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Yin J, Ma Y, Fu H, Fan Y, Xiang D, Ding L, Huang J. Spartin Promotes Smurf1-Mediated Ubiquitination Modification of YWHAZ to Inhibit Cisplatin Resistance in Ovarian Cancer. FASEB J 2025; 39:e70658. [PMID: 40386996 DOI: 10.1096/fj.202401164r] [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: 05/29/2024] [Revised: 04/18/2025] [Accepted: 05/12/2025] [Indexed: 05/20/2025]
Abstract
Cisplatin (DDP) remains the commonly used chemotherapeutic drug for ovarian cancer (OV); however, DDP resistance poses a great challenge to the outcomes of patients. This work investigated the biological function and mechanism of Spartin in DDP resistance of OV. The growth and apoptosis of DDP-resistant OV cells were assessed by CCK-8, colony formation, and flow cytometry, respectively. Autolysosome fusion was observed by immunofluorescent staining of LC3 and LAMP2. The interaction between E3 ligase Smurf1 and YWHAZ or Spartin protein, and the ubiquitination level of YWHAZ were determined by Co-IP assay. Expression levels of autophagy or apoptosis-related markers were measured by RT-qPCR, western blotting, and immunohistochemistry. DDP resistance was assessed by xenograft tumor experiments in vivo. We found that Spartin expression was lower, while YWHAZ expression was higher in DDP-resistant OV samples and cells. Lower expression of Spartin indicated a poorer survival rate of OV patients. In addition, overexpression of Spartin sensitized OV cells to DDP and repressed autophagy. Moreover, Spartin bound to Smurf1 to promote Smurf1-mediated ubiquitination and degradation of YWHAZ, restraining autophagy and DDP resistance. Overexpression of YWHAZ counteracted the effects of Spartin against DDP resistance by promoting autophagy. In conclusion, Spartin-induced Smurf1-mediated ubiquitination modification of YWHAZ to inactivate autophagy, thereby increasing the sensitivity of OV cells to DDP. Our findings suggest that Spartin-combined therapy might act as an effective approach to fight against DDP resistance in OV.
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Affiliation(s)
- Jun Yin
- Department of Pharmaceutics, The Affiliated Shunde Hospital of Jinan University, Foshan, Guangdong Province, P.R. China
- Department of Gynecology, Affiliated Tumor Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, P.R. China
- Department of Pharmaceutics, Chongqing University Jiangjin Hospital, Chongqing, P.R. China
| | - Yan Ma
- Department of Gynecology, Affiliated Tumor Hospital of Xinjiang Medical University, Xinjiang Uygur Autonomous Region, P.R. China
| | - Hong Fu
- Department of Pediatrics, Chongqing University Jiangjin Hospital, Chongqing, P.R. China
| | - Ying Fan
- Department of Pharmaceutics, Chongqing University Jiangjin Hospital, Chongqing, P.R. China
| | - Debing Xiang
- Oncology, Chongqing University Jiangjin Hospital, Chongqing, P.R. China
| | - Ling Ding
- Department of Pharmaceutics, Chongqing University Jiangjin Hospital, Chongqing, P.R. China
| | - Jing Huang
- Department of Pediatrics, Chongqing University Jiangjin Hospital, Chongqing, P.R. China
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Nagano S, Kurokawa Y, Hagi T, Yoshioka R, Takahashi T, Saito T, Yamamoto K, Momose K, Yamashita K, Tanaka K, Makino T, Nakajima K, Eguchi H, Doki Y. Extensive methylation analysis of circulating tumor DNA in plasma of patients with gastric cancer. Sci Rep 2024; 14:30739. [PMID: 39730450 DOI: 10.1038/s41598-024-79252-y] [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: 06/03/2024] [Accepted: 11/07/2024] [Indexed: 12/29/2024] Open
Abstract
DNA methylation is known to be involved in tumor progression. This is the first study to perform an extensive methylation analysis of plasma circulating tumor DNA (ctDNA) using targeted bisulfite sequencing in gastric cancer (GC) patients to evaluate the usefulness of ctDNA methylation as a new biomarker. Sixteen patients who received chemotherapy for recurrent GC were included. After confirmation of the methylation status of 63 genes using the Cancer Genome Atlas (TCGA) dataset, the methylation status in paired tumor and non-tumor tissues and plasma were investigated using targeted bisulfite sequencing in these genes. Forty-four of the 63 genes were significantly hypermethylated in GC patients in the TCGA cohort. Of these 44 genes, hierarchical clustering showed that five (SPG20, FBN1, SDC2, TFPI2, SEPT9) were particularly hypermethylated in tumor compared to non-tumor tissues in our GC cohort. In plasma methylation analysis, patients with high methylation of these genes had significantly worse overall survival than those with low methylation (log-rank P = 0.009). In a patient who underwent blood sampling at multiple points, the methylation levels of these five genes varied closely with clinical tumor status. The plasma ctDNA methylation levels of these five genes could be useful as a noninvasive prognostic biomarker for GC.
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Affiliation(s)
- Shinnosuke Nagano
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita City, Osaka, 565-0871, Japan
| | - Yukinori Kurokawa
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita City, Osaka, 565-0871, Japan.
| | - Takaomi Hagi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita City, Osaka, 565-0871, Japan
| | - Ryo Yoshioka
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita City, Osaka, 565-0871, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita City, Osaka, 565-0871, Japan
| | - Takuro Saito
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita City, Osaka, 565-0871, Japan
| | - Kazuyoshi Yamamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita City, Osaka, 565-0871, Japan
| | - Kota Momose
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita City, Osaka, 565-0871, Japan
| | - Kotaro Yamashita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita City, Osaka, 565-0871, Japan
| | - Koji Tanaka
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita City, Osaka, 565-0871, Japan
| | - Tomoki Makino
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita City, Osaka, 565-0871, Japan
| | - Kiyokazu Nakajima
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita City, Osaka, 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita City, Osaka, 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamada-Oka, Suita City, Osaka, 565-0871, Japan
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Lei Y, Klionsky DJ. A delicate decision between repair and degradation of damaged lysosomes. Autophagy 2024; 20:1471-1472. [PMID: 38744436 PMCID: PMC11210907 DOI: 10.1080/15548627.2024.2350738] [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] [Indexed: 05/16/2024] Open
Abstract
The destination of a damaged lysosome is either being repaired if the damage is small or degraded through a lysosome-specific macroautophagy/autophagy pathway named lysophagy when the damage is too extensive to repair. Even though previous studies report lumenal glycan exposure during lysosome damage as a signal to trigger lysophagy, it is possibly beneficial for cells to initiate lysophagy earlier than membrane rupture. In a recently published article, Gahlot et al. determined that SPART/SPG20 senses lipid-packing defects and recruits and activates the ubiquitin ligase ITCH, which labels damaged lysosomes with ubiquitin chains to initiate lysophagy.
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Affiliation(s)
- Yuchen Lei
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
| | - Daniel J. Klionsky
- Life Sciences Institute and Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA
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4
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Kiss RS, Chicoine J, Khalil Y, Sladek R, Chen H, Pisaturo A, Martin C, Dale JD, Brudenell TA, Kamath A, Kyei-Boahen J, Hafiane A, Daliah G, Alecki C, Hopes TS, Heier M, Aligianis IA, Lebrun JJ, Aspden J, Paci E, Kerksiek A, Lütjohann D, Clayton P, Wills JC, von Kriegsheim A, Nilsson T, Sheridan E, Handley MT. Comparative proximity biotinylation implicates the small GTPase RAB18 in sterol mobilization and biosynthesis. J Biol Chem 2023; 299:105295. [PMID: 37774976 PMCID: PMC10641524 DOI: 10.1016/j.jbc.2023.105295] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 09/14/2023] [Accepted: 09/17/2023] [Indexed: 10/01/2023] Open
Abstract
Loss of functional RAB18 causes the autosomal recessive condition Warburg Micro syndrome. To better understand this disease, we used proximity biotinylation to generate an inventory of potential RAB18 effectors. A restricted set of 28 RAB18 interactions were dependent on the binary RAB3GAP1-RAB3GAP2 RAB18-guanine nucleotide exchange factor complex. Twelve of these 28 interactions are supported by prior reports, and we have directly validated novel interactions with SEC22A, TMCO4, and INPP5B. Consistent with a role for RAB18 in regulating membrane contact sites, interactors included groups of microtubule/membrane-remodeling proteins, membrane-tethering and docking proteins, and lipid-modifying/transporting proteins. Two of the putative interactors, EBP and OSBPL2/ORP2, have sterol substrates. EBP is a Δ8-Δ7 sterol isomerase, and ORP2 is a lipid transport protein. This prompted us to investigate a role for RAB18 in cholesterol biosynthesis. We found that the cholesterol precursor and EBP-product lathosterol accumulates in both RAB18-null HeLa cells and RAB3GAP1-null fibroblasts derived from an affected individual. Furthermore, de novo cholesterol biosynthesis is impaired in cells in which RAB18 is absent or dysregulated or in which ORP2 expression is disrupted. Our data demonstrate that guanine nucleotide exchange factor-dependent Rab interactions are highly amenable to interrogation by proximity biotinylation and may suggest that Micro syndrome is a cholesterol biosynthesis disorder.
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Affiliation(s)
- Robert S Kiss
- Cardiovascular Health Across the Lifespan (CHAL) Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
| | - Jarred Chicoine
- Metabolic Disorders and Complications (MEDIC) Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Youssef Khalil
- Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Robert Sladek
- Metabolic Disorders and Complications (MEDIC) Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - He Chen
- Cardiovascular Health Across the Lifespan (CHAL) Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Alessandro Pisaturo
- Cardiovascular Health Across the Lifespan (CHAL) Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Cyril Martin
- Cardiovascular Health Across the Lifespan (CHAL) Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Jessica D Dale
- Leeds Institute of Medical Research, St James's University Hospital, Leeds, United Kingdom
| | - Tegan A Brudenell
- Leeds Institute of Medical Research, St James's University Hospital, Leeds, United Kingdom
| | - Archith Kamath
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom; Division of Medical Sciences, University of Oxford, Oxford, United Kingdom
| | - Jeffrey Kyei-Boahen
- Department of Medicine, McGill University Health Centre, CHAL Research Program, Montreal, Canada
| | - Anouar Hafiane
- Department of Medicine, McGill University Health Centre, CHAL Research Program, Montreal, Canada
| | - Girija Daliah
- Department of Medicine, McGill University Health Centre, Cancer Research Program, Montreal, Canada
| | - Célia Alecki
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
| | - Tayah S Hopes
- Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
| | - Martin Heier
- Department of Clinical Neuroscience for Children, Oslo University Hospital, Oslo, Norway
| | - Irene A Aligianis
- Medical and Developmental Genetics, Medical Research Council Human Genetics Unit, Edinburgh, United Kingdom
| | - Jean-Jacques Lebrun
- Department of Medicine, McGill University Health Centre, Cancer Research Program, Montreal, Canada
| | - Julie Aspden
- Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom
| | - Emanuele Paci
- Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom
| | - Anja Kerksiek
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
| | - Dieter Lütjohann
- Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany
| | - Peter Clayton
- Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, United Kingdom
| | - Jimi C Wills
- Cancer Research United Kingdom Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom; Firefinch Software Ltd, Edinburgh, United Kingdom
| | - Alex von Kriegsheim
- Cancer Research United Kingdom Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, United Kingdom
| | - Tommy Nilsson
- Cancer Research Program (CRP), Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Eamonn Sheridan
- Leeds Institute of Medical Research, St James's University Hospital, Leeds, United Kingdom
| | - Mark T Handley
- Leeds Institute of Medical Research, St James's University Hospital, Leeds, United Kingdom; Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
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Delmas D, Cotte AK, Connat JL, Hermetet F, Bouyer F, Aires V. Emergence of Lipid Droplets in the Mechanisms of Carcinogenesis and Therapeutic Responses. Cancers (Basel) 2023; 15:4100. [PMID: 37627128 PMCID: PMC10452604 DOI: 10.3390/cancers15164100] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/04/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Cancer shares common risk factors with cardiovascular diseases such as dyslipidemia, obesity and inflammation. In both cases, dysregulations of lipid metabolism occur, and lipid vesicles emerge as important factors that can influence carcinogenesis. In this review, the role of different lipids known to be involved in cancer and its response to treatments is detailed. In particular, lipid droplets (LDs), initially described for their role in lipid storage, exert multiple functions, from the physiological prevention of LD coalescence and regulation of endoplasmic reticulum homeostasis to pathological involvement in tumor progression and aggressiveness. Analysis of LDs highlights the importance of phosphatidylcholine metabolism and the diversity of lipid synthesis enzymes. In many cancers, the phosphatidylcholine pathways are disrupted, modifying the expression of genes coding for metabolic enzymes. Tumor microenvironment conditions, such as hypoxia, different types of stress or inflammatory conditions, are also important determinants of LD behavior in cancer cells. Therefore, LDs represent therapeutic targets in cancer, and many lipid mediators have emerged as potential biomarkers for cancer onset, progression, and/or resistance.
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Affiliation(s)
- Dominique Delmas
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
- Centre de Lutte Contre le Cancer Georges François Leclerc, 21000 Dijon, France
| | - Alexia K. Cotte
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
| | - Jean-Louis Connat
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
| | - François Hermetet
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
| | - Florence Bouyer
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
| | - Virginie Aires
- UFR of Heatlh Sciences, Université de Bourgogne, 21000 Dijon, France; (A.K.C.); (J.-L.C.); (F.H.); (F.B.); (V.A.)
