. Although breast, prostate, lung, and colorectal cancers have been among the most commonly studied diseases, the MPE approach can be used to study any disease. In addition to molecular features, host immune status and microbiome profile likely affect a disease process, and thus serve as informative biomarkers. As such, further integration of several disciplines into MPE has been achieved (e.g., pharmaco-MPE, immuno-MPE, and microbial MPE), to provide novel insights into underlying etiologic mechanisms. With the advent of high-throughput sequencing technologies, available genomic and epigenomic data have expanded dramatically. The MPE approach can also provide a specific risk estimate for each disease subgroup, thereby enhancing the impact of genome-wide association studies on public health. In this article, we present recent progress of MPE, and discuss the importance of accounting for the disease heterogeneity in the era of big-data health science and precision medicine.
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Affiliation(s)
- Tsuyoshi Hamada
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Room SM1036, Boston, MA, 02215, USA
| | - NaNa Keum
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Reiko Nishihara
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Room SM1036, Boston, MA, 02215, USA.
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, 450 Brookline Ave., Room SM1036, Boston, MA, 02215, USA.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 450 Brookline Ave., Room SM1036, Boston, MA, 02215, USA.
- Department of Oncologic Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
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31
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Campbell PT, Rebbeck TR, Nishihara R, Beck AH, Begg CB, Bogdanov AA, Cao Y, Coleman HG, Freeman GJ, Heng YJ, Huttenhower C, Irizarry RA, Kip NS, Michor F, Nevo D, Peters U, Phipps AI, Poole EM, Qian ZR, Quackenbush J, Robins H, Rogan PK, Slattery ML, Smith-Warner SA, Song M, VanderWeele TJ, Xia D, Zabor EC, Zhang X, Wang M, Ogino S. Proceedings of the third international molecular pathological epidemiology (MPE) meeting. Cancer Causes Control 2017; 28:167-176. [PMID: 28097472 PMCID: PMC5303153 DOI: 10.1007/s10552-016-0845-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 12/20/2016] [Indexed: 02/07/2023]
Abstract
Molecular pathological epidemiology (MPE) is a transdisciplinary and relatively new scientific discipline that integrates theory, methods, and resources from epidemiology, pathology, biostatistics, bioinformatics, and computational biology. The underlying objective of MPE research is to better understand the etiology and progression of complex and heterogeneous human diseases with the goal of informing prevention and treatment efforts in population health and clinical medicine. Although MPE research has been commonly applied to investigating breast, lung, and colorectal cancers, its methodology can be used to study most diseases. Recent successes in MPE studies include: (1) the development of new statistical methods to address etiologic heterogeneity; (2) the enhancement of causal inference; (3) the identification of previously unknown exposure-subtype disease associations; and (4) better understanding of the role of lifestyle/behavioral factors on modifying prognosis according to disease subtype. Central challenges to MPE include the relative lack of transdisciplinary experts, educational programs, and forums to discuss issues related to the advancement of the field. To address these challenges, highlight recent successes in the field, and identify new opportunities, a series of MPE meetings have been held at the Dana-Farber Cancer Institute in Boston, MA. Herein, we share the proceedings of the Third International MPE Meeting, held in May 2016 and attended by 150 scientists from 17 countries. Special topics included integration of MPE with immunology and health disparity research. This meeting series will continue to provide an impetus to foster further transdisciplinary integration of divergent scientific fields.
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Affiliation(s)
- Peter T Campbell
- Epidemiology Research Program, American Cancer Society, 250 Williams Street NW, Atlanta, GA, 30303, USA.
| | - Timothy R Rebbeck
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Reiko Nishihara
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Andrew H Beck
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA
- Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Colin B Begg
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alexei A Bogdanov
- Department of Radiology, University of Massachusetts Medical School, Worcester, MA, USA
| | - Yin Cao
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Helen G Coleman
- Epidemiology and Health Services Research Group, Centre for Public Health, Queens University Belfast, Belfast, Northern Ireland
| | - Gordon J Freeman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Yujing J Heng
- Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA
- Department of Pathology, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Curtis Huttenhower
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Microbial Systems and Communities, Genome Sequencing and Analysis Program, The Broad Institute, Cambridge, MA, USA
| | - Rafael A Irizarry
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - N Sertac Kip
- Laboratory Medicine and Pathology, Geisinger Health System, Danville, PA, USA
| | - Franziska Michor
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Daniel Nevo
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA
| | - Elizabeth M Poole
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Zhi Rong Qian
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - John Quackenbush
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Harlan Robins
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Peter K Rogan
- Department of Biochemistry, University of Western Ontario, London, Canada
| | | | - Stephanie A Smith-Warner
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Mingyang Song
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Tyler J VanderWeele
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Daniel Xia
- Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA
| | - Emily C Zabor
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Xuehong Zhang
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Molin Wang
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Shuji Ogino
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
- Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 450 Brookline Ave, Room SM1036, Boston, MA, 02215, USA.
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA.
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Nakaji Y, Oki E, Nakanishi R, Ando K, Sugiyama M, Nakashima Y, Yamashita N, Saeki H, Oda Y, Maehara Y. Prognostic value of BRAF V600E mutation and microsatellite instability in Japanese patients with sporadic colorectal cancer. J Cancer Res Clin Oncol 2017; 143:151-160. [PMID: 27672042 DOI: 10.1007/s00432-016-2275-4] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Accepted: 09/20/2016] [Indexed: 01/02/2023]
Abstract
PURPOSE In colorectal cancer (CRC), the BRAF V600E mutation is an important biomarker for poor prognosis, while high microsatellite instability (MSI-H) indicates good prognosis. Using a commercial BRAF V600E-specific antibody, we investigated the BRAF V600E mutation according to immunohistochemistry (IHC) and the MSI status in Japanese patients with CRC. METHODS In this retrospective study, tissue samples from 472 Japanese patients with CRC, stratified for MSI, were analyzed to determine the prognostic value of BRAF V600E, as assessed using IHC. Mutations in 254 patients were evaluated using the direct sequencing method to check for concordance. RESULTS The frequency of MSI-H was 9.3 % (44/472), and BRAF V600E mutation was detected immunohistochemically in 8.7 % patients (41/472). The sensitivity and specificity for detection of BRAF V600E mutations by IHC were 100 % (17/17) and 98.7 % (234/237), respectively. BRAF V600E mutations were significantly correlated with the anatomical tumor site (P = 0.0035), histological type (P < 0.0001), and MSI status (P < 0.0001). Consistent with other published series, patients with BRAF V600E mutation exhibited a significantly shorter overall survival (hazard ratio = 1.500, P = 0.0432). In particular, the microsatellite stable/BRAF mutation group had inferior prognosis compared with the MSI-H/BRAF wild-type group (hazard ratio = 2.621, P = 0.0004). CONCLUSIONS IHC using a BRAF V600E-specific antibody was useful for diagnosis and concurred with direct sequencing results. CRC cases could be stratified by combining BRAF V600E mutation and MSI status as a prognostic factor in Japanese patients.