- INSERM Research Center U1231—Bioactive Molecules and Health Research Group, Cancer and Adaptive Immune Response Team, 21000 Dijon, France
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Sarwar MS, Ramirez CN, Dina Kuo HC, Chou P, Wu R, Sargsyan D, Yang Y, Shannar A, Mary Peter R, Yin R, Wang Y, Su X, Kong AN. The environmental carcinogen benzo[a]pyrene regulates epigenetic reprogramming and metabolic rewiring in a two-stage mouse skin carcinogenesis model. Carcinogenesis 2023; 44:436-449. [PMID: 37100755 PMCID: PMC10414144 DOI: 10.1093/carcin/bgad024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 03/30/2023] [Accepted: 04/25/2023] [Indexed: 04/28/2023] Open
Abstract
Non-melanoma skin cancer (NMSC) is the most common cancer in the world. Environmental exposure to carcinogens is one of the major causes of NMSC initiation and progression. In the current study, we utilized a two-stage skin carcinogenesis mouse model generated by sequential exposure to cancer-initiating agent benzo[a]pyrene (BaP) and promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA), to study epigenetic, transcriptomic and metabolic changes at different stages during the development of NMSC. BaP/TPA caused significant alterations in DNA methylation and gene expression profiles in skin carcinogenesis, as evidenced by DNA-seq and RNA-seq analysis. Correlation analysis between differentially expressed genes and differentially methylated regions found that the mRNA expression of oncogenes leucine rich repeat LGI family member 2 (Lgi2), kallikrein-related peptidase 13 (Klk13) and SRY-Box transcription factor (Sox5) are correlated with the promoter CpG methylation status, indicating BaP/TPA regulates these oncogenes through regulating their promoter methylation at different stages of NMSC. Pathway analysis identified that the modulation of macrophage-stimulating protein-recepteur d'origine nantais and high-mobility group box 1 signaling pathways, superpathway of melatonin degradation, melatonin degradation 1, sirtuin signaling and actin cytoskeleton signaling pathways are associated with the development of NMSC. The metabolomic study showed BaP/TPA regulated cancer-associated metabolisms like pyrimidine and amino acid metabolisms/metabolites and epigenetic-associated metabolites, such as S-adenosylmethionine, methionine and 5-methylcytosine, indicating a critical role in carcinogen-mediated metabolic reprogramming and its consequences on cancer development. Altogether, this study provides novel insights integrating methylomic, transcriptomic and metabolic-signaling pathways that could benefit future skin cancer treatment and interception studies.
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Affiliation(s)
- Md. Shahid Sarwar
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Christina N Ramirez
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Hsiao-Chen Dina Kuo
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Pochung Chou
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Renyi Wu
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Davit Sargsyan
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Yuqing Yang
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Ahmad Shannar
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Rebecca Mary Peter
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Ran Yin
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Yujue Wang
- Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
| | - Xiaoyang Su
- Metabolomics Shared Resource, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA
| | - Ah-Ng Kong
- Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
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7
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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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8
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Cusenza VY, Bonora E, Amodio N, Frazzi R. Spartin: At the crossroad between ubiquitination and metabolism in cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188813. [PMID: 36195276 DOI: 10.1016/j.bbcan.2022.188813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/28/2022] [Accepted: 09/28/2022] [Indexed: 12/01/2022]
Abstract
SPART is a gene coding for a multifunctional protein called spartin, localized in various organelles of human cells. Mutations in the coding region are responsible for a hereditary form of spastic paraplegia called Troyer syndrome while the epigenetic silencing has been demonstrated for some types of tumors. The main functions of this gene are associated to endosomic trafficking and receptor degradation, microtubule interaction, cytokinesis, fatty acids and oxidative metabolism. Spartin has been shown to be a target regulated by STAT3 and localizes also at the level of the mitochondrial outer membrane, where it forms part of a complex maintaining the integrity of the membrane potential. The most recent evidences report a downregulation of spartin in tumor tissues when compared to adjacent normal samples. This intriguing evidence supports further research aimed at clarifying the role of this protein in cancer development and metabolism.
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Affiliation(s)
- Vincenza Ylenia Cusenza
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy
| | - Elena Bonora
- Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna, Italy; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Nicola Amodio
- Department of Experimental and Clinical Medicine, Magna Graecia University of Catanzaro, Catanzaro, Italy
| | - Raffaele Frazzi
- Laboratory of Translational Research, Azienda Unità Sanitaria Locale - IRCCS di Reggio Emilia, Reggio Emilia, Italy.
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9
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The Puzzle of Hereditary Spastic Paraplegia: From Epidemiology to Treatment. Int J Mol Sci 2022; 23:ijms23147665. [PMID: 35887006 PMCID: PMC9321931 DOI: 10.3390/ijms23147665] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 07/08/2022] [Accepted: 07/08/2022] [Indexed: 01/03/2023] Open
Abstract
Inherited neurodegenerative pathology characterized by lower muscle tone and increasing spasticity in the lower limbs is termed hereditary spastic paraplegia (HSP). HSP is associated with changes in about 80 genes and their products involved in various biochemical pathways, such as lipid droplet formation, endoplasmic reticulum shaping, axon transport, endosome trafficking, and mitochondrial function. With the inheritance patterns of autosomal dominant, autosomal recessive, X-linked recessive, and mitochondrial inheritance, HSP is prevalent around the globe at a rate of 1–5 cases in every 100,000 individuals. Recent technology and medical interventions somewhat aid in recognizing and managing the malaise. However, HSP still lacks an appropriate and adequate therapeutic approach. Current therapies are based on the clinical manifestations observed in the patients, for example, smoothing the relaxant spastic muscle and physiotherapies. The limited clinical trial studies contribute to the absence of specific pharmaceuticals for HSPs. Our current work briefly explains the causative genes, epidemiology, underlying mechanism, and the management approach undertaken to date. We have also mentioned the latest approved drugs to summarise the available knowledge on therapeutic strategies for HSP.
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Methylation Heterogeneity and Gene Expression of SPG20 in Solid Tumors. Genes (Basel) 2022; 13:genes13050861. [PMID: 35627246 PMCID: PMC9140344 DOI: 10.3390/genes13050861] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/06/2022] [Accepted: 05/10/2022] [Indexed: 12/31/2022] Open
Abstract
Introduction. The downregulation of the Spastic Paraplegia-20 (SPG20) gene is correlated with a rare autosomal recessive disorder called Troyer Syndrome. Only in recent years has SPG20 been studied and partially characterized in cancer. SPG20 has been shown to be hypermethylated in colorectal cancer, gastric cancer, non-Hodgkin’s lymphoma and hepatocellular carcinoma. In this study, we analyze the methylation status and the gene expression of SPG20 in different tumors of various histological origins. Methods. We analyzed the data generated through Infinium Human Methylation 450 BeadChip arrays and RNA-seq approaches extrapolated from The Cancer Genome Atlas (TCGA) database. The statistics were performed with R 4.0.4. Results. We aimed to assess whether the hypermethylation of this target gene was a common characteristic among different tumors and if there was a correlation between the m-values and the gene expression in paired tumor versus solid tissue normal. Overall, our analysis highlighted that SPG20 open sea upstream the TSS is altogether hypermethylated, and the tumor tissues display a higher methylation heterogeneity compared to the solid tissue normal. The gene expression evidences a reproducible, higher gene expression in normal tissues. Conclusion. Our research, based on data mining from TCGA, evidences that colon and liver tumors display a consistent methylation heterogeneity compared to their normal counterparts. This parallels a downregulation of SPG20 gene expression in tumor samples and suggests a role for this multifunctional protein in the control of tumor progression.
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Müller D, Győrffy B. DNA methylation-based diagnostic, prognostic, and predictive biomarkers in colorectal cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188722. [PMID: 35307512 DOI: 10.1016/j.bbcan.2022.188722] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/21/2022] [Accepted: 03/13/2022] [Indexed: 12/12/2022]
Abstract
DNA methylation is an epigenetic mechanism regulating gene expression. Changes in DNA methylation were suggested to be useful biomarkers for diagnosis, and for the determination of prognosis and treatment response. Here, we provide an overview of methylation-based biomarkers in colorectal cancer. First, we start with the two methylation-based diagnostic biomarkers already approved for colorectal cancer, SEPT9 and the combination of NDRG4 and BMP3. Then, we provide a list-based overview of new biomarker candidates depending on the sample source including plasma, stool, urine, and surgically removed tumor tissues. The most often identified markers like SDC2, VIM, APC, MGMT, SFRP1, SFRP2, and NDRG4 have distinct functions previously linked to tumor progression. Although numerous studies have identified tumor-specific methylation changes, most of these alterations were observed in a single study only. The lack of validation in independent samples means low reproducibility and is a major limitation. The genome-wide determination of methylation status (methylome) can provide data to solve these issues. In the third section of the review, methylome studies focusing on different aspects related to CRC, including precancerous lesions, CRC-specific changes, molecular subtypes, aging, and chemotherapy response are summarized. Notably, techniques simultaneously analyzing a large set of regions can also uncover epigenetic regulation of genes which have not yet been associated with tumorigenesis previously. A remaining constraint of studies published to date is the low patient number utilized in these preventing the identification of clinically valuable biomarker candidates. Either future large-scale studies or the integration of already available methylome-level data will be necessary to uncover biomarkers sufficiently robust for clinical application.
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Affiliation(s)
- Dalma Müller
- Dept. of Bioinformatics, Semmelweis University, Budapest, Hungary; Cancer Biomarker Research Group, RCNS, Budapest, Hungary
| | - Balázs Győrffy
- Dept. of Bioinformatics, Semmelweis University, Budapest, Hungary; Cancer Biomarker Research Group, RCNS, Budapest, Hungary.
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12
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Alizadeh-Sedigh M, Fazeli MS, Mahmoodzadeh H, Sharif SB, Teimoori-Toolabi L. Methylation of FBN1, SPG20, ITF2, RUNX3, SNCA, MLH1, and SEPT9 genes in circulating cell-free DNA as biomarkers of colorectal cancer. Cancer Biomark 2021; 34:221-250. [PMID: 34957998 DOI: 10.3233/cbm-210315] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Investigating aberrant tumor-specific methylation in plasma cell-free DNA provides a promising and noninvasive biomarker for cancer detection. OBJECTIVE We aimed to investigate methylation status of some promoter regions in the plasma and tumor tissues to find biomarkers for early detection of colorectal cancer. METHODS This case-control study on seventy colorectal cancer patients and fifty matched healthy controls used Methylation-Specific High-Resolution Melting Curve analysis to evaluate the methylation of the selected promoter regions in converted genomic tissue DNA and plasma cfDNA. RESULTS The methylation levels in selected regions of SPG20 (+24375 to +24680, +24209 to +24399, and +23625 to +23883), SNCA (+807 to +1013, +7 to +162, and -180 to +7), FBN1 (+223 to +429, +1 to +245, and -18 to -175), ITF2 (+296 to +436 and -180 to +55), SEPT9 (-914412 to -91590 and -99083 to -92264), and MLH1 (-13 to +22) were significantly higher in tumor tissues compared with normal adjacent tissues. The methylation levels of FBN1, ITF2, SNCA, and SPG20 promoters were significantly higher in the patient's plasma compared to patient's normal tissue and plasma of healthy control subjects. FBN1, SPG20, and SEPT9 promoter methylation had a good diagnostic performance for discriminating CRC tissues from normal adjacent tissues (AUC > 0.8). A panel of SPG20, FBN1, and SEPT9 methylation had a higher diagnostic value than that of any single biomarker and other panels in tissue-based assay (AUC > 0.9). The methylation of FBN1(a) and SPG20(a) regions, as the closest region to the first coding sequence (CDS), had a good diagnostic performance in plasma cfDNA (AUC > 0.8) while a panel consisted of FBN1(a) and SPG20(a) regions showed excellent diagnostic performance for CRC detection in plasma cfDNA (AUC > 0.9). CONCLUSION Methylation of FBN1(a) and SPG20(a) promoter regions in the plasma cfDNA can be an excellent simple, non-invasive blood-based test for early detection of CRC.
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Affiliation(s)
- Maryam Alizadeh-Sedigh
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Mohammad Sadegh Fazeli
- Department of Surgery, Division of Colorectal Surgery, Imam Khomeini Medical Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Habibollah Mahmoodzadeh
- Cancer Institute of Iran, Imam Khomeini Medical Complex, Tehran University of Medical Sciences, Tehran, Iran
| | - Shahin Behrouz Sharif
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Ladan Teimoori-Toolabi
- Molecular Medicine Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
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13
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Gachabayov M, Lebovics E, Rojas A, Felsenreich DM, Latifi R, Bergamaschi R. Performance evaluation of stool DNA methylation tests in colorectal cancer screening: a systematic review and meta-analysis. Colorectal Dis 2021; 23:1030-1042. [PMID: 33410272 DOI: 10.1111/codi.15521] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 12/30/2020] [Accepted: 12/30/2020] [Indexed: 12/16/2022]
Abstract
AIM There is not sufficient evidence about whether stool DNA methylation tests allow prioritizing patients to colonoscopy. Due to the COVID-19 pandemic, there will be a wait-list for rescheduling colonoscopies once the mitigation is lifted. The aim of this meta-analysis was to evaluate the accuracy of stool DNA methylation tests in detecting colorectal cancer. METHODS The PubMed, Cochrane Library and MEDLINE via Ovid were searched. Studies reporting the accuracy (Sackett phase 2 or 3) of stool DNA methylation tests to detect sporadic colorectal cancer were included. The DerSimonian-Laird method with random-effects model was utilized for meta-analysis. RESULTS Forty-six studies totaling 16 149 patients were included in the meta-analysis. The pooled sensitivity and specificity of all single genes and combinations was 62.7% (57.7%, 67.4%) and 91% (89.5%, 92.2%), respectively. Combinations of genes provided higher sensitivity compared to single genes (80.8% [75.1%, 85.4%] vs. 57.8% [52.3%, 63.1%]) with no significant decrease in specificity (87.8% [84.1%, 90.7%] vs. 92.1% [90.4%, 93.5%]). The most accurate single gene was found to be SDC2 with a sensitivity of 83.1% (72.6%, 90.2%) and a specificity of 91.2% (88.6%, 93.2%). CONCLUSIONS Stool DNA methylation tests have high specificity (92%) with relatively lower sensitivity (81%). Combining genes increases sensitivity compared to single gene tests. The single most accurate gene is SDC2, which should be considered for further research.
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Affiliation(s)
- Mahir Gachabayov
- Section of Colorectal Surgery, Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Edward Lebovics
- Section of Gastroenterology, Department of Medicine, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Aram Rojas
- Section of Colorectal Surgery, Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Daniel M Felsenreich
- Section of Colorectal Surgery, Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Rifat Latifi
- Section of Colorectal Surgery, Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Roberto Bergamaschi
- Section of Colorectal Surgery, Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
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Akhlaghipour I, Bina AR, Abbaszadegan MR, Moghbeli M. Methylation as a critical epigenetic process during tumor progressions among Iranian population: an overview. Genes Environ 2021; 43:14. [PMID: 33883026 PMCID: PMC8059047 DOI: 10.1186/s41021-021-00187-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 04/07/2021] [Indexed: 11/10/2022] Open
Abstract
Cancer is one of the main health challenges and leading causes of deaths in the world. Various environmental and genetic risk factors are associated with tumorigenesis. Epigenetic deregulations are also important risk factors during tumor progression which are reversible transcriptional alterations without any genomic changes. Various mechanisms are involved in epigenetic regulations such as DNA methylation, chromatin modifications, and noncoding RNAs. Cancer incidence and mortality have a growing trend during last decades among Iranian population which are significantly related to the late diagnosis. Therefore, it is required to prepare efficient molecular diagnostic panels for the early detection of cancer in this population. Promoter hyper methylation is frequently observed as an inhibitory molecular mechanism in various genes associated with DNA repair, cell cycle regulation, and apoptosis during tumor progression. Since aberrant promoter methylations have critical roles in early stages of neoplastic transformations, in present review we have summarized all of the aberrant methylations which have been reported during tumor progression among Iranian cancer patients. Aberrant promoter methylations are targetable and prepare novel therapeutic options for the personalized medicine in cancer patients. This review paves the way to introduce a non-invasive methylation specific panel of diagnostic markers for the early detection of cancer among Iranians.
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Affiliation(s)
- Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Reza Bina
- Student Research Committee, Faculty of Medicine, Birjand University of Medical Sciences, Birjand, Iran
| | | | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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15
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Laugsand EA, Brenne SS, Skorpen F. DNA methylation markers detected in blood, stool, urine, and tissue in colorectal cancer: a systematic review of paired samples. Int J Colorectal Dis 2021; 36:239-251. [PMID: 33030559 PMCID: PMC7801356 DOI: 10.1007/s00384-020-03757-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/17/2020] [Indexed: 02/04/2023]
Abstract
PURPOSE Methylated cell-free DNA in liquid biopsies are promising non-invasive biomarkers for colorectal cancer (CRC). Optimal markers would have high sensitivity and specificity for early detection of CRC and could be detected in more than one type of material from the patient. We systematically reviewed the literature on DNA methylation markers of colorectal cancer, detected in more than one type of material, regarding their potential as contributors to a panel for screening and follow-up of CRC. METHODS The databases MEDLINE, Web of Science, and Embase were systematically searched. Data extraction and review was performed by two authors independently. Agreement between methylation status in tissue and other materials (blood/stool/urine) was analyzed using the McNemar test and Cohen's kappa. RESULTS From the 51 included studies, we identified seven single markers with sensitivity ≥ 75% and specificity ≥ 90% for CRC. We also identified one promising plasma panel and two stool panels. The correspondence of methylation status was evaluated as very good for four markers, but only marginal for most of the other markers investigated (12 of 21). CONCLUSION The included studies reported only some of the variables and markers of interest and included few patients. Hence, a meta-analysis was not possible at this point. Larger, prospective studies must be designed to study the discordant detection of markers in tissue and liquid biopsies. When reporting their findings, such studies should use a standardized format.
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Affiliation(s)
- Eivor Alette Laugsand
- Department of Surgery, Levanger Hospital, Nord-Trøndelag Hospital trust, N-7600, Levanger, Norway.
- Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), N-7491, Trondheim, Norway.
| | - Siv Sellæg Brenne
- Department of Surgery, Levanger Hospital, Nord-Trøndelag Hospital trust, N-7600, Levanger, Norway
- Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), N-7491, Trondheim, Norway
| | - Frank Skorpen
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), N-7491, Trondheim, Norway
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16
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Bedon L, Dal Bo M, Mossenta M, Busato D, Toffoli G, Polano M. A Novel Epigenetic Machine Learning Model to Define Risk of Progression for Hepatocellular Carcinoma Patients. Int J Mol Sci 2021; 22:1075. [PMID: 33499054 PMCID: PMC7865606 DOI: 10.3390/ijms22031075] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/11/2021] [Accepted: 01/20/2021] [Indexed: 12/24/2022] Open
Abstract
Although extensive advancements have been made in treatment against hepatocellular carcinoma (HCC), the prognosis of HCC patients remains unsatisfied. It is now clearly established that extensive epigenetic changes act as a driver in human tumors. This study exploits HCC epigenetic deregulation to define a novel prognostic model for monitoring the progression of HCC. We analyzed the genome-wide DNA methylation profile of 374 primary tumor specimens using the Illumina 450 K array data from The Cancer Genome Atlas. We initially used a novel combination of Machine Learning algorithms (Recursive Features Selection, Boruta) to capture early tumor progression features. The subsets of probes obtained were used to train and validate Random Forest models to predict a Progression Free Survival greater or less than 6 months. The model based on 34 epigenetic probes showed the best performance, scoring 0.80 accuracy and 0.51 Matthews Correlation Coefficient on testset. Then, we generated and validated a progression signature based on 4 methylation probes capable of stratifying HCC patients at high and low risk of progression. Survival analysis showed that high risk patients are characterized by a poorer progression free survival compared to low risk patients. Moreover, decision curve analysis confirmed the strength of this predictive tool over conventional clinical parameters. Functional enrichment analysis highlighted that high risk patients differentiated themselves by the upregulation of proliferative pathways. Ultimately, we propose the oncogenic MCM2 gene as a methylation-driven gene of which the representative epigenetic markers could serve both as predictive and prognostic markers. Briefly, our work provides several potential HCC progression epigenetic biomarkers as well as a new signature that may enhance patients surveillance and advances in personalized treatment.
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Affiliation(s)
- Luca Bedon
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (L.B.); (M.D.B.); (M.M.); (D.B.)
- Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via L. Giorgieri 1, 34127 Trieste, Italy
| | - Michele Dal Bo
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (L.B.); (M.D.B.); (M.M.); (D.B.)
| | - Monica Mossenta
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (L.B.); (M.D.B.); (M.M.); (D.B.)
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Davide Busato
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (L.B.); (M.D.B.); (M.M.); (D.B.)
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (L.B.); (M.D.B.); (M.M.); (D.B.)
| | - Maurizio Polano
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (L.B.); (M.D.B.); (M.M.); (D.B.)
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Zhang S, Zeng T, Hu B, Zhang YH, Feng K, Chen L, Niu Z, Li J, Huang T, Cai YD. Discriminating Origin Tissues of Tumor Cell Lines by Methylation Signatures and Dys-Methylated Rules. Front Bioeng Biotechnol 2020; 8:507. [PMID: 32528944 PMCID: PMC7264161 DOI: 10.3389/fbioe.2020.00507] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2020] [Accepted: 04/30/2020] [Indexed: 12/18/2022] Open
Abstract
DNA methylation is an essential epigenetic modification for multiple biological processes. DNA methylation in mammals acts as an epigenetic mark of transcriptional repression. Aberrant levels of DNA methylation can be observed in various types of tumor cells. Thus, DNA methylation has attracted considerable attention among researchers to provide new and feasible tumor therapies. Conventional studies considered single-gene methylation or specific loci as biomarkers for tumorigenesis. However, genome-scale methylated modification has not been completely investigated. Thus, we proposed and compared two novel computational approaches based on multiple machine learning algorithms for the qualitative and quantitative analyses of methylation-associated genes and their dys-methylated patterns. This study contributes to the identification of novel effective genes and the establishment of optimal quantitative rules for aberrant methylation distinguishing tumor cells with different origin tissues.
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Affiliation(s)
- Shiqi Zhang
- School of Life Sciences, Shanghai University, Shanghai, China.,Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark
| | - Tao Zeng
- Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, China
| | - Bin Hu
- State Key Laboratory of Livestock and Poultry Breeding, Guangdong Public Laboratory of Animal Breeding and Nutrition, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Yu-Hang Zhang
- Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Kaiyan Feng
- Department of Computer Science, Guangdong AIB Polytechnic, Guangzhou, China
| | - Lei Chen
- College of Information Engineering, Shanghai Maritime University, Shanghai, China
| | - Zhibin Niu
- College of Intelligence and Computing, Tianjin University, Tianjin, China
| | - Jianhao Li
- State Key Laboratory of Livestock and Poultry Breeding, Guangdong Public Laboratory of Animal Breeding and Nutrition, Guangdong Key Laboratory of Animal Breeding and Nutrition, Institute of Animal Science, Guangdong Academy of Agricultural Sciences, Guangzhou, China
| | - Tao Huang
- Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Yu-Dong Cai
- School of Life Sciences, Shanghai University, Shanghai, China
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18
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Milliron HYY, Weiland MJ, Kort EJ, Jovinge S. Isolation of Cardiomyocytes Undergoing Mitosis With Complete Cytokinesis. Circ Res 2019; 125:1070-1086. [PMID: 31648614 DOI: 10.1161/circresaha.119.314908] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
RATIONALE Adult human cardiomyocytes do not complete cytokinesis despite passing through the S-phase of the cell cycle. As a result, polyploidization and multinucleation occur. To get a deeper understanding of the mechanisms surrounding division of cardiomyocytes, there is a crucial need for a technique to isolate cardiomyocytes that complete cell division/cytokinesis. OBJECTIVE Markers of cell cycle progression based on DNA content cannot distinguish between mitotic cardiomyocytes that fail to complete cytokinesis from those cells that undergo true cell division. With the use of molecular beacons (MBs) targeting specific mRNAs, we aimed to identify truly proliferative cardiomyocytes derived from human induced pluripotent stem cells. METHODS AND RESULTS Fluorescence-activated cell sorting combined with MBs was performed to sort cardiomyocyte populations enriched for mitotic cells. Expressions of cell cycle specific genes were confirmed by means of reverse transcription-quantitative polymerase chain reaction and single-cell RNA sequencing (scRNA-seq) combined with gene signatures of cell cycle progression. We characterized the sorted groups by proliferation assays and time-lapse microscopy which confirmed the proliferative advantage of MB-positive cell populations relative to MB-negative and G2/M populations. Gene expression analysis revealed that the MB-positive cardiomyocyte subpopulation exhibited patterns consistent with the processes of nuclear division, chromosome segregation, and transition from M to G1 phase. The use of dual-MBs targeting CDC20 and SPG20 mRNAs enabled the enrichment of cytokinetic events (CDC20highSPG20high). Interestingly, cells that did not complete cytokinesis and remained binucleated were found to be CDC20lowSPG20high while polyploid cardiomyocytes that replicated DNA but failed to complete karyokinesis were found to be CDC20lowSPG20low. CONCLUSIONS This study demonstrates a novel alternative to existing DNA content-based approaches for sorting cardiomyocytes with true mitotic potential that can be used to study the unique dynamics of cardiomyocyte nuclei during mitosis. Our technique for sorting live cardiomyocytes undergoing cytokinesis would provide a basis for future studies to uncover mechanisms underlying the development and regeneration of heart tissue.
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Affiliation(s)
- Hsiao-Yun Y Milliron
- From the DeVos Cardiovascular Program, Van Andel Research Institute and Fredrik Meijer Heart and Vascular Institute/Spectrum Health, Grand Rapids, MI (H.Y.M., M.J.W., E.J.K., S.J.)
| | - Matthew J Weiland
- From the DeVos Cardiovascular Program, Van Andel Research Institute and Fredrik Meijer Heart and Vascular Institute/Spectrum Health, Grand Rapids, MI (H.Y.M., M.J.W., E.J.K., S.J.)
| | - Eric J Kort
- From the DeVos Cardiovascular Program, Van Andel Research Institute and Fredrik Meijer Heart and Vascular Institute/Spectrum Health, Grand Rapids, MI (H.Y.M., M.J.W., E.J.K., S.J.).,Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, East Lansing (E.J.K.)
| | - Stefan Jovinge
- From the DeVos Cardiovascular Program, Van Andel Research Institute and Fredrik Meijer Heart and Vascular Institute/Spectrum Health, Grand Rapids, MI (H.Y.M., M.J.W., E.J.K., S.J.).,Cardiovascular Institute, Stanford University, Palo Alto, CA (S.J.)