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Affiliation(s)
- Yu Nakaji
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
| | - Ryota Nakanishi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Koji Ando
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Masahiko Sugiyama
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yuichiro Nakashima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Nami Yamashita
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Hiroshi Saeki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
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Zhuo C, Li Q, Wu Y, Li Y, Nie J, Li D, Peng J, Lian P, Li B, Cai G, Li X, Cai S. LINE-1 hypomethylation in normal colon mucosa is associated with poor survival in Chinese patients with sporadic colon cancer. Oncotarget 2016; 6:23820-36. [PMID: 26172297 PMCID: PMC4695154 DOI: 10.18632/oncotarget.4450] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Accepted: 06/19/2015] [Indexed: 12/20/2022] Open
Abstract
Genetic and epigenetic pathways are not independent in colorectal cancer (CRC) carcinogenesis. We aimed to determine the influence of various molecular features on Chinese patients' colon cancer-specific survival (CCSS). Various genetic and epigenetic modifications were detected in paired tumor and normal mucosa tissue samples. The prognostic variables regarding patient CCSS were determined. Overall, 127 patients, including 83 males and 44 females, completed a median follow-up of 65 (3–85) months. A mean LINE-1 methylation rate of 64.62% (range, 9.45–86.93) was observed. Hypermethylation at the hMLH1 gene promoter was detected in 26 (20.47%) patients. KRAS was mutated in 52 (40.94%) patients. Sixteen (12.60%) patients were confirmed as microsatellite instability (MSI)-High, and 76 (59.84%) were found to have loss of heterozygosity at 18q. The LINE-1 methylation level, MSI status, perineural invasion and distant metastases were confirmed as independent prognostic factors for patient CCSS. A stratified survival analysis further revealed that certain subgroups of patients with LINE-1 hypomethylation had significantly worse survival (all p < 0.05). Our data revealed that both genetic and epigenetic abnormalities can concurrently exist during colonic tumorigenesis. As a global epigenetic change, LINE-1 hypomethylation in normal colon mucosa might be associated with a worse outcome in certain Chinese patients with colon cancer.
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Affiliation(s)
- Changhua Zhuo
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China.,Department of Surgical Oncology, Fujian Provincial Cancer Hospital, Teaching Hospital of Fujian Medical University, Fuzhou 350014, People's Republic of China
| | - Qingguo Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Yuchen Wu
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Yiwei Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Jia Nie
- Key Laboratory of Molecular Virology & Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China
| | - Dawei Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Junjie Peng
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Peng Lian
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Bin Li
- Key Laboratory of Molecular Virology & Immunology, Unit of Molecular Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China
| | - Guoxiang Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Xinxiang Li
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
| | - Sanjun Cai
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, People's Republic of China
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Matos P, Gonçalves V, Jordan P. Targeting the serrated pathway of colorectal cancer with mutation in BRAF. Biochim Biophys Acta Rev Cancer 2016; 1866:51-63. [DOI: 10.1016/j.bbcan.2016.06.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2016] [Revised: 06/15/2016] [Accepted: 06/19/2016] [Indexed: 12/19/2022]
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Minarikova P, Benesova L, Halkova T, Belsanova B, Suchanek S, Cyrany J, Tuckova I, Bures J, Zavoral M, Minarik M. Longitudinal molecular characterization of endoscopic specimens from colorectal lesions. World J Gastroenterol 2016; 22:4936-4945. [PMID: 27239120 PMCID: PMC4873886 DOI: 10.3748/wjg.v22.i20.4936] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Revised: 04/09/2016] [Accepted: 05/04/2016] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare molecular profiles of proximal colon, distal colon and rectum in large adenomas, early and late carcinomas. To assess feasibility of testing directed at molecular markers from this study in routine clinical practice.
METHODS: A prospective 3-year study has resulted in the acquisition of samples from 159 large adenomas and 138 carcinomas along with associated clinical parameters including localization, grade and histological type for adenomas and localization and stage for carcinomas. A complex molecular phenotyping has been performed using multiplex ligation-dependent probe amplification technique for the evaluation of CpG-island methylator phenotype (CIMP), PCR fragment analysis for detection of microsatellite instability and denaturing capillary electrophoresis for sensitive detection of somatic mutations in KRAS, BRAF, TP53 and APC genes.
RESULTS: Molecular types according to previously introduced Jass classification have been evaluated for large adenomas and early and late carcinomas. An increase in CIMP+ type, eventually accompanied with KRAS mutations, was notable between large adenomas and early carcinomas. As expected, the longitudinal observations revealed a correlation of the CIMP+/BRAF+ type with proximal location.
CONCLUSION: Prospective molecular classification of tissue specimens is feasible in routine endoscopy practice. Increased frequency of some molecular types corresponds to the developmental stages of colorectal tumors. As expected, a clear distinction is notable for tumors located in proximal colon supposedly arising from the serrated (methylation) pathway.