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Circulating biomarkers for early detection and clinical management of colorectal cancer. Mol Aspects Med 2019; 69:107-122. [PMID: 31189073 DOI: 10.1016/j.mam.2019.06.002] [Citation(s) in RCA: 189] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 06/07/2019] [Accepted: 06/08/2019] [Indexed: 02/06/2023]
Abstract
New non-invasive approaches that can complement and improve on current strategies for colorectal cancer (CRC) screening and management are urgently needed. A growing number of publications have documented that components of tumors, which are shed into the circulation, can be detected in the form of liquid biopsies and can be used to detect CRC at early stages, to predict response to certain therapies and to detect CRC recurrence in a minimally invasive way. The analysis of circulating tumor DNA (ctDNA), tumor-derived cells (CTC, circulating tumor cells) or circulating microRNA (miRNA) in blood and other body fluids, have a great potential to improve different aspects of CRC management. The challenge now is to find which types of components, biofluids and detection methods would be the most suitable to be applied in the different steps of CRC detection and treatment. This chapter will provide an up to date review on ctDNA, CTCs and circulating miRNAs as new biomarkers for CRC, either for clinical management or early detection, highlighting their advantages and limitations.
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20
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Wei KL, Chou JL, Chen YC, Jin H, Chuang YM, Wu CS, Chan MWY. Methylomics analysis identifies a putative STAT3 target, SPG20, as a noninvasive epigenetic biomarker for early detection of gastric cancer. PLoS One 2019; 14:e0218338. [PMID: 31194837 PMCID: PMC6564691 DOI: 10.1371/journal.pone.0218338] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 05/30/2019] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is a leading cause of cancer worldwide. Our previous studies showed that aberrant activation of JAK/STAT3 signaling confer epigenetically silences STAT3 target genes in gastric cancer. To further investigate the clinical significance of this phenomenon, we performed Illumina 850K methylation microarray analysis in AGS gastric cancer cells, and cells depleted of STAT3. Integrative computational analysis identified SPG20 as a putative STAT3 epigenetic target, showing promoter hypomethylation in STAT3-depleted AGS cells. Bisulphite pyrosequencing and qRT-PCR confirmed that SPG20 is epigenetically silenced by promoter hypermethylation in a panel of gastric cancer cell lines including AGS cells, but not in immortalized gastric epithelial GES cells. Expression of SPG20 could be restored by the treatment with a DNMT inhibitor, further suggesting that SPG20 is epigenetically silenced by promoter methylation. Clinically, a progressive increase in SPG20 methylation was observed in tissues samples from gastritis (n = 34), to intestinal metaplasia (IM, n = 33), to gastric cancer (n = 53). Importantly, SPG20 methylation could be detected in cell-free DNA isolated from serum samples of gastritis, IM and gastric cancer patients, having a progressive similar to tissues. Taken together, SPG20, a potential STAT3 target, is frequently methylated in gastric cancer, representing a novel noninvasive biomarker for early detection of this deadly disease.
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Affiliation(s)
- Kuo-Liang Wei
- Division of Gastroenterology, Chang Gung Memorial Hospital, Chia-Yi, Taiwan
| | - Jian-Liang Chou
- Division of Gastroenterology, Chang Gung Memorial Hospital, Chia-Yi, Taiwan
| | - Yin-Chen Chen
- Division of Gastroenterology, Chang Gung Memorial Hospital, Chia-Yi, Taiwan
| | - Hongchuan Jin
- Laboratory of Cancer Biology, Key Lab of Biotherapy in Zhejiang, Sir Run Run Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
| | - Yu-Min Chuang
- Department Biomedical Sciences, National Chung Cheng University, Chia Yi, Taiwan
| | - Cheng-Shyong Wu
- Division of Gastroenterology, Chang Gung Memorial Hospital, Chia-Yi, Taiwan
- * E-mail: (CSW); (MC)
| | - Michael W. Y. Chan
- Department Biomedical Sciences, National Chung Cheng University, Chia Yi, Taiwan
- Center for Innovative Research on Aging Society, National Chung Cheng University, Chia Yi, Taiwan
- Center for Nano Bio-Detection, National Chung Cheng University, Chia Yi, Taiwan
- Epigenomics and Human Disease Research Center, National Chung Cheng University, Chia Yi, Taiwan
- * E-mail: (CSW); (MC)
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21
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Aberrant methylation status of SPG20 promoter in hepatocellular carcinoma: A potential tumor metastasis biomarker. Cancer Genet 2019; 233-234:48-55. [PMID: 31109594 DOI: 10.1016/j.cancergen.2019.04.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 03/01/2019] [Accepted: 04/09/2019] [Indexed: 12/15/2022]
Abstract
PURPOSE The aim of this study is to analyze the methylation levels of SPG20 promotor region and explore the association between the methylation levels and clinical features in hepatocellular carcinoma (HCC). MATERIALS AND METHODS We collected paired of HCC and adjacent non-cancerous tissues (ANT) from 160 HCC patients and analyze the methylation levels through MassARRAY Analyzer 4. The statistical calculations were performed using SPSS version 22.0. Real-time-quantification PCR was performed to assess expression levels of SPG20 in HCC cell lines. Wound healing assay and transwell assay was used to measure cell migration capacity. RESULT We found that mean methylation level of SPG20 in tumor tissues was significantly higher than that in ANT (7.3% vs. 16.2%, P<0.0013). There was a significantly negative correlation between expression level and methylation level of SPG20 (P<0.01). In addition, the methylation levels in HCC were correlated with age and HBV infection. Meanwhile, micro-satellite tumors (P = 0.016) and tumor number (P = 0.018) was found significantly associated with increased methylation levels of several CpG sites and the mean levels of SPG20 promotor in ANT. In addtion, the capacity of cell migration was significantly enhanced in SPG20 knock-down HCC cells. CONCLUSION The hypermethylation status of SPG20 gene promoter is significantly associated with intra-hepatic metastasis and contribute to HCC metastasis.
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22
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Liu R, Su X, Long Y, Zhou D, Zhang X, Ye Z, Ma J, Tang T, Wang F, He C. A systematic review and quantitative assessment of methylation biomarkers in fecal DNA and colorectal cancer and its precursor, colorectal adenoma. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2019; 779:45-57. [PMID: 31097151 DOI: 10.1016/j.mrrev.2019.01.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 11/15/2018] [Accepted: 01/16/2019] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) arises from accumulated genetic and epigenetic alterations, which provide the possibility to identify tumor-specific biomarkers by analyzing fecal DNA. Methylation status in human genes from tumor tissue is highlighted as promising biomarker in the early detection of CRC. A number of studies have documented altered methylation levels in DNA extracted from stool samples, but generated heterogeneous results. We performed a systematic review and quantitative assessment of existing studies to compare levels of DNA methylation in most frequently studied genes and their diagnostic value in CRC and its precursor, colorectal adenoma, with their counterparts in healthy subjects. Robust searches of the literature were performed in our study with explicit strategies and definite inclusion/exclusion criteria. Pooled data revealed that methylation levels of SFRP2, SFRP1, TFPI2, BMP3, NDRG4, SPG20, and BMP3 plus NDRG4 genes exceeded a sensitivity of 70% and a specificity of 80% for CRC detection. The DOR of the seven candidate biomarkers ranged from 19.80 to 334.33, indicating a good diagnostic power in discriminating cancer from normal tissues. The AUC range was from 0.88 to 0.95, indicating a good or very good discriminatory performance. When test results for BMP3 and NDRG4 were combined, the DOR of CRC detection was 98.36, which was higher than that for BMP3 and NDRG4 separately. As for adenoma detection, the DOR of methylated NDRG4 is higher than that for CRC (CRC vs. adenoma: 54.86 vs. 57.22). Both the sensitivity and specificity of NDRG4 for adenoma detection exceeded 70%. These findings demonstrate the eligibility and feasibility of DNA methylation as a minimally invasive biomarker in feces in the diagnosis of CRC and adenoma. The use of DNA from human stools has the potential to be readily applicable to detect aberrant DNA methylation levels among many subjects for CRC early screening.
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Affiliation(s)
- Rongbin Liu
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xuan Su
- Department of Head and Neck, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, China
| | - Yakang Long
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Dalei Zhou
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xiao Zhang
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zulu Ye
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jiangjun Ma
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Tao Tang
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Fang Wang
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
| | - Caiyun He
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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23
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Abstract
Whole-genome and centrosome duplication as a consequence of cytokinesis failure can drive tumorigenesis in experimental model systems. However, whether cytokinesis failure is in fact an important cause of human cancers has remained unclear. In this Review, we summarize evidence that whole-genome-doubling events are frequently observed in human cancers and discuss the contribution that cytokinesis defects can make to tumorigenesis. We provide an overview of the potential causes of cytokinesis failure and discuss how tetraploid cells that are generated through cytokinesis defects are used in cancer as a transitory state on the route to aneuploidy. Finally, we discuss how cytokinesis defects can facilitate genetic diversification within the tumour to promote cancer development and could constitute the path of least resistance in tumour evolution.
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Affiliation(s)
- Susanne M A Lens
- Oncode Institute, Utrecht, Netherlands.
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
| | - René H Medema
- Oncode Institute, Utrecht, Netherlands.
- Division of Cell Biology and Cancer Genomics Center, The Netherlands Cancer Institute, Amsterdam, Netherlands.
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24
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An N, Zhao C, Yu Z, Yang X. Identification of prognostic genes in colorectal cancer through transcription profiling of multi-stage carcinogenesis. Oncol Lett 2018; 17:432-441. [PMID: 30655784 DOI: 10.3892/ol.2018.9632] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2017] [Accepted: 07/09/2018] [Indexed: 01/02/2023] Open
Abstract
Colorectal cancer is a complex multistage process following the adenoma-carcinoma sequence. Additional research on the basis of molecular dysregulations, particularly in the precancerous stage, may provide insight into the realization of potential biomarkers and therapeutic targets for the disease. In the present study, the expression profile of human multistage colorectal mucosa tissues, including healthy, adenoma and adenocarcinoma samples, was downloaded. Genes that were consistently differentially expressed in precancerous tissues and cancer samples were collected. Based on a merged biological network, the biggest connected component composed of these identified genes and their one-step neighbors were retrieved to conduct random walk with restart algorithm, in order to identify genes significantly affected during carcinogenesis. Therefore, 35 genes significantly affected by carcinogenic dysregulation were successfully identified. Survival and Cox analysis indicated that the expression of these genes was an independent prognostic factor confirmed by six cohorts. In summary, based on the transcription profile of multi-stage carcinogenesis and bioinformatics analysis, 35 genes significantly associated with patient survival were successfully identified, which may serve as promising therapeutic targets for the disease.
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Affiliation(s)
- Ning An
- Department of Oncology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Chen Zhao
- Department of Anatomy, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Zhuang Yu
- Department of Oncology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Xue Yang
- Department of Oncology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
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25
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Methylation-induced silencing of SPG20 facilitates gastric cancer cell proliferation by activating the EGFR/MAPK pathway. Biochem Biophys Res Commun 2018; 500:411-417. [DOI: 10.1016/j.bbrc.2018.04.089] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 04/11/2018] [Indexed: 12/15/2022]
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26
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Mutation hotspots at CTCF binding sites coupled to chromosomal instability in gastrointestinal cancers. Nat Commun 2018; 9:1520. [PMID: 29670109 PMCID: PMC5906695 DOI: 10.1038/s41467-018-03828-2] [Citation(s) in RCA: 107] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 03/15/2018] [Indexed: 01/06/2023] Open
Abstract
Tissue-specific driver mutations in non-coding genomic regions remain undefined for most cancer types. Here, we unbiasedly analyze 212 gastric cancer (GC) whole genomes to identify recurrently mutated non-coding regions in GC. Applying comprehensive statistical approaches to accurately model background mutational processes, we observe significant enrichment of non-coding indels (insertions/deletions) in three gastric lineage-specific genes. We further identify 34 mutation hotspots, of which 11 overlap CTCF binding sites (CBSs). These CBS hotspots remain significant even after controlling for a genome-wide elevated mutation rate at CBSs. In 3 out of 4 tested CBS hotspots, mutations are nominally associated with expression change of neighboring genes. CBS hotspot mutations are enriched in tumors showing chromosomal instability, co-occur with neighboring chromosomal aberrations, and are common in gastric (25%) and colorectal (19%) tumors but rare in other cancer types. Mutational disruption of specific CBSs may thus represent a tissue-specific mechanism of tumorigenesis conserved across gastrointestinal cancers. The impact of non-coding somatic mutations in gastric cancer is unknown. Here, using whole genome sequencing data from 212 gastric tumors, the authors identify recurring mutations at specific CTCF binding sites that are common across gastrointestinal cancers and associated with chromosomal instability.