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Zong L, Abe M, Ji J, Zhu WG, Yu D. Tracking the Correlation Between CpG Island Methylator Phenotype and Other Molecular Features and Clinicopathological Features in Human Colorectal Cancers: A Systematic Review and Meta-Analysis. Clin Transl Gastroenterol 2016; 7:e151. [PMID: 26963001 PMCID: PMC4822093 DOI: 10.1038/ctg.2016.14] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Accepted: 01/21/2016] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVES The controversy of CpG island methylator phenotype (CIMP) in colorectal cancers (CRCs) persists, despite many studies that have been conducted on its correlation with molecular and clinicopathological features. To drive a more precise estimate of the strength of this postulated relationship, a meta-analysis was performed. METHODS A comprehensive search for studies reporting molecular and clinicopathological features of CRCs stratified by CIMP was performed within the PubMed, EMBASE, and Cochrane Library. CIMP was defined by either one of the three panels of gene-specific CIMP markers (Weisenberger panel, classic panel, or a mixture panel of the previous two) or the genome-wide DNA methylation profile. The associations of CIMP with outcome parameters were estimated using odds ratio (OR) or weighted mean difference (WMD) or hazard ratios (HRs) with 95% confidence interval (CI) for each study using a fixed effects or random effects model. RESULTS A total of 29 studies involving 9,393 CRC patients were included for analysis. We observed more BRAF mutations (OR 34.87; 95% CI, 22.49-54.06) and microsatellite instability (MSI) (OR 12.85 95% CI, 8.84-18.68) in CIMP-positive vs. -negative CRCs, whereas KRAS mutations were less frequent (OR 0.47; 95% CI, 0.30-0.75). Subgroup analysis showed that only the genome-wide methylation profile-defined CIMP subset encompassed all BRAF-mutated CRCs. As expected, CIMP-positive CRCs displayed significant associations with female (OR 0.64; 95% CI, 0.56-0.72), older age at diagnosis (WMD 2.77; 95% CI, 1.15-4.38), proximal location (OR 6.91; 95% CI, 5.17-9.23), mucinous histology (OR 3.81; 95% CI, 2.93-4.95), and poor differentiation (OR 4.22; 95% CI, 2.52-7.08). Although CIMP did not show a correlation with tumor stage (OR 1.10; 95% CI, 0.82-1.46), it was associated with shorter overall survival (HR 1.73; 95% CI, 1.27-2.37). CONCLUSIONS The meta-analysis highlights that CIMP-positive CRCs take their own molecular feature, especially overlapping with BRAF mutations, and clinicopathological features and worse prognosis from CIMP-negative CRCs, suggesting CIMP could be used as an independent prognostic marker for CRCs.
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Affiliation(s)
- Liang Zong
- Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan
- Department of Gastrointestinal Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- Department of Gastrointestinal Surgery, Su Bei People's Hospital of Jiangsu Province, Yangzhou University, Yangzhou, China
| | - Masanobu Abe
- Division for Health Service Promotion, University of Tokyo Hospital, Tokyo, Japan
| | - Jiafu Ji
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery, Peking University Cancer Hospital and Institute, Beijing, China
| | - Wei-Guo Zhu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing, China
- Peking-Tsinghua University Center for Life Sciences, Peking University, Beijing, China
| | - Duonan Yu
- Non-coding RNA Center, Yangzhou University, Yangzhou, China
- Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Disease, Yangzhou, China
- Institute of Comparative Medicine, Yangzhou University, Yangzhou, China
- Jiangsu Co-Innovation Center for Prevention and Control of Important Animal Infectious Disease and Zoonosis, Yangzhou, China
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Yamagishi H, Kuroda H, Imai Y, Hiraishi H. Molecular pathogenesis of sporadic colorectal cancers. CHINESE JOURNAL OF CANCER 2016; 35:4. [PMID: 26738600 PMCID: PMC4704376 DOI: 10.1186/s40880-015-0066-y] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2015] [Accepted: 09/01/2015] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) results from the progressive accumulation of genetic and epigenetic alterations that lead to the transformation of normal colonic mucosa to adenocarcinoma. Approximately 75% of CRCs are sporadic and occur in people without genetic predisposition or family history of CRC. During the past two decades, sporadic CRCs were classified into three major groups according to frequently altered/mutated genes. These genes have been identified by linkage analyses of cancer-prone families and by individual mutation analyses of candidate genes selected on the basis of functional data. In the first half of this review, we describe the genetic pathways of sporadic CRCs and their clinicopathologic features. Recently, large-scale genome analyses have detected many infrequently mutated genes as well as a small number of frequently mutated genes. These infrequently mutated genes are likely described in a limited number of pathways. Gene-oriented models of CRC progression are being replaced by pathway-oriented models. In the second half of this review, we summarize the present knowledge of this research field and discuss its prospects.
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Affiliation(s)
- Hidetsugu Yamagishi
- Department of Diagnostic Pathology, Dokkyo Medical University, 880 Kita-Kobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.
| | - Hajime Kuroda
- Department of Pathology, International University of Health and Welfare Hospital, 537-3 Iguchi, Nasushiobara, Tochigi, 329-2763, Japan.
| | - Yasuo Imai
- Department of Diagnostic Pathology, Dokkyo Medical University, 880 Kita-Kobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.
- Department of Diagnostic Pathology, Ota Memorial Hospital, Fuji Heavy Industries Health Insurance Society, 455-1 Oshima, Ota, Gunma, 373-8585, Japan.
| | - Hideyuki Hiraishi
- Department of Gastroenterology, Dokkyo Medical University, 880 Kita-Kobayashi, Mibu, Shimotsuga, Tochigi, 321-0293, Japan.
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Nishi A, Milner DA, Giovannucci EL, Nishihara R, Tan AS, Kawachi I, Ogino S. Integration of molecular pathology, epidemiology and social science for global precision medicine. Expert Rev Mol Diagn 2015; 16:11-23. [PMID: 26636627 PMCID: PMC4713314 DOI: 10.1586/14737159.2016.1115346] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The precision medicine concept and the unique disease principle imply that each patient has unique pathogenic processes resulting from heterogeneous cellular genetic and epigenetic alterations and interactions between cells (including immune cells) and exposures, including dietary, environmental, microbial and lifestyle factors. As a core method field in population health science and medicine, epidemiology is a growing scientific discipline that can analyze disease risk factors and develop statistical methodologies to maximize utilization of big data on populations and disease pathology. The evolving transdisciplinary field of molecular pathological epidemiology (MPE) can advance biomedical and health research by linking exposures to molecular pathologic signatures, enhancing causal inference and identifying potential biomarkers for clinical impact. The MPE approach can be applied to any diseases, although it has been most commonly used in neoplastic diseases (including breast, lung and colorectal cancers) because of availability of various molecular diagnostic tests. However, use of state-of-the-art genomic, epigenomic and other omic technologies and expensive drugs in modern healthcare systems increases racial, ethnic and socioeconomic disparities. To address this, we propose to integrate molecular pathology, epidemiology and social science. Social epidemiology integrates the latter two fields. The integrative social MPE model can embrace sociology, economics and precision medicine, address global health disparities and inequalities, and elucidate biological effects of social environments, behaviors and networks. We foresee advancements of molecular medicine, including molecular diagnostics, biomedical imaging and targeted therapeutics, which should benefit individuals in a global population, by means of an interdisciplinary approach of integrative MPE and social health science.
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Affiliation(s)
- Akihiro Nishi
- Yale Institute for Network Science, New Haven, CT, USA (AN); Department of Sociology, Yale University, New Haven, CT, USA (AN); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (DAM, SO); Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA (DAM); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN, SO); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (ELG); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA (RN); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA (RN, AST, SO); Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA (AST, IK)
| | - Danny A Milner
- Yale Institute for Network Science, New Haven, CT, USA (AN); Department of Sociology, Yale University, New Haven, CT, USA (AN); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (DAM, SO); Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA (DAM); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN, SO); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (ELG); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA (RN); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA (RN, AST, SO); Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA (AST, IK)
| | - Edward L. Giovannucci
- Yale Institute for Network Science, New Haven, CT, USA (AN); Department of Sociology, Yale University, New Haven, CT, USA (AN); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (DAM, SO); Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA (DAM); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN, SO); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (ELG); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA (RN); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA (RN, AST, SO); Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA (AST, IK)
| | - Reiko Nishihara
- Yale Institute for Network Science, New Haven, CT, USA (AN); Department of Sociology, Yale University, New Haven, CT, USA (AN); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (DAM, SO); Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA (DAM); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN, SO); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (ELG); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA (RN); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA (RN, AST, SO); Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA (AST, IK)
| | - Andy S. Tan
- Yale Institute for Network Science, New Haven, CT, USA (AN); Department of Sociology, Yale University, New Haven, CT, USA (AN); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (DAM, SO); Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA (DAM); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN, SO); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (ELG); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA (RN); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA (RN, AST, SO); Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA (AST, IK)
| | - Ichiro Kawachi
- Yale Institute for Network Science, New Haven, CT, USA (AN); Department of Sociology, Yale University, New Haven, CT, USA (AN); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (DAM, SO); Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA (DAM); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN, SO); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (ELG); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA (RN); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA (RN, AST, SO); Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA (AST, IK)
| | - Shuji Ogino
- Yale Institute for Network Science, New Haven, CT, USA (AN); Department of Sociology, Yale University, New Haven, CT, USA (AN); Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (DAM, SO); Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA (DAM); Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN, SO); Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA (ELG, RN); Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA (ELG); Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA (RN); Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA (RN, AST, SO); Department of Social and Behavioral Sciences, Harvard T.H. Chan School of Public Health, Boston, MA, USA (AST, IK)
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Maletzki C, Huehns M, Knapp P, Waukosin N, Klar E, Prall F, Linnebacher M. Functional Characterization and Drug Response of Freshly Established Patient-Derived Tumor Models with CpG Island Methylator Phenotype. PLoS One 2015; 10:e0143194. [PMID: 26618628 PMCID: PMC4664421 DOI: 10.1371/journal.pone.0143194] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2015] [Accepted: 11/02/2015] [Indexed: 12/16/2022] Open
Abstract
Patient-individual tumor models constitute a powerful platform for basic and translational analyses both in vitro and in vivo. However, due to the labor-intensive and highly time-consuming process, only few well-characterized patient-derived cell lines and/or corresponding xenografts exist. In this study, we describe successful generation and functional analysis of novel tumor models from patients with sporadic primary colorectal carcinomas (CRC) showing CpG island methylator phenotype (CIMP). Initial DNA fingerprint analysis confirmed identity with the patient in all four cases. These freshly established cells showed characteristic features associated with the CIMP-phenotype (HROC40: APCwt, TP53 mut, KRAS mut; 3/8 marker methylated; HROC43: APC mut, TP53 mut, KRAS mut; 4/8 marker methylated; HROC60: APCwt, TP53 mut, KRASwt; 4/8 marker methylated; HROC183: APC mut, TP53 mut, KRAS mut; 6/8 marker methylated). Cell lines were of epithelial origin (EpCAM+) with distinct morphology and growth kinetics. Response to chemotherapeutics was quite individual between cells, with stage I-derived cell line HROC60 being most susceptible towards standard clinically approved chemotherapeutics (e.g. 5-FU, Irinotecan). Of note, most cell lines were sensitive towards "non-classical" CRC standard drugs (sensitivity: Gemcitabin > Rapamycin > Nilotinib). This comprehensive analysis of tumor biology, genetic alterations and assessment of chemosensitivity towards a broad range of (chemo-) therapeutics helps bringing forward the concept of personalized tumor therapy.