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27
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Pinto D, Pinto C, Guerra J, Pinheiro M, Santos R, Vedeld HM, Yohannes Z, Peixoto A, Santos C, Pinto P, Lopes P, Lothe R, Lind GE, Henrique R, Teixeira MR. Contribution of MLH1 constitutional methylation for Lynch syndrome diagnosis in patients with tumor MLH1 downregulation. Cancer Med 2018; 7:433-444. [PMID: 29341452 PMCID: PMC6193414 DOI: 10.1002/cam4.1285] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 11/14/2017] [Accepted: 11/16/2017] [Indexed: 12/23/2022] Open
Abstract
Constitutional epimutation of the two major mismatch repair genes, MLH1 and MSH2, has been identified as an alternative mechanism that predisposes to the development of Lynch syndrome. In the present work, we aimed to investigate the prevalence of MLH1 constitutional methylation in colorectal cancer (CRC) patients with abnormal expression of the MLH1 protein in their tumors. In a series of 38 patients who met clinical criteria for Lynch syndrome genetic testing, with loss of MLH1 expression in the tumor and with no germline mutations in the MLH1 gene (35/38) or with tumors presenting the BRAF p.Val600Glu mutation (3/38), we screened for constitutional methylation of the MLH1 gene promoter using methylation‐specific multiplex ligation‐dependent probe amplification (MS‐MLPA) in various biological samples. We found four (4/38; 10.5%) patients with constitutional methylation in the MLH1 gene promoter. RNA studies demonstrated decreased MLH1 expression in the cases with constitutional methylation when compared with controls. We could infer the mosaic nature of MLH1 constitutional hypermethylation in tissues originated from different embryonic germ layers, and in one family we could show that it occurred de novo. We conclude that constitutional MLH1 methylation occurs in a significant proportion of patients who have loss of MLH1 protein expression in their tumors and no MLH1 pathogenic germline mutation. Furthermore, we provide evidence that MLH1 constitutional hypermethylation is the molecular mechanism behind about 3% of Lynch syndrome families diagnosed in our institution, especially in patients with early onset or multiple primary tumors without significant family history.
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Affiliation(s)
- Diana Pinto
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Carla Pinto
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Joana Guerra
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Manuela Pinheiro
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Rui Santos
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Hege Marie Vedeld
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norway
| | - Zeremariam Yohannes
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norway
| | - Ana Peixoto
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Catarina Santos
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Pedro Pinto
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Paula Lopes
- Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Ragnhild Lothe
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norway
| | - Guro Elisabeth Lind
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norway
| | - Rui Henrique
- Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Cancer Biology and Epigenetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Manuel R Teixeira
- Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
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28
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Ring J, Rockenfeller P, Abraham C, Tadic J, Poglitsch M, Schimmel K, Westermayer J, Schauer S, Achleitner B, Schimpel C, Moitzi B, Rechberger GN, Sigrist SJ, Carmona-Gutierrez D, Kroemer G, Büttner S, Eisenberg T, Madeo F. Mitochondrial energy metabolism is required for lifespan extension by the spastic paraplegia-associated protein spartin. MICROBIAL CELL (GRAZ, AUSTRIA) 2017; 4:411-422. [PMID: 29234670 PMCID: PMC5722644 DOI: 10.15698/mic2017.12.603] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2017] [Accepted: 11/20/2017] [Indexed: 01/11/2023]
Abstract
Hereditary spastic paraplegias, a group of neurodegenerative disorders, can be caused by loss-of-function mutations in the protein spartin. However, the physiological role of spartin remains largely elusive. Here we show that heterologous expression of human or Drosophila spartin extends chronological lifespan of yeast, reducing age-associated ROS production, apoptosis, and necrosis. We demonstrate that spartin localizes to the proximity of mitochondria and physically interacts with proteins related to mitochondrial and respiratory metabolism. Interestingly, Nde1, the mitochondrial external NADH dehydrogenase, and Pda1, the core enzyme of the pyruvate dehydrogenase complex, are required for spartin-mediated cytoprotection. Furthermore, spartin interacts with the glycolysis enhancer phospo-fructo-kinase-2,6 (Pfk26) and is sufficient to complement for PFK26-deficiency at least in early aging. We conclude that mitochondria-related energy metabolism is crucial for spartin's vital function during aging and uncover a network of specific interactors required for this function.
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Affiliation(s)
- Julia Ring
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
| | - Patrick Rockenfeller
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
- Kent Fungal Group, School of Biosciences, University of Kent, Canterbury, UK
| | - Claudia Abraham
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
| | - Jelena Tadic
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
| | - Michael Poglitsch
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
| | - Katherina Schimmel
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
- Institute of Molecular and Translational Therapeutic Strategies (IMTTS), IFB-Tx, Hannover Medical School, Hannover, Germany
| | - Julia Westermayer
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
| | - Simon Schauer
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
| | - Bettina Achleitner
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
| | - Christa Schimpel
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
- BioNanoNet Forschungsgesellschaft mbH, Graz, Austria
| | - Barbara Moitzi
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
| | - Gerald N. Rechberger
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
- Omics Center Graz, BioTechMed-Graz, Graz, Austria
| | - Stephan J. Sigrist
- Institute for Biology, Freie Universität Berlin, Berlin, Germany
- NeuroCure, Charité, Berlin, Germany
| | | | - Guido Kroemer
- BioTechMed Graz, Graz, Austria
- Cell Biology and Metabolomics Platforms, Gustave Roussy Comprehensive Cancer Center, Villejuif, France
- INSERM, U1138, Paris, France
- Université Paris Descartes, Sorbonne Paris Cité, Paris, France
- Université Pierre et Marie Curie, Paris, France
- Pôle de Biologie, Hôpital Européen Georges Pompidou, Paris, France
- Karolinska Institute, Department of Women's and Children's Health, Karolinska University Hospital Stockholm, Sweden
| | - Sabrina Büttner
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
- Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden
| | - Tobias Eisenberg
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
| | - Frank Madeo
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
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29
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Prognostic relevance of an epigenetic biomarker panel in sentinel lymph nodes from colon cancer patients. Clin Epigenetics 2017; 9:97. [PMID: 28878843 PMCID: PMC5584052 DOI: 10.1186/s13148-017-0397-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2017] [Accepted: 08/28/2017] [Indexed: 02/01/2023] Open
Abstract
BACKGROUND Patients with early colorectal cancer (stages I-II) generally have a good prognosis, but a subgroup of 15-20% experiences relapse and eventually die of disease. Occult metastases have been suggested as a marker for increased risk of recurrence in patients with node-negative disease. Using a previously identified, highly accurate epigenetic biomarker panel for early detection of colorectal tumors, we aimed at evaluating the prognostic value of occult metastases in sentinel lymph nodes of colon cancer patients. RESULTS The biomarker panel was analyzed by quantitative methylation-specific PCR in primary tumors and 783 sentinel lymph nodes from 201 patients. The panel status in sentinel lymph nodes showed a strong association with lymph node stage (P = 8.2E-17). Compared with routine lymph node diagnostics, the biomarker panel had a sensitivity of 79% (31/39). Interestingly, among 162 patients with negative lymph nodes from routine diagnostics, 13 (8%) were positive for the biomarker panel. Colon cancer patients with high sentinel lymph node methylation had an inferior prognosis (5-year overall survival P = 3.0E-4; time to recurrence P = 3.1E-4), although not significant. The same trend was observed in multivariate analyses (P = 1.4E-1 and P = 6.7E-2, respectively). Occult sentinel lymph node metastases were not detected in early stage (I-II) colon cancer patients who experienced relapse. CONCLUSIONS Colon cancer patients with high sentinel lymph node methylation of the analyzed epigenetic biomarker panel had an inferior prognosis, although not significant in multivariate analyses. Occult metastases in TNM stage II patients that experienced relapse were not detected.
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30
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Rezvani N, Alibakhshi R, Vaisi-Raygani A, Bashiri H, Saidijam M. Detection of SPG20 gene promoter-methylated DNA, as a novel epigenetic biomarker, in plasma for colorectal cancer diagnosis using the MethyLight method. Oncol Lett 2017; 13:3277-3284. [PMID: 28521434 PMCID: PMC5431389 DOI: 10.3892/ol.2017.5815] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Accepted: 01/17/2017] [Indexed: 02/06/2023] Open
Abstract
Aberrant promoter methylation of genes is a common epigenetic alteration in colorectal cancer (CRC). In the present study, spastic paraplegia 20 (SPG20) promoter-methylated DNA, as a potential diagnostic biomarker, was investigated in plasma and tumor tissue samples from patients with CRC. To the best of our knowledge, the quantification of SPG20 promoter-methylated DNA in plasma samples remains unreported. SPG20 promoter methylation was investigated in 32 paired tumor and healthy adjacent tissues, 37 plasma samples from patients with CRC, and in 37 plasma samples from a healthy control group, using the MethyLight method. The percentage of methylated reference (PMR) values was determined for each sample, and the sensitivity and specificity of this unique biomarker were evaluated. PMR values were significantly higher in plasma samples from patients with CRC compared with in those from the control group (P<0.05). Plasma specimens from patients and healthy controls exhibited median PMR values of 7.7 (95% CI, 4.15-15.28) and 0.59 (95% CI, 0.14-1.12), respectively. Notably, the median PMR values were identified as 42.39 (95% CI, 27.69-72.26) and 3.61 (95% CI, 1.07-5.29) in tumor and adjacent healthy tissues, respectively. Using receiver-operating characteristics curve analysis, the area under curve (AUC) was demonstrated to be 0.984 for plasma samples, exhibiting a sensitivity of 81.1% and a specificity of 96.9%. Furthermore, the AUC was 0.996 for tissue samples, revealing a sensitivity of 93.8% and specificity of 99.96%. Results from the present study indicate that the identification of SPG20 promoter-methylated DNA in plasma is a potential diagnostic biomarker for the detection of CRC. Furthermore, the results demonstrate a satisfactory sensitivity and specificity, indicating the importance of SPG20 methylation as a novel noninvasive biomarker.
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Affiliation(s)
- Nayebali Rezvani
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan 6517838736, Iran
- Department of Clinical Biochemistry, Kermanshah University of Medical Sciences, Kermanshah 6714869914, Iran
| | - Reza Alibakhshi
- Department of Clinical Biochemistry, Kermanshah University of Medical Sciences, Kermanshah 6714869914, Iran
| | - Assad Vaisi-Raygani
- Department of Clinical Biochemistry, Kermanshah University of Medical Sciences, Kermanshah 6714869914, Iran
- Fertility and Infertility Research Center, Kermanshah University of Medical Sciences, Kermanshah 6714869914, Iran
- Molecular Diagnostic Research Center, Kermanshah University of Medical Sciences, Kermanshah 6714869914, Iran
| | - Homayoon Bashiri
- Department of Gastroenterology, Kermanshah University of Medical Sciences, Kermanshah 6714869914, Iran
| | - Massoud Saidijam
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan 6517838736, Iran
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31
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Davudian S, Shajari N, Kazemi T, Mansoori B, Salehi S, Mohammadi A, Shanehbandi D, Shahgoli VK, Asadi M, Baradaran B. BACH1 silencing by siRNA inhibits migration of HT-29 colon cancer cells through reduction of metastasis-related genes. Biomed Pharmacother 2016; 84:191-198. [DOI: 10.1016/j.biopha.2016.09.021] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2016] [Accepted: 09/07/2016] [Indexed: 01/08/2023] Open
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32
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Rasmussen SL, Krarup HB, Sunesen KG, Pedersen IS, Madsen PH, Thorlacius-Ussing O. Hypermethylated DNA as a biomarker for colorectal cancer: a systematic review. Colorectal Dis 2016; 18:549-61. [PMID: 26998585 DOI: 10.1111/codi.13336] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 02/03/2016] [Indexed: 12/11/2022]
Abstract
AIM Improved methods for early detection of colorectal cancer (CRC) are essential for increasing survival. Hypermethylated DNA in blood or stool has been proposed as a biomarker for CRC. Biochemical methods have improved in recent years, and several hypermethylated genes that are sensitive and specific for CRC have been proposed. Articles describing the use of hypermethylated promoter regions in blood or stool as biomarkers for CRC were systematically reviewed. METHOD A systematic literature search was performed using the Medline, Web of Science and Embase databases. Studies were included if they analysed hypermethylated genes from stool or blood samples in correlation with CRC. Studies in languages other than English and those based on animal models or cell lines were excluded. RESULTS The literature search yielded 74 articles, including 43 addressing blood samples and 31 addressing stool samples. In blood samples, hypermethylated ALX4, FBN2, HLTF, P16, TMEFF1 and VIM were associated with poor prognosis, hypermethylated APC, NEUROG1, RASSF1A, RASSF2A, SDC2, SEPT9, TAC1 and THBD were detected in early stage CRC and hypermethylated P16 and TFPI2 were associated with CRC recurrence. In stool samples, hypermethylated BMP3, PHACTR3, SFRP2, SPG20, TFPI2 and TMEFF2 were associated with early stage CRC. CONCLUSION Hypermethylation of the promoters of specific genes measured in blood or stool samples could be used as a CRC biomarker and provide prognostic information. The majority of studies, however, include only a few patients with poorly defined control groups. Further studies are therefore needed before hypermethylated DNA can be widely applied as a clinical biomarker for CRC detection and prognosis.