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Affiliation(s)
- Claudia Maletzki
- Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany
| | - Maja Huehns
- Institute of Pathology, University of Rostock, Rostock, Germany
| | - Patrick Knapp
- Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany
| | - Nancy Waukosin
- Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany
| | - Ernst Klar
- Department of General Surgery, University of Rostock, Rostock, Germany
| | - Friedrich Prall
- Institute of Pathology, University of Rostock, Rostock, Germany
| | - Michael Linnebacher
- Molecular Oncology and Immunotherapy, University of Rostock, Rostock, Germany
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Moarii M, Reyal F, Vert JP. Integrative DNA methylation and gene expression analysis to assess the universality of the CpG island methylator phenotype. Hum Genomics 2015; 9:26. [PMID: 26463173 PMCID: PMC4603341 DOI: 10.1186/s40246-015-0048-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2015] [Accepted: 10/01/2015] [Indexed: 01/26/2023] Open
Abstract
Background The CpG island methylator phenotype (CIMP) was first characterized in colorectal cancer but since has been extensively studied in several other tumor types such as breast, bladder, lung, and gastric. CIMP is of clinical importance as it has been reported to be associated with prognosis or response to treatment. However, the identification of a universal molecular basis to define CIMP across tumors has remained elusive. Results We perform a genome-wide methylation analysis of over 2000 tumor samples from 5 cancer sites to assess the existence of a CIMP with common molecular basis across cancers. We then show that the CIMP phenotype is associated with specific gene expression variations. However, we do not find a common genetic signature in all tissues associated with CIMP. Conclusion Our results suggest the existence of a universal epigenetic and transcriptomic signature that defines the CIMP across several tumor types but does not indicate the existence of a common genetic signature of CIMP. Electronic supplementary material The online version of this article (doi:10.1186/s40246-015-0048-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Matahi Moarii
- CBIO-Centre for Computational Biology, Mines Paristech, PSL-Research University, 35 Rue Saint-Honore, Fontainebleau, F-77300, France. .,Department of Bioinformatics, Biostatistics and System Biology, Institut Curie, 11-13 Rue Pierre et Marie Curie, Paris, F-75248, France. .,U900, INSERM, 11-13 Rue Pierre et Marie Curie, Paris, F-75248, France.
| | - Fabien Reyal
- UMR932, Immunity and Cancer Team, Institut Curie, 26 Rue d'Ulm, Paris, 75006, France. .,Department of Translational Research, Residual Tumor and Response to Treatment Team, Institut Curie, 26 Rue d'Ulm, Paris, 75006, France. .,Department of Surgery, Institut Curie, 26 Rue d'Ulm, Paris, 75006, France.
| | - Jean-Philippe Vert
- CBIO-Centre for Computational Biology, Mines Paristech, PSL-Research University, 35 Rue Saint-Honore, Fontainebleau, F-77300, France. .,Department of Bioinformatics, Biostatistics and System Biology, Institut Curie, 11-13 Rue Pierre et Marie Curie, Paris, F-75248, France. .,U900, INSERM, 11-13 Rue Pierre et Marie Curie, Paris, F-75248, France.
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Nistal E, Fernández-Fernández N, Vivas S, Olcoz JL. Factors Determining Colorectal Cancer: The Role of the Intestinal Microbiota. Front Oncol 2015; 5:220. [PMID: 26528432 PMCID: PMC4601259 DOI: 10.3389/fonc.2015.00220] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 09/24/2015] [Indexed: 12/26/2022] Open
Abstract
The gastrointestinal tract, in particular the colon, holds a complex community of microorganisms, which are essential for maintaining homeostasis. However, in recent years, many studies have implicated microbiota in the development of colorectal cancer (CRC), with this disease considered a major cause of death in the western world. The mechanisms underlying bacterial contribution in its development are complex and are not yet fully understood. However, there is increasing evidence showing a connection between intestinal microbiota and CRC. Intestinal microorganisms cause the onset and progression of CRC using different mechanisms, such as the induction of a chronic inflammation state, the biosynthesis of genotoxins that interfere with cell cycle regulation, the production of toxic metabolites, or heterocyclic amine activation of pro-diet carcinogenic compounds. Despite these advances, additional studies in humans and animal models will further decipher the relationship between microbiota and CRC, and aid in developing alternate therapies based on microbiota manipulation.
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Affiliation(s)
- Esther Nistal
- Instituto de Biomedicina (IBIOMED), Universidad de León , León , Spain
| | | | - Santiago Vivas
- Instituto de Biomedicina (IBIOMED), Universidad de León , León , Spain ; Gastroenterología, Hospital Universitario de León , León , Spain
| | - José Luis Olcoz
- Gastroenterología, Hospital Universitario de León , León , Spain
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Nishihara R, VanderWeele TJ, Shibuya K, Mittleman MA, Wang M, Field AE, Giovannucci E, Lochhead P, Ogino S. Molecular pathological epidemiology gives clues to paradoxical findings. Eur J Epidemiol 2015; 30:1129-35. [PMID: 26445996 PMCID: PMC4639412 DOI: 10.1007/s10654-015-0088-4] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 09/26/2015] [Indexed: 12/23/2022]
Abstract
A number of epidemiologic studies have described what appear to be paradoxical associations, where an incongruous relationship is observed between a certain well-established risk factor for disease incidence and favorable clinical outcome among patients with that disease. For example, the "obesity paradox" represents the association between obesity and better survival among patients with a certain disease such as coronary heart disease. Paradoxical observations cause vexing clinical and public health problems as they raise questions on causal relationships and hinder the development of effective interventions. Compelling evidence indicates that pathogenic processes encompass molecular alterations within cells and the microenvironment, influenced by various exogenous and endogenous exposures, and that interpersonal heterogeneity in molecular pathology and pathophysiology exists among patients with any given disease. In this article, we introduce methods of the emerging integrative interdisciplinary field of molecular pathological epidemiology (MPE), which is founded on the unique disease principle and disease continuum theory. We analyze and decipher apparent paradoxical findings, utilizing the MPE approach and available literature data on tumor somatic genetic and epigenetic characteristics. Through our analyses in colorectal cancer, renal cell carcinoma, and glioblastoma (malignant brain tumor), we can readily explain paradoxical associations between disease risk factors and better prognosis among disease patients. The MPE paradigm and approach can be applied to not only neoplasms but also various non-neoplastic diseases where there exists indisputable ubiquitous heterogeneity of pathogenesis and molecular pathology. The MPE paradigm including consideration of disease heterogeneity plays an essential role in advancements of precision medicine and public health.
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Affiliation(s)
- Reiko Nishihara
- Department of Nutrition, Harvard T.H. Chan School of Public Health, 655 Huntington Ave., Boston, MA, 02115, USA.
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Boston, MA, 02215, USA.
- Department of Global Health Policy, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan.
| | - Tyler J VanderWeele
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave., Boston, MA, 02115, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, 677 Huntington Ave., Boston, MA, 02115, USA
| | - Kenji Shibuya
- Department of Global Health Policy, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, Japan
| | - Murray A Mittleman
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave., Boston, MA, 02115, USA
- Cardiovascular Epidemiology Research Unit, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, 375 Longwood Ave., Boston, MA, USA
| | - Molin Wang
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave., Boston, MA, 02115, USA
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, 677 Huntington Ave., Boston, MA, 02115, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Ave., Boston, MA, 02115, USA
| | - Alison E Field
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave., Boston, MA, 02115, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Ave., Boston, MA, 02115, USA
- Division of Adolescent Medicine, Boston Children's Hospital, 300 Longwood Ave., Boston, MA, 02115, USA
- Department of Epidemiology, Brown University, 121 South Main Street, Providence, RI, 02912, USA
| | - Edward Giovannucci
- Department of Nutrition, Harvard T.H. Chan School of Public Health, 655 Huntington Ave., Boston, MA, 02115, USA
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave., Boston, MA, 02115, USA
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 181 Longwood Ave., Boston, MA, 02115, USA
| | - Paul Lochhead
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA
| | - Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, 450 Brookline Ave., Boston, MA, 02215, USA.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave., Boston, MA, 02115, USA.
- Department of Pathology, Brigham and Women's Hospital, Boston, Harvard Medical School, 75 Francis Street, Boston, MA, 02115, USA.
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Li P, Hao S, Bi Z, Zhang J, Wu Z, Ren X. Methylation of Werner syndrome protein is associated with the occurrence and development of invasive meningioma via the regulation of Myc and p53 expression. Exp Ther Med 2015; 10:498-502. [PMID: 26622343 DOI: 10.3892/etm.2015.2519] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Accepted: 05/08/2015] [Indexed: 11/05/2022] Open
Abstract
The aim of the present study was to investigate the positive rate of Werner syndrome protein (WRN) methylation in meningioma patients, and further assess the association between WRN methylation and the occurrence of meningioma. A total of 56 consecutive meningioma patients and 26 healthy individuals were enrolled in the study. A methylation-specific polymerase chain reaction assay was performed to detect the positive rate of WRN methylation in the peripheral blood and tissue samples collected from the recruited subjects. In addition, western blot analysis was performed to determine the protein expression levels of WRN, Myc and p53 in the peripheral blood and tissue samples. The positive rate of WRN methylation in the peripheral blood of the meningioma group was increased when compared with the control group (P<0.05). In addition, the protein expression levels of WRN were significantly decreased in the peripheral blood and tissue samples collected from the individuals with a positive WRN methylation status (P<0.05), as compared with the samples without WRN methylation. Furthermore, the protein expression levels of Myc and p53 were increased in the peripheral blood and tissue samples that exhibited positive WRN methylation when compared with those without WRN methylation (P<0.05). Therefore, WRN methylation was demonstrated to be associated with the occurrence and development of invasive meningioma, possibly through the regulation of Myc and p53 expression.
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Affiliation(s)
- Puxian Li
- Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Shuyu Hao
- Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Zhiyong Bi
- Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Junting Zhang
- Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Zhen Wu
- Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, P.R. China
| | - Xiaohui Ren
- Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing 100050, P.R. China
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Ogino S, Campbell PT, Nishihara R, Phipps AI, Beck AH, Sherman ME, Chan AT, Troester MA, Bass AJ, Fitzgerald KC, Irizarry RA, Kelsey KT, Nan H, Peters U, Poole EM, Qian ZR, Tamimi RM, Tchetgen Tchetgen EJ, Tworoger SS, Zhang X, Giovannucci EL, van den Brandt PA, Rosner BA, Wang M, Chatterjee N, Begg CB. Proceedings of the second international molecular pathological epidemiology (MPE) meeting. Cancer Causes Control 2015; 26:959-72. [PMID: 25956270 DOI: 10.1007/s10552-015-0596-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 04/27/2015] [Indexed: 02/07/2023]
Abstract
Disease classification system increasingly incorporates information on pathogenic mechanisms to predict clinical outcomes and response to therapy and intervention. Technological advancements to interrogate omics (genomics, epigenomics, transcriptomics, proteomics, metabolomics, metagenomics, interactomics, etc.) provide widely open opportunities in population-based research. Molecular pathological epidemiology (MPE) represents integrative science of molecular pathology and epidemiology. This unified paradigm requires multidisciplinary collaboration between pathology, epidemiology, biostatistics, bioinformatics, and computational biology. Integration of these fields enables better understanding of etiologic heterogeneity, disease continuum, causal inference, and the impact of environment, diet, lifestyle, host factors (including genetics and immunity), and their interactions on disease evolution. Hence, the Second International MPE Meeting was held in Boston in December 2014, with aims to: (1) develop conceptual and practical frameworks; (2) cultivate and expand opportunities; (3) address challenges; and (4) initiate the effort of specifying guidelines for MPE. The meeting mainly consisted of presentations of method developments and recent data in various malignant neoplasms and tumors (breast, prostate, ovarian and colorectal cancers, renal cell carcinoma, lymphoma, and leukemia), followed by open discussion sessions on challenges and future plans. In particular, we recognized need for efforts to further develop statistical methodologies. This meeting provided an unprecedented opportunity for interdisciplinary collaboration, consistent with the purposes of the Big Data to Knowledge, Genetic Associations and Mechanisms in Oncology, and Precision Medicine Initiative of the US National Institute of Health. The MPE meeting series can help advance transdisciplinary population science and optimize training and education systems for twenty-first century medicine and public health.