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Affiliation(s)
- S L Rasmussen
- Department of Gastrointestinal Surgery and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - H B Krarup
- Section of Molecular Diagnostics, Clinical Biochemistry and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - K G Sunesen
- Department of Gastrointestinal Surgery and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - I S Pedersen
- Section of Molecular Diagnostics, Clinical Biochemistry and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - P H Madsen
- Section of Molecular Diagnostics, Clinical Biochemistry and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - O Thorlacius-Ussing
- Department of Gastrointestinal Surgery and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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Porrello A, Piergentili RB. Contextualizing the Genes Altered in Bladder Neoplasms in Pediatric andTeen Patients Allows Identifying Two Main Classes of Biological ProcessesInvolved and New Potential Therapeutic Targets. Curr Genomics 2016; 17:33-61. [PMID: 27013923 PMCID: PMC4780474 DOI: 10.2174/1389202916666151014222603] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 06/29/2015] [Accepted: 07/08/2015] [Indexed: 12/19/2022] Open
Abstract
Research on bladder neoplasms in pediatric and teen patients (BNPTP) has described 21 genes, which are variously involved in this disease and are mostly responsible for deregulated cell proliferation. However, due to the limited number of publications on this subject, it is still unclear what type of relationships there are among these genes and which are the chances that, while having different molecular functions, they i) act as downstream effector genes of well-known pro- or anti- proliferative stimuli and/or interplay with biochemical pathways having oncological relevance or ii) are specific and, possibly, early biomarkers of these pathologies. A Gene Ontology (GO)-based analysis showed that these 21 genes are involved in biological processes, which can be split into two main classes: cell regulation-based and differentiation/development-based. In order to understand the involvement/overlapping with main cancer-related pathways, we performed a meta-analysis dependent on the 189 oncogenic signatures of the Molecular Signatures Database (OSMSD) curated by the Broad Institute. We generated a binary matrix with 53 gene signatures having at least one hit; this analysis i) suggests that some genes of the original list show inconsistencies and might need to be experimentally re- assessed or evaluated as biomarkers (in particular, ACTA2) and ii) allows hypothesizing that important (proto)oncogenes (E2F3, ERBB2/HER2, CCND1, WNT1, and YAP1) and (putative) tumor suppressors (BRCA1, RBBP8/CTIP, and RB1-RBL2/p130) may participate in the onset of this disease or worsen the observed phenotype, thus expanding the list of possible molecular targets for the treatment of BNPTP.
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Affiliation(s)
- A. Porrello
- Comprehensive Cancer Center (LCCC), University of North Carolina (UNC)-Chapel Hill, Chapel Hill, 27599 NC, USA
| | - R. b Piergentili
- Institute of Molecular Biology and Pathology at CNR (CNR-IBPM); Department of Biology and Biotechnologies, Sapienza – Università di Roma, Italy
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Bonda C, Sharma P, LaFaver K. Clinical Reasoning: A 28-year-old woman with lower extremity spasticity and microcytic anemia. Neurology 2015; 85:e11-4. [PMID: 26170404 DOI: 10.1212/wnl.0000000000001736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Affiliation(s)
- Chaitanya Bonda
- From the Department of Neurology, University of Louisville, KY.
| | - Pankaj Sharma
- From the Department of Neurology, University of Louisville, KY
| | - Kathrin LaFaver
- From the Department of Neurology, University of Louisville, KY
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35
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Tormos AM, Taléns-Visconti R, Sastre J. Regulation of cytokinesis and its clinical significance. Crit Rev Clin Lab Sci 2015; 52:159-67. [DOI: 10.3109/10408363.2015.1012191] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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36
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Kok-Sin T, Mokhtar NM, Ali Hassan NZ, Sagap I, Mohamed Rose I, Harun R, Jamal R. Identification of diagnostic markers in colorectal cancer via integrative epigenomics and genomics data. Oncol Rep 2015; 34:22-32. [PMID: 25997610 PMCID: PMC4484611 DOI: 10.3892/or.2015.3993] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 03/30/2015] [Indexed: 12/12/2022] Open
Abstract
Apart from genetic mutations, epigenetic alteration is a common phenomenon that contributes to neoplastic transformation in colorectal cancer. Transcriptional silencing of tumor-suppressor genes without changes in the DNA sequence is explained by the existence of promoter hypermethylation. To test this hypothesis, we integrated the epigenome and transcriptome data from a similar set of colorectal tissue samples. Methylation profiling was performed using the Illumina InfiniumHumanMethylation27 BeadChip on 55 paired cancer and adjacent normal epithelial cells. Fifteen of the 55 paired tissues were used for gene expression profiling using the Affymetrix GeneChip Human Gene 1.0 ST array. Validation was carried out on 150 colorectal tissues using the methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) technique. PCA and supervised hierarchical clustering in the two microarray datasets showed good separation between cancer and normal samples. Significant genes from the two analyses were obtained based on a ≥2-fold change and a false discovery rate (FDR) p-value of <0.05. We identified 1,081 differentially hypermethylated CpG sites and 36 hypomethylated CpG sites. We also found 709 upregulated and 699 downregulated genes from the gene expression profiling. A comparison of the two datasets revealed 32 overlapping genes with 27 being hypermethylated with downregulated expression and 4 hypermethylated with upregulated expression. One gene was found to be hypomethylated and downregulated. The most enriched molecular pathway identified was cell adhesion molecules that involved 4 overlapped genes, JAM2, NCAM1, ITGA8 and CNTN1. In the present study, we successfully identified a group of genes that showed methylation and gene expression changes in well-defined colorectal cancer tissues with high purity. The integrated analysis gives additional insight regarding the regulation of colorectal cancer-associated genes and their underlying mechanisms that contribute to colorectal carcinogenesis.
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Affiliation(s)
- Teow Kok-Sin
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Norfilza Mohd Mokhtar
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Nur Zarina Ali Hassan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Ismail Sagap
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Isa Mohamed Rose
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Roslan Harun
- Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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Nicholson JM, Macedo JC, Mattingly AJ, Wangsa D, Camps J, Lima V, Gomes AM, Dória S, Ried T, Logarinho E, Cimini D. Chromosome mis-segregation and cytokinesis failure in trisomic human cells. eLife 2015; 4. [PMID: 25942454 PMCID: PMC4443816 DOI: 10.7554/elife.05068] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Accepted: 05/01/2015] [Indexed: 12/11/2022] Open
Abstract
Cancer cells display aneuploid karyotypes and typically mis-segregate chromosomes at high rates, a phenotype referred to as chromosomal instability (CIN). To test the effects of aneuploidy on chromosome segregation and other mitotic phenotypes we used the colorectal cancer cell line DLD1 (2n = 46) and two variants with trisomy 7 or 13 (DLD1+7 and DLD1+13), as well as euploid and trisomy 13 amniocytes (AF and AF+13). We found that trisomic cells displayed higher rates of chromosome mis-segregation compared to their euploid counterparts. Furthermore, cells with trisomy 13 displayed a distinctive cytokinesis failure phenotype. We showed that up-regulation of SPG20 expression, brought about by trisomy 13 in DLD1+13 and AF+13 cells, is sufficient for the cytokinesis failure phenotype. Overall, our study shows that aneuploidy can induce chromosome mis-segregation. Moreover, we identified a trisomy 13-specific mitotic phenotype that is driven by up-regulation of a gene encoded on the aneuploid chromosome. DOI:http://dx.doi.org/10.7554/eLife.05068.001 The DNA in a human cell is divided between forty-six structures called chromosomes. Before a cell divides, it copies every chromosome so that each daughter cell will have the same DNA as the parent cell. These chromosomes align in the center of the cell and then the matching chromosomes are separated and pulled to opposite ends. However, in some cases the separation process does not work properly, which can produce cells that either have too many, or too few, chromosomes. Abnormal numbers of chromosomes within cells—called aneuploidy—is a leading cause of miscarriage and birth defects in humans. Aneuploidy is also a common feature of cancer cells. It is common for the chromosomes in cancer cells to be distributed unequally when the cell divides. This phenomenon is known as chromosomal instability, but the link between aneuploidy and chromosomal instability in cancer cells is not fully understood. Here, Nicholson et al. used live-cell imaging techniques to analyze healthy human cells and cancer cells that had either the normal forty-six chromosomes, or a defined extra chromosome. Nicholson et al. found that when the cells divided, the chromosomes in the cells that had an extra copy of chromosome 7 or 13 were more prone to distributing chromosomes unequally, compared to cells with a normal number of chromosomes. Nicholson et al. also observed that the cells with an extra chromosome 13 were unable to properly divide into two. These cells had increased levels of a protein called Spartin—which is important for the last stage in cell division—and this was responsible for the failure to produce two daughter cells. These findings show that aneuploidy can cause chromosomal instability in human cells. Furthermore, Nicholson et al. have identified a defect in cell division that is specifically caused by the presence of an extra chromosome 13 in human cells. A future challenge will be to determine how, and to what extent, different chromosomes can affect chromosome stability. This could be useful in the development of therapies against cancer cells with aneuploidy. DOI:http://dx.doi.org/10.7554/eLife.05068.002
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Affiliation(s)
- Joshua M Nicholson
- Department of Biological Sciences, Virginia Tech, Blacksburg, United States
| | - Joana C Macedo
- Aging and Aneuploidy Laboratory, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
| | - Aaron J Mattingly
- Department of Biological Sciences, Virginia Tech, Blacksburg, United States
| | - Darawalee Wangsa
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States
| | - Jordi Camps
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States
| | - Vera Lima
- Department of Genetics, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - Ana M Gomes
- Aging and Aneuploidy Laboratory, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
| | - Sofia Dória
- Department of Genetics, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - Thomas Ried
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States
| | - Elsa Logarinho
- Aging and Aneuploidy Laboratory, Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal
| | - Daniela Cimini
- Department of Biological Sciences, Virginia Tech, Blacksburg, United States
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Andresen K, Boberg KM, Vedeld HM, Honne H, Jebsen P, Hektoen M, Wadsworth CA, Clausen OP, Lundin KE, Paulsen V, Foss A, Mathisen Ø, Aabakken L, Schrumpf E, Lothe RA, Lind GE. Four DNA methylation biomarkers in biliary brush samples accurately identify the presence of cholangiocarcinoma. Hepatology 2015; 61:1651-9. [PMID: 25644509 PMCID: PMC4832263 DOI: 10.1002/hep.27707] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 01/12/2015] [Indexed: 12/19/2022]
Abstract
UNLABELLED Early detection of the highly aggressive malignancy cholangiocarcinoma (CCA) remains a challenge but has the potential to render the tumor curable by surgical removal. This study evaluates a biomarker panel for the diagnosis of CCA by DNA methylation analyses of biliary brush samples. The methylation status of 13 candidate genes (CDO1, CNRIP1, DCLK1, FBN1, INA, MAL, SEPT9, SFRP1, SNCA, SPG20, TMEFF2, VIM, and ZSCAN18) was investigated in 93 tissue samples (39 CCAs and 54 nonmalignant controls) using quantitative methylation-specific polymerase chain reaction. The 13 genes were further analyzed in a test series of biliary brush samples (15 CCAs and 20 nonmalignant primary sclerosing cholangitis controls), and the methylation status of the four best performing markers was validated (34 CCAs and 34 primary sclerosing cholangitis controls). Receiver operating characteristic curve analyses were used to evaluate the performance of individual biomarkers and the combination of biomarkers. The 13 candidate genes displayed a methylation frequency of 26%-82% in tissue samples. The four best-performing genes (CDO1, CNRIP1, SEPT9, and VIM) displayed individual methylation frequencies of 45%-77% in biliary brushes from CCA patients. Across the test and validation biliary brush series, this four-gene biomarker panel achieved a sensitivity of 85% and a specificity of 98%, with an area under the receiver operating characteristic curve of 0.944. CONCLUSION We report a straightforward biomarker assay with high sensitivity and specificity for CCA, outperforming standard brush cytology, and suggest that the biomarker panel, potentially in combination with cytological evaluation, may improve CCA detection, particularly among primary sclerosing cholangitis patients.
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Affiliation(s)
- Kim Andresen
- Department of Molecular OncologyInstitute for Cancer ResearchOslo University Hospital–The Norwegian Radium HospitalOsloNorway,Centre for Cancer Biomedicine, Faculty of MedicineUniversity of OsloOsloNorway,Norwegian PSC Research Center, Division of Cancer, Surgery and TransplantationOslo University HospitalOsloNorway
| | - Kirsten Muri Boberg
- Norwegian PSC Research Center, Division of Cancer, Surgery and TransplantationOslo University HospitalOsloNorway,Institute for Clinical MedicineUniversity of OsloOsloNorway
| | - Hege Marie Vedeld
- Department of Molecular OncologyInstitute for Cancer ResearchOslo University Hospital–The Norwegian Radium HospitalOsloNorway,Centre for Cancer Biomedicine, Faculty of MedicineUniversity of OsloOsloNorway
| | - Hilde Honne
- Department of Molecular OncologyInstitute for Cancer ResearchOslo University Hospital–The Norwegian Radium HospitalOsloNorway,Centre for Cancer Biomedicine, Faculty of MedicineUniversity of OsloOsloNorway
| | - Peter Jebsen
- Department of Pathology, Division of Diagnostics and InterventionOslo University HospitalOsloNorway
| | - Merete Hektoen
- Department of Molecular OncologyInstitute for Cancer ResearchOslo University Hospital–The Norwegian Radium HospitalOsloNorway,Centre for Cancer Biomedicine, Faculty of MedicineUniversity of OsloOsloNorway
| | - Christopher A. Wadsworth
- Hepatology and Gastroenterology Section, Division of Diabetes, Endocrinology and Metabolism, Department of MedicineImperial College LondonLondonUK
| | - Ole Petter Clausen
- Department of Pathology, Division of Diagnostics and InterventionOslo University HospitalOsloNorway
| | - Knut E.A. Lundin
- Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer, Surgery, and TransplantationOslo University HospitalOsloNorway
| | - Vemund Paulsen
- Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer, Surgery, and TransplantationOslo University HospitalOsloNorway
| | - Aksel Foss
- Institute for Clinical MedicineUniversity of OsloOsloNorway,Section for Transplantation Surgery, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery, and TransplantationOslo University HospitalOsloNorway
| | - Øystein Mathisen
- Section for Hepatopancreatic and Biliary Surgery, Department of Gastrointestinal Surgery, Division of Cancer, Surgery, and TransplantationOslo University HospitalOsloNorway
| | - Lars Aabakken
- Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer, Surgery, and TransplantationOslo University HospitalOsloNorway,Institute for Clinical MedicineUniversity of OsloOsloNorway
| | - Erik Schrumpf
- Norwegian PSC Research Center, Division of Cancer, Surgery and TransplantationOslo University HospitalOsloNorway,Institute for Clinical MedicineUniversity of OsloOsloNorway
| | - Ragnhild A. Lothe
- Department of Molecular OncologyInstitute for Cancer ResearchOslo University Hospital–The Norwegian Radium HospitalOsloNorway,Centre for Cancer Biomedicine, Faculty of MedicineUniversity of OsloOsloNorway
| | - Guro E. Lind
- Department of Molecular OncologyInstitute for Cancer ResearchOslo University Hospital–The Norwegian Radium HospitalOsloNorway,Centre for Cancer Biomedicine, Faculty of MedicineUniversity of OsloOsloNorway
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Fleischhacker M, Schmidt B. Extracellular Nucleic Acids and Cancer. ADVANCES IN PREDICTIVE, PREVENTIVE AND PERSONALISED MEDICINE 2015. [DOI: 10.1007/978-94-017-9168-7_10] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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40
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Giansanti MG, Sechi S, Frappaolo A, Belloni G, Piergentili R. Cytokinesis in Drosophila male meiosis. SPERMATOGENESIS 2014; 2:185-196. [PMID: 23094234 PMCID: PMC3469441 DOI: 10.4161/spmg.21711] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Cytokinesis separates the cytoplasm and the duplicated genome into two daughter cells at the end of cell division. This process must be finely regulated to maintain ploidy and prevent tumor formation. Drosophila male meiosis provides an excellent cell system for investigating cytokinesis. Mutants affecting this process can be easily identified and spermatocytes are large cells particularly suitable for cytological analysis of cytokinetic structures. Over the past decade, the powerful tools of Drosophila genetics and the unique characteristics of this cell system have led researchers to identify molecular players of the cell cleavage machinery and to address important open questions. Although spermatocyte cytokinesis is incomplete, resulting in formation of stable intercellular bridges, the molecular mechanisms are largely conserved in somatic cells. Thus, studies of Drosophila male meiosis will shed new light on the complex cell circuits regulating furrow ingression and substantially further our knowledge of cancer and other human diseases.
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Affiliation(s)
- Maria Grazia Giansanti
- Istituto di Biologia e Patologia Molecolari del CNR; Dipartimento di Biologia e Biotecnologie Università Sapienza di Roma; Rome, Italy
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41
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Danielsen SA, Lind GE, Kolberg M, Høland M, Bjerkehagen B, Sundby Hall K, van den Berg E, Mertens F, Smeland S, Picci P, Lothe RA. Methylated RASSF1A in malignant peripheral nerve sheath tumors identifies neurofibromatosis type 1 patients with inferior prognosis. Neuro Oncol 2014; 17:63-9. [PMID: 25038505 PMCID: PMC4416132 DOI: 10.1093/neuonc/nou140] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/03/2022] Open
Abstract
Background Malignant peripheral nerve sheath tumor (MPNST) is a rare and highly aggressive disease with no evidence of effect from adjuvant therapy. It is further associated with the hereditary syndrome neurofibromatosis type 1 (NF1). Silencing of the tumor suppressor gene RASSF1A through DNA promoter hypermethylation is known to be involved in cancer development, but its impact in MPNSTs remains unsettled. Methods The RASSF1A promoter was analyzed by methylation-specific PCR in 113 specimens, including 44 NF1-associated MPNSTs, 47 sporadic MPNSTs, 21 benign neurofibromas, and 1 nonneoplastic nerve sheath control. Results RASSF1A methylation was found only in the malignant samples (60%) and identified a subgroup among patients with NF1-associated MPNST with a poor prognosis. These patients had a mean 5-year disease-specific survival of 27.3 months (95% CI: 17.2–37.4) versus 47.4 months (95% CI: 37.5–57.2) for NF1 patients with unmethylated promoters, P = 0.014. In multivariate Cox regression analysis, methylated RASSF1A remained an adverse prognostic factor independent of clinical risk factors, P = .013 (hazard ratio: 5.2; 95% CI: 1.4–19.4). Conclusion A considerable number of MPNST samples display hypermethylation of the RASSF1A gene promoter, and for these tumors, this is the first molecular marker that if validated can characterize a subgroup of patients with inferior prognosis, restricted to individuals with NF1.
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Affiliation(s)
- Stine A Danielsen
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.)
| | - Guro E Lind
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.)
| | - Matthias Kolberg
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.)
| | - Maren Høland
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.)
| | - Bodil Bjerkehagen
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.)
| | - Kirsten Sundby Hall
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.)
| | - Eva van den Berg
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.)
| | - Fredrik Mertens
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.)
| | - Sigbjørn Smeland
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.)
| | - Piero Picci
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.)
| | - Ragnhild A Lothe
- Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.)
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Shah R, Jones E, Vidart V, Kuppen PJK, Conti JA, Francis NK. Biomarkers for early detection of colorectal cancer and polyps: systematic review. Cancer Epidemiol Biomarkers Prev 2014; 23:1712-28. [PMID: 25004920 DOI: 10.1158/1055-9965.epi-14-0412] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
There is growing interest in early detection of colorectal cancer as current screening modalities lack compliance and specificity. This study systematically reviewed the literature to identify biomarkers for early detection of colorectal cancer and polyps. Literature searches were conducted for relevant papers since 2007. Human studies reporting on early detection of colorectal cancer and polyps using biomarkers were included. Methodologic quality was evaluated, and sensitivity, specificity, and the positive predictive value (PPV) were reported. The search strategy identified 3,348 abstracts. A total of 44 papers, examining 67 different tumor markers, were included. Overall sensitivities for colorectal cancer detection by fecal DNA markers ranged from 53% to 87%. Combining fecal DNA markers increased the sensitivity of colorectal cancer and adenoma detection. Canine scent detection had a sensitivity of detecting colorectal cancer of 99% and specificity of 97%. The PPV of immunochemical fecal occult blood test (iFOBT) is 1.26%, compared with 0.31% for the current screening method of guaiac fecal occult blood test (gFOBT). A panel of serum protein biomarkers provides a sensitivity and specificity above 85% for all stages of colorectal cancer, and a PPV of 0.72%. Combinations of fecal and serum biomarkers produce higher sensitivities, specificities, and PPVs for early detection of colorectal cancer and adenomas. Further research is required to validate these biomarkers in a well-structured population-based study.
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Affiliation(s)
- Reena Shah
- Yeovil District Hospital NHS Trust, Yeovil, United Kingdom.
| | - Emma Jones
- University of Leicester, Leicester, United Kingdom
| | | | - Peter J K Kuppen
- Department of Surgery, Leiden University Medical Centre, Leiden, the Netherlands
| | - John A Conti
- Portsmouth Hospital NHS Trust, Portsmouth, United Kingdom. University of Southampton, Southampton, United Kingdom
| | - Nader K Francis
- Yeovil District Hospital NHS Trust, Yeovil, United Kingdom. University of Bristol, Bristol, United Kingdom
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43
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Wang X, Kuang YY, Hu XT. Advances in epigenetic biomarker research in colorectal cancer. World J Gastroenterol 2014; 20:4276-4287. [PMID: 24764665 PMCID: PMC3989963 DOI: 10.3748/wjg.v20.i15.4276] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 11/05/2013] [Accepted: 01/15/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) causes approximately 600000 deaths annually and is the third leading cause of cancer mortality worldwide. Despite significant advancements in treatment options, CRC patient survival is still poor owing to a lack of effective tools for early diagnosis and a limited capacity for optimal therapeutic decision making. Since there exists a need to find new biomarkers to improve diagnosis of CRC, the research on epigenetic biomarkers for molecular diagnostics encourages the translation of this field from the bench to clinical practice. Epigenetic alterations are thought to hold great promise as tumor biomarkers. In this review, we will primarily focus on recent advances in the study of epigenetic biomarkers for colorectal cancer and discuss epigenetic biomarkers, including DNA methylation, microRNA expression and histone modification, in cancer tissue, stool, plasma, serum, cell lines and xenografts. These studies have improved the chances that epigenetic biomarkers will find a place in the clinical practices of screening, early diagnosis, prognosis, therapy choice and recurrence surveillance for CRC patients. However, these studies have typically been small in size, and evaluation at a larger scale of well-controlled randomized clinical trials is the next step that is necessary to increase the quality of epigenetic biomarkers and ensure their widespread clinical use.
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44
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Dong L, Sun X, Chao Z, Zhang S, Zheng J, Gurung R, Du J, Shi J, Xu Y, Zhang Y, Wu J. Evaluation of FTIR spectroscopy as diagnostic tool for colorectal cancer using spectral analysis. SPECTROCHIMICA ACTA. PART A, MOLECULAR AND BIOMOLECULAR SPECTROSCOPY 2014; 122:288-294. [PMID: 24316544 DOI: 10.1016/j.saa.2013.11.031] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2013] [Revised: 10/09/2013] [Accepted: 11/02/2013] [Indexed: 06/02/2023]
Abstract
The aim of this study is to confirm FTIR spectroscopy as a diagnostic tool for colorectal cancer. 180 freshly removed colorectal samples were collected from 90 patients for spectrum analysis. The ratios of spectral intensity and relative intensity (/I1460) were calculated. Principal component analysis (PCA) and Fisher's discriminant analysis (FDA) were applied to distinguish the malignant from normal. The FTIR parameters of colorectal cancer and normal tissues were distinguished due to the contents or configurations of nucleic acids, proteins, lipids and carbohydrates. Related to nitrogen containing, water, protein and nucleic acid were increased significantly in the malignant group. Six parameters were selected as independent factors to perform discriminant functions. The sensitivity for FTIR in diagnosing colorectal cancer was 96.6% by discriminant analysis. Our study demonstrates that FTIR can be a useful technique for detection of colorectal cancer and may be applied in clinical colorectal cancer diagnosis.
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Affiliation(s)
- Liu Dong
- Department of General Surgery, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Xuejun Sun
- Department of General Surgery, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
| | - Zhang Chao
- Department of General Surgery, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Shiyun Zhang
- Department of General Surgery, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jianbao Zheng
- Department of General Surgery, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Rajendra Gurung
- Department of General Surgery, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Junkai Du
- Department of General Surgery, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Jingsen Shi
- Department of General Surgery, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yizhuang Xu
- College of Chemistry and Molecular Engineering, Peking University, Beijing, China
| | - Yuanfu Zhang
- College of Chemistry and Molecular Engineering, Peking University, Beijing, China
| | - Jinguang Wu
- College of Chemistry and Molecular Engineering, Peking University, Beijing, China
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45
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Zhang H, Song Y, Xia P, Cheng Y, Guo Q, Diao D, Wang W, Wu X, Liu D, Dang C. Detection of aberrant hypermethylated spastic paraplegia-20 as a potential biomarker and prognostic factor in gastric cancer. Med Oncol 2014; 31:830. [PMID: 24381142 DOI: 10.1007/s12032-013-0830-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2013] [Accepted: 12/25/2013] [Indexed: 01/04/2023]
Abstract
The aim of this study was to evaluate hypermethylation of the spastic paraplegia-20 promoter as a potential biomarker and prognostic factor in gastric cancer. Four human gastric cancer cell lines, 41 primary gastric cancer tissue samples and corresponding peripheral blood samples, and blood samples of 21 healthy individuals were analyzed using methylation-specific polymerase chain reaction. Additionally, the expression of Spartin, the protein product encoded by spastic paraplegia-20, was analyzed in tissues from 119 gastric cancer patients who underwent radical gastrectomy at Xi'an Jiaotong University between 2005 and 2010. Hypermethylation of the spastic paraplegia-20 promoter was observed in 26 of 41 (63.4 %) primary tumors and 1 of 35 (2.9 %) adjacent normal gastric tissues (P < 0.001). Among matched peripheral blood samples from gastric cancer patients, 48.8 % exhibited hypermethylation of the spastic paraplegia-20 promoter. In contrast, no methylation of the spastic paraplegia-20 promoter was observed in blood samples from 21 healthy individuals (P < 0.001). Additionally, demethylation by 5-aza-dC treatment led to gene reactivation in gastric cancer cells exhibiting hypermethylation of the spastic paraplegia-20 promoter. Finally, immunohistochemical staining indicated that low expression of Spartin was a prognostic factor predicting poor outcomes in gastric cancer patients (P = 0.037). These findings suggested that hypermethylation of the spastic paraplegia-20 promoter occurred frequently in gastric cancer and could represent a novel prognostic factor. Furthermore, detection of this molecular feature in the peripheral blood of gastric cancer patients suggested that evaluation of the methylation state of the spastic paraplegia-20 promoter may be used as a noninvasive screening method.