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Affiliation(s)
- Shuji Ogino
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 450 Brookline Ave., Room M422, Boston, MA, 02215, USA,
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Sánchez-Vega F, Gotea V, Margolin G, Elnitski L. Pan-cancer stratification of solid human epithelial tumors and cancer cell lines reveals commonalities and tissue-specific features of the CpG island methylator phenotype. Epigenetics Chromatin 2015; 8:14. [PMID: 25960768 PMCID: PMC4424513 DOI: 10.1186/s13072-015-0007-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 03/30/2015] [Indexed: 12/16/2022] Open
Abstract
Background The term CpG island methylator phenotype (CIMP) has been used to describe widespread DNA hypermethylation at CpG-rich genomic regions affecting clinically distinct subsets of cancer patients. Even though there have been numerous studies of CIMP in individual cancer types, a uniform analysis across tissues is still lacking. Results We analyze genome-wide patterns of CpG island hypermethylation in 5,253 solid epithelial tumors from 15 cancer types from TCGA and 23 cancer cell lines from ENCODE. We identify differentially methylated loci that define CIMP+ and CIMP− samples, and we use unsupervised clustering to provide a robust molecular stratification of tumor methylomes for 12 cancer types and all cancer cell lines. With a minimal set of 89 discriminative loci, we demonstrate accurate pan-cancer separation of the 12 CIMP+/− subpopulations, based on their average levels of methylation. Tumor samples in different CIMP subclasses show distinctive correlations with gene expression profiles and recurrence of somatic mutations, copy number variations, and epigenetic silencing. Enrichment analyses indicate shared canonical pathways and upstream regulators for CIMP-targeted regions across cancer types. Furthermore, genomic alterations showing consistent associations with CIMP+/− status include genes involved in DNA repair, chromatin remodeling genes, and several histone methyltransferases. Associations of CIMP status with specific clinical features, including overall survival in several cancer types, highlight the importance of the CIMP+/− designation for individual tumor evaluation and personalized medicine. Conclusions We present a comprehensive computational study of CIMP that reveals pan-cancer commonalities and tissue-specific differences underlying concurrent hypermethylation of CpG islands across tumors. Our stratification of solid tumors and cancer cell lines based on CIMP status is data-driven and agnostic to tumor type by design, which protects against known biases that have hindered classic methods previously used to define CIMP. The results that we provide can be used to refine existing molecular subtypes of cancer into more homogeneously behaving subgroups, potentially leading to more uniform responses in clinical trials. Electronic supplementary material The online version of this article (doi:10.1186/s13072-015-0007-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Francisco Sánchez-Vega
- Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD USA
| | - Valer Gotea
- Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD USA
| | - Gennady Margolin
- Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD USA
| | - Laura Elnitski
- Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD USA
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Walter T, van Brakel B, Vercherat C, Hervieu V, Forestier J, Chayvialle JA, Molin Y, Lombard-Bohas C, Joly MO, Scoazec JY. O6-Methylguanine-DNA methyltransferase status in neuroendocrine tumours: prognostic relevance and association with response to alkylating agents. Br J Cancer 2015; 112:523-31. [PMID: 25584486 PMCID: PMC4453664 DOI: 10.1038/bjc.2014.660] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Revised: 12/10/2014] [Accepted: 12/19/2014] [Indexed: 12/17/2022] Open
Abstract
Background: O6-Methylguanine-DNA methyltransferase (MGMT) loss of expression has been suggested to be predictive of response to temozolomide in neuroendocrine tumours (NETs), but so far, only limited data are available. We evaluated the prognostic and predictive value of MGMT status, assessed by two molecular methods and immunohistochemistry, in a large series of NETs of different origins. Methods: A total of 107 patients, including 53 treated by alkylants (temozolomide, dacarbazine or streptozotocin), were retrospectively studied. In each case, we used methyl-specific PCR (MS-PCR) and pyrosequencing for evaluation of promoter methylation and immunohistochemistry for evaluation of protein status. Results: MGMT promoter methylation was detected in 12 out of 99 (12%) interpretable cases by MS-PCR and in 24 out of 99 (24%) by pyrosequencing. O6-Methylguanine-DNA methyltransferase loss of expression was observed in 29 out of 89 (33%) interpretable cases. Status of MGMT was not correlated with overall survival (OS) from diagnosis. Progression-free survival and OS from first alkylant use (temozolomide, dacarbazine and streptozotocin) were higher in patients with MGMT protein loss (respectively, 20.2 vs 7.6 months, P<0.001 and 105 vs 34 months, P=0.006) or MGMT promoter methylation assessed by pyrosequencing (respectively, 26.4 vs 10.8 months, P=0.002 and 77 vs 43 months, P=0.026). Conclusions: Our results suggest that MGMT status is associated with response to alkylant-based chemotherapy in NETs.