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Affiliation(s)
- Hao Zhang
- Oncology Department, The First Affiliated Hospital, Xi'an Jiaotong University, 277 W. Yanta Road, Xi'an, 710061, Shaanxi, China
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46
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Bethge N, Lothe RA, Honne H, Andresen K, Trøen G, Eknæs M, Liestøl K, Holte H, Delabie J, Smeland EB, Lind GE. Colorectal cancer DNA methylation marker panel validated with high performance in Non-Hodgkin lymphoma. Epigenetics 2013; 9:428-36. [PMID: 24362313 PMCID: PMC4053461 DOI: 10.4161/epi.27554] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Genes with altered DNA methylation can be used as biomarkers for cancer detection and assessment of prognosis. Here we analyzed the methylation status of a colorectal cancer biomarker panel (CNRIP1, FBN1, INA, MAL, SNCA, and SPG20) in 97 cancer cell lines, derived from 17 different cancer types. Interestingly, the genes were frequently methylated also in hematological cancer types and were therefore subjected to analyses in primary tumor samples from the major types of non-Hodgkin lymphomas (NHL) and in healthy controls. In total, the genes CNRIP1, FBN1, INA, MAL, SNCA, and SPG20 were methylated in 53%, 23%, 52%, 69%, 97%, and 92% of the tumor samples, respectively, and were unmethylated in all healthy controls. With the exception of a single tumor sample, a correct prediction of lymphoma or normal sample was made in a blinded analysis of the validation series using a combination of SNCA and SPG20. The combined ROC-curve analysis of these genes resulted in an area under the curve of 0.999 (P = 4.2 × 10−18), and a sensitivity and specificity of 98% and 100%, respectively, across the test and validation series. Interestingly, the promoter methylation of CNRIP1 was associated with decreased overall survival in diffuse large B-cell lymphoma (DLBCL) (P = 0.03).
In conclusion, our results demonstrate that SNCA and SPG20 methylation might be suitable for early detection and monitoring of NHL. Furthermore, CNRIP1 could potentially be used as a prognostic factor in DLBCL.
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Affiliation(s)
- Nicole Bethge
- Department of Immunology; Institute for Cancer Research; Oslo University Hospital; Oslo, Norway; Centre for Cancer Biomedicine; University of Oslo; Oslo, Norway
| | - Ragnhild A Lothe
- Centre for Cancer Biomedicine; University of Oslo; Oslo, Norway; Department of Cancer Prevention; Institute for Cancer Research; Oslo University Hospital; Oslo, Norway
| | - Hilde Honne
- Centre for Cancer Biomedicine; University of Oslo; Oslo, Norway; Department of Cancer Prevention; Institute for Cancer Research; Oslo University Hospital; Oslo, Norway
| | - Kim Andresen
- Centre for Cancer Biomedicine; University of Oslo; Oslo, Norway; Department of Cancer Prevention; Institute for Cancer Research; Oslo University Hospital; Oslo, Norway
| | - Gunhild Trøen
- Department of Pathology; Oslo University Hospital; Oslo, Norway
| | - Mette Eknæs
- Centre for Cancer Biomedicine; University of Oslo; Oslo, Norway; Department of Cancer Prevention; Institute for Cancer Research; Oslo University Hospital; Oslo, Norway
| | - Knut Liestøl
- Centre for Cancer Biomedicine; University of Oslo; Oslo, Norway; Department of Informatics; University of Oslo; Oslo, Norway
| | - Harald Holte
- Centre for Cancer Biomedicine; University of Oslo; Oslo, Norway; Department of Oncology; The Norwegian Radium Hospital; Oslo University Hospital; Oslo, Norway
| | - Jan Delabie
- Department of Pathology; Oslo University Hospital; Oslo, Norway
| | - Erlend B Smeland
- Department of Immunology; Institute for Cancer Research; Oslo University Hospital; Oslo, Norway; Centre for Cancer Biomedicine; University of Oslo; Oslo, Norway
| | - Guro E Lind
- Centre for Cancer Biomedicine; University of Oslo; Oslo, Norway; Department of Cancer Prevention; Institute for Cancer Research; Oslo University Hospital; Oslo, Norway
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47
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Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol 2013; 126:307-28. [PMID: 23897027 DOI: 10.1007/s00401-013-1115-8] [Citation(s) in RCA: 365] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Revised: 03/25/2013] [Accepted: 04/02/2013] [Indexed: 12/11/2022]
Abstract
Hereditary spastic paraplegia (HSP) is a syndrome designation describing inherited disorders in which lower extremity weakness and spasticity are the predominant symptoms. There are more than 50 genetic types of HSP. HSP affects individuals of diverse ethnic groups with prevalence estimates ranging from 1.2 to 9.6 per 100,000. Symptoms may begin at any age. Gait impairment that begins after childhood usually worsens very slowly over many years. Gait impairment that begins in infancy and early childhood may not worsen significantly. Postmortem studies consistently identify degeneration of corticospinal tract axons (maximal in the thoracic spinal cord) and degeneration of fasciculus gracilis fibers (maximal in the cervico-medullary region). HSP syndromes thus appear to involve motor-sensory axon degeneration affecting predominantly (but not exclusively) the distal ends of long central nervous system (CNS) axons. In general, proteins encoded by HSP genes have diverse functions including (1) axon transport (e.g. SPG30/KIF1A, SPG10/KIF5A and possibly SPG4/Spastin); (2) endoplasmic reticulum morphology (e.g. SPG3A/Atlastin, SPG4/Spastin, SPG12/reticulon 2, and SPG31/REEP1, all of which interact); (3) mitochondrial function (e.g. SPG13/chaperonin 60/heat-shock protein 60, SPG7/paraplegin; and mitochondrial ATP6); (4) myelin formation (e.g. SPG2/Proteolipid protein and SPG42/Connexin 47); (5) protein folding and ER-stress response (SPG6/NIPA1, SPG8/K1AA0196 (Strumpellin), SGP17/BSCL2 (Seipin), "mutilating sensory neuropathy with spastic paraplegia" owing to CcT5 mutation and presumably SPG18/ERLIN2); (6) corticospinal tract and other neurodevelopment (e.g. SPG1/L1 cell adhesion molecule and SPG22/thyroid transporter MCT8); (7) fatty acid and phospholipid metabolism (e.g. SPG28/DDHD1, SPG35/FA2H, SPG39/NTE, SPG54/DDHD2, and SPG56/CYP2U1); and (8) endosome membrane trafficking and vesicle formation (e.g. SPG47/AP4B1, SPG48/KIAA0415, SPG50/AP4M1, SPG51/AP4E, SPG52/AP4S1, and VSPG53/VPS37A). The availability of animal models (including bovine, murine, zebrafish, Drosophila, and C. elegans) for many types of HSP permits exploration of disease mechanisms and potential treatments. This review highlights emerging concepts of this large group of clinically similar disorders.
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48
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Dulak AM, Stojanov P, Peng S, Lawrence MS, Fox C, Stewart C, Bandla S, Imamura Y, Schumacher SE, Shefler E, McKenna A, Cibulskis K, Sivachenko A, Carter SL, Saksena G, Voet D, Ramos AH, Auclair D, Thompson K, Sougnez C, Onofrio RC, Guiducci C, Beroukhim R, Zhou D, Lin L, Lin J, Reddy R, Chang A, Luketich JD, Pennathur A, Ogino S, Golub TR, Gabriel SB, Lander ES, Beer DG, Godfrey TE, Getz G, Bass AJ. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat Genet 2013; 45:478-486. [PMID: 23525077 PMCID: PMC3678719 DOI: 10.1038/ng.2591] [Citation(s) in RCA: 602] [Impact Index Per Article: 50.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2012] [Accepted: 03/01/2013] [Indexed: 12/11/2022]
Abstract
The incidence of esophageal adenocarcinoma (EAC) has risen 600% over the last 30 years. With a 5-year survival rate of ~15%, the identification of new therapeutic targets for EAC is greatly important. We analyze the mutation spectra from whole-exome sequencing of 149 EAC tumor-normal pairs, 15 of which have also been subjected to whole-genome sequencing. We identify a mutational signature defined by a high prevalence of A>C transversions at AA dinucleotides. Statistical analysis of exome data identified 26 significantly mutated genes. Of these genes, five (TP53, CDKN2A, SMAD4, ARID1A and PIK3CA) have previously been implicated in EAC. The new significantly mutated genes include chromatin-modifying factors and candidate contributors SPG20, TLR4, ELMO1 and DOCK2. Functional analyses of EAC-derived mutations in ELMO1 identifies increased cellular invasion. Therefore, we suggest the potential activation of the RAC1 pathway as a contributor to EAC tumorigenesis.
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Affiliation(s)
- Austin M. Dulak
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Petar Stojanov
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Shouyong Peng
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Michael S. Lawrence
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Cameron Fox
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Chip Stewart
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Santhoshi Bandla
- Department of Surgery, University of Rochester, Rochester, NY 14642, USA
| | - Yu Imamura
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Steven E. Schumacher
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Erica Shefler
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Aaron McKenna
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Kristian Cibulskis
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Andrey Sivachenko
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Scott L. Carter
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Gordon Saksena
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Douglas Voet
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Alex H. Ramos
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Daniel Auclair
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Kristin Thompson
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Carrie Sougnez
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Robert C. Onofrio
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Candace Guiducci
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Rameen Beroukhim
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Brigham and Women’s Hospital, Boston, MA, 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - David Zhou
- Department of Surgery, University of Rochester, Rochester, NY 14642, USA
| | - Lin Lin
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Jules Lin
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rishindra Reddy
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Andrew Chang
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - James D. Luketich
- Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15206, USA
| | - Arjun Pennathur
- Department of Cardiothoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15206, USA
| | - Shuji Ogino
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Brigham and Women’s Hospital, Boston, MA, 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA
| | - Todd R. Golub
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA
| | - Stacey B. Gabriel
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Eric S. Lander
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - David G. Beer
- Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Tony E. Godfrey
- Department of Surgery, University of Rochester, Rochester, NY 14642, USA
| | - Gad Getz
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
| | - Adam J. Bass
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
- Brigham and Women’s Hospital, Boston, MA, 02115, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
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49
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Slater AA, Alokail M, Gentle D, Yao M, Kovacs G, Maher ER, Latif F. DNA methylation profiling distinguishes histological subtypes of renal cell carcinoma. Epigenetics 2013; 8:252-67. [PMID: 23428843 DOI: 10.4161/epi.23817] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Renal cell carcinoma (RCC) accounts for around 3% of cancers in the UK, and both incidence and mortality are increasing with the aging population. RCC can be divided into several subtypes: conventional RCC (the most common, comprising 75% of all cases), papillary RCC (15%) and chromophobe RCC (5%). Renal oncocytoma is a benign tumor and accounts for 5% of RCC. Cancer and epigenetics are closely associated, with DNA hypermethylation being widely accepted as a feature of many cancers. In this study the DNA methylation profiles of chromophobe RCC and renal oncocytomas were investigated by utilizing the Infinium HumanMethylation450 BeadChips. Cancer-specific hypermethylation was identified in 9.4% and 5.2% of loci in chromophobe RCC and renal oncocytoma samples, respectively, while the majority of the genome was hypomethylated. Thirty (hypermethylated) and 41 (hypomethylated) genes were identified as differentially methylated between chromophobe RCC and renal oncocytomas (p < 0.05). Pathway analysis identified some of the differentially hypermethylated genes to be involved in Wnt (EN2), MAPK (CACNG7) and TGFβ (AMH) signaling, Hippo pathway (NPHP4), and cell death and apoptosis (SPG20, NKX6-2, PAX3 and BAG2). In addition, we analyzed ccRCC and papillary RCC data available from The Cancer Genome Atlas portal to identify differentially methylated loci in chromophobe RCC and renal oncocytoma in relation to the other histological subtypes, providing insight into the pathology of RCC subtypes and classification of renal tumors.
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Affiliation(s)
- Amy A Slater
- Centre for Rare Diseases and Personalised Medicine, Department of Medical & Molecular Genetics, School of Clinical and Experimental Medicine, University of Birmingham College of Medical and Dental Sciences, Birmingham, UK
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Zhang H, Song YC, Dang CX. Detection of hypermethylated spastic paraplegia-20 in stool samples of patients with colorectal cancer. Int J Med Sci 2013; 10:230-4. [PMID: 23372428 PMCID: PMC3558710 DOI: 10.7150/ijms.5278] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2012] [Accepted: 01/07/2013] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Analysis of aberrant hypermethylation in stool DNA might provide a novel strategy for noninvasive detection of colorectal cancer. AIMS To explore the feasibility of detecting hypermethylation in Spastic paraplegia-20 promoter as a stool-based DNA marker for detection of colorectal cancer. METHODS We collected 96 tissue and stool samples from patients with colorectal cancer and 30 stool samples healthy individuals. RESULTS Hypermethylated Spastic paraplegia-20 occurs in 85.4% (82/96) of patients with colorectal cancer in the tissue samples. In the stool samples, the results indicate 80.2% (77/96) sensitivity and 100% (30/30) specificity of the test for detecting colorectal cancer by using the stool samples as a noninvasive method. CONCLUSIONS The study reveals that hypermethylation in Spastic paraplegia-20 promoter is a highly specific and sensitive biomarker for screening colorectal cancer in stool samples as a noninvasive method.
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Affiliation(s)
- Hao Zhang
- Department of Surgical Oncology the First Affiliated Hospital, Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi 710061, China
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