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Affiliation(s)
- T Walter
- 1] Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'oncologie Digestive, 69437 Lyon, France [2] INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372 Lyon, France [3] Université de Lyon, Université Claude Bernard Lyon 1, 69622 Villeurbanne, France
| | - B van Brakel
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'oncologie Digestive, 69437 Lyon, France
| | - C Vercherat
- INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372 Lyon, France
| | - V Hervieu
- 1] INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372 Lyon, France [2] Université de Lyon, Université Claude Bernard Lyon 1, 69622 Villeurbanne, France [3] Hospices Civils de Lyon, Hôpital Edouard Herriot, Service Central d'Anatomie et Cytologie Pathologiques, 69437 Lyon, France
| | - J Forestier
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'oncologie Digestive, 69437 Lyon, France
| | - J-A Chayvialle
- 1] INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372 Lyon, France [2] Université de Lyon, Université Claude Bernard Lyon 1, 69622 Villeurbanne, France [3] Hospices Civils de Lyon, Hôpital Edouard Herriot, Hépatogastroentérologie, 69437 Lyon, France
| | - Y Molin
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'oncologie Digestive, 69437 Lyon, France
| | - C Lombard-Bohas
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Service d'oncologie Digestive, 69437 Lyon, France
| | - M-O Joly
- 1] INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372 Lyon, France [2] Université de Lyon, Université Claude Bernard Lyon 1, 69622 Villeurbanne, France [3] Hospices Civils de Lyon, Hôpital Edouard Herriot, Service Central d'Anatomie et Cytologie Pathologiques, 69437 Lyon, France
| | - J-Y Scoazec
- 1] INSERM, UMR 1052, Lyon Cancer Research Center, Faculté Laennec, 69372 Lyon, France [2] Université de Lyon, Université Claude Bernard Lyon 1, 69622 Villeurbanne, France [3] Hospices Civils de Lyon, Hôpital Edouard Herriot, Service Central d'Anatomie et Cytologie Pathologiques, 69437 Lyon, France
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Lochhead P, Chan AT, Nishihara R, Fuchs CS, Beck AH, Giovannucci E, Ogino S. Etiologic field effect: reappraisal of the field effect concept in cancer predisposition and progression. Mod Pathol 2015; 28:14-29. [PMID: 24925058 PMCID: PMC4265316 DOI: 10.1038/modpathol.2014.81] [Citation(s) in RCA: 159] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Revised: 02/12/2014] [Accepted: 04/02/2014] [Indexed: 02/07/2023]
Abstract
The term 'field effect' (also known as field defect, field cancerization, or field carcinogenesis) has been used to describe a field of cellular and molecular alteration, which predisposes to the development of neoplasms within that territory. We explore an expanded, integrative concept, 'etiologic field effect', which asserts that various etiologic factors (the exposome including dietary, lifestyle, environmental, microbial, hormonal, and genetic factors) and their interactions (the interactome) contribute to a tissue microenvironmental milieu that constitutes a 'field of susceptibility' to neoplasia initiation, evolution, and progression. Importantly, etiological fields predate the acquisition of molecular aberrations commonly considered to indicate presence of filed effect. Inspired by molecular pathological epidemiology (MPE) research, which examines the influence of etiologic factors on cellular and molecular alterations during disease course, an etiologically focused approach to field effect can: (1) broaden the horizons of our inquiry into cancer susceptibility and progression at molecular, cellular, and environmental levels, during all stages of tumor evolution; (2) embrace host-environment-tumor interactions (including gene-environment interactions) occurring in the tumor microenvironment; and, (3) help explain intriguing observations, such as shared molecular features between bilateral primary breast carcinomas, and between synchronous colorectal cancers, where similar molecular changes are absent from intervening normal colon. MPE research has identified a number of endogenous and environmental exposures which can influence not only molecular signatures in the genome, epigenome, transcriptome, proteome, metabolome and interactome, but also host immunity and tumor behavior. We anticipate that future technological advances will allow the development of in vivo biosensors capable of detecting and quantifying 'etiologic field effect' as abnormal network pathology patterns of cellular and microenvironmental responses to endogenous and exogenous exposures. Through an 'etiologic field effect' paradigm, and holistic systems pathology (systems biology) approaches to cancer biology, we can improve personalized prevention and treatment strategies for precision medicine.
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Affiliation(s)
- Paul Lochhead
- Gastrointestinal Research Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
| | - Andrew T Chan
- 1] Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Reiko Nishihara
- 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA [2] Department of Nutrition, Harvard School of Public Health, Boston, MA, USA
| | - Charles S Fuchs
- 1] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Andrew H Beck
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Edward Giovannucci
- 1] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Department of Nutrition, Harvard School of Public Health, Boston, MA, USA [3] Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
| | - Shuji Ogino
- 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA [2] Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA [3] Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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Das S, Martinez LR, Ray S. Phospholipid remodeling and eicosanoid signaling in colon cancer cells. INDIAN JOURNAL OF BIOCHEMISTRY & BIOPHYSICS 2014; 51:512-519. [PMID: 25823224 PMCID: PMC4460191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Phospholipid remodeling and eicosanoid synthesis are central to lipid-based inflammatory reactions. Studies have revealed that membrane phospholipid remodeling by fatty acids through deacylation/reacylation reactions increases the risk of colorectal cancers (CRC) by allowing the cells to produce excess inflammatory eicosanoids, such as prostaglandins, thromboxanes and leukotrienes. Over the years, efforts have been made to understand the lipid remodeling pathways and to design anti-cancer drugs targeting the enzymes of eicosanoid biosynthesis. Here, we discuss the recent progress in phospholipid remodeling and eicosanoid biosynthesis in CRC.
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Affiliation(s)
- Siddhartha Das
- Infectious Disease and Immunology Cluster, the Border Biomedical Research Center and Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas 79968-0519, USA
| | - Leobarda Robles Martinez
- Infectious Disease and Immunology Cluster, the Border Biomedical Research Center and Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas 79968-0519, USA
| | - Suparna Ray
- Department of Biology, University of Erlangen-Nüremberg, Erlangen, Germany
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Establishing a biological profile for interval colorectal cancers. Dig Dis Sci 2014; 59:2390-402. [PMID: 24839919 DOI: 10.1007/s10620-014-3210-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2014] [Accepted: 05/07/2014] [Indexed: 12/16/2022]
Abstract
Colorectal cancer (CRC) remains the second leading cause of cancer-related deaths in North America. Screening for CRC and its precursor lesions is highly effective in reducing the incidence and deaths due to the disease. However, there remain a substantial number of individuals who are diagnosed with CRC soon after a negative/clearing colonoscopy with no documented evidence of CRC. The occurrence of these interval CRCs (I-CRCs) reduces the effectiveness of CRC screening and detection tests and has only recently attracted wide spread attention. I-CRCs can be subdivided into those that occur most likely due to the failure of the colonoscopy examination (missed CRC and CRC that developed from missed or incompletely resected precursor lesions) and those that develop rapidly after the colonoscopy (de novo I-CRCs). In this review, we discuss the current literature and present both the clinical and biological factors that have been identified to account for I-CRCs, with a particular focus on the aberrant molecular features that are candidate causative agents for I-CRCs. We conclude additional studies are required to fully understand the molecular features that lead to the development of I-CRCs, which in turn is essential to develop measures to prevent the occurrence of this group of CRCs and thereby improve CRC screening and detection strategies.
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