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Febres-Aldana CA, Fanaroff R, Offin M, Zauderer MG, Sauter JL, Yang SR, Ladanyi M. Diffuse Pleural Mesothelioma: Advances in Molecular Pathogenesis, Diagnosis, and Treatment. ANNUAL REVIEW OF PATHOLOGY 2024; 19:11-42. [PMID: 37722697 DOI: 10.1146/annurev-pathol-042420-092719] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/20/2023]
Abstract
Diffuse pleural mesothelioma (DPM) is a highly aggressive malignant neoplasm arising from the mesothelial cells lining the pleural surfaces. While DPM is a well-recognized disease linked to asbestos exposure, recent advances have expanded our understanding of molecular pathogenesis and transformed our clinical practice. This comprehensive review explores the current concepts and emerging trends in DPM, including risk factors, pathobiology, histologic subtyping, and therapeutic management, with an emphasis on a multidisciplinary approach to this complex disease.
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Affiliation(s)
- Christopher A Febres-Aldana
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA; ,
| | - Rachel Fanaroff
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA; ,
| | - Michael Offin
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Marjorie G Zauderer
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Jennifer L Sauter
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA; ,
| | - Soo-Ryum Yang
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA; ,
| | - Marc Ladanyi
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA; ,
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2
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Tuncel T, Metintas M, Güntülü AK, Güneş HV. Whole-Genome Comparative Copy Number Alteration Profiling between Malignant Pleural Mesothelioma and Asbestos-Induced Chronic Pleuritis. J Environ Pathol Toxicol Oncol 2024; 43:31-44. [PMID: 37824368 DOI: 10.1615/jenvironpatholtoxicoloncol.2023047755] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2023] Open
Abstract
Malignant pleural mesothelioma (MPM) is rare and aggressive cancer. The most important risk factor for MPM is exposure to asbestos. In this study, we scanned the genomes of individuals MPM and asbestos-induced chronic pleuritis (AICP) to compare and determine copy number alterations (CNAs) between two asbestos-related diseases. We used high-resolution SNP arrays to compare CNA profiles between MPM (n = 55) and AICP (n = 18). DNAs extracted from pleural tissues in both groups. SNP array analysis revealed common losses at 1p, 3p, 6q, 9p, 13q, 14q, 15q, 16q, 22q and frequent gains at chromosomes 1, 3, 5, 7, 8, and 6p, 12q, 15q, 17p, 20q in MPMs (frequencies max 67%-min 30%; these alterations were not detected in AICPs. Besides detecting well-known MPM-associated CNAs, our high -resolution copy number profiling also detected comparatively rare CNAs for MPMs including losses like 9q33.3, 16q and gains of 1p, 1q, 3p, 3q, 6p, 7q, 15q, 12q, 17p, 20q at significant frequencies in the MPM cohort. We also observed Copy Number gains clustered on the NF2 locus in AICPs, whereas this region was commonly deleted in MPMs. According to this distinct genomic profiles between the two groups, AICPs genomes can be clearly distinguished from highly altered MPM genomes. Hence, we can suggest that SNP arrays can be used as a supporting diagnostic tool in terms of discriminating asbestos-related malignant disease such as MPM and benign pleural lesions, which can be challenging in most instances.
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Affiliation(s)
- Tunç Tuncel
- Health Institutes of Turkey, Turkish Biotechnology Institute, Ankara, Turkey
| | - Muzaffer Metintas
- Eskisehir Osmangazi University Medical Faculty, Department of Chest Diseases, Lung and Pleural Cancers Research and Clinical Center, Eskisehir, Turkey
| | - A K Güntülü
- Eskisehir Osmangazi University Medical Faculty, Department of Chest Diseases, Lung and Pleural Cancers Research and Clinical Center, Eskisehir, Turkey
| | - Hasan Veysi Güneş
- Eskisehir Osmangazi University Medical Faculty, Department of Medical Biology, Eskisehir, Turkey
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3
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Xing J, Griffith CC. CDKN2A/p16 evaluation in cytology specimens. Cancer Cytopathol 2023; 131:672-676. [PMID: 37068112 DOI: 10.1002/cncy.22701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 03/06/2023] [Indexed: 04/18/2023]
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Vrugt B, Kirschner MB, Meerang M, Oehl K, Wagner U, Soltermann A, Moch H, Opitz I, Wild PJ. Deletions of CDKN2A and MTAP Detected by Copy-Number Variation Array Are Associated with Loss of p16 and MTAP Protein in Pleural Mesothelioma. Cancers (Basel) 2023; 15:4978. [PMID: 37894345 PMCID: PMC10605896 DOI: 10.3390/cancers15204978] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 10/10/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
CDKN2A deletion is a common alteration in pleural mesothelioma (PM) and frequently associated with co-deletion of MTAP. Since the standard detection method for CDKN2A deletion and FISH analysis is relatively expensive, we here investigated the suitability of inexpensive p16 and MTAP IHC by comparing concordance between IHC and OncoScan CNV arrays on samples from 52 PM patients. Concordance was determined using Cohen's kappa statistics. Loss of CDKN2A was associated with co-deletion of MTAP in 71% of cases. CDKN2A-MTAP copy-number normal cases were also IHC positive in 93% of cases for p16 and 100% for MTAP, while homozygous deletion of CDKN2A-MTAP was always associated with negative IHC for both proteins. In cases with heterozygous CDKN2A-MTAP loss, IHC expression of p16 and MTAP was negative in 100% and 71%, respectively. MTAP and p16 IHC showed high sensitivity (MTAP 86.5%, p16 100%) and specificity (MTAP 100%, p16 93.3%) for the detection of any gene loss. Loss of MTAP expression occurred exclusively in conjunction with loss of p16 labeling. Both p16 and MTAP IHC showed high concordance with Oncoscan CNV arrays (kappa = 0.952, p < 0.0001, and kappa = 0.787, p < 0.0001 respectively). We recommend combined MTAP and p16 immunohistochemistry to confirm the diagnosis of PM.
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Affiliation(s)
- Bart Vrugt
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland (U.W.); (A.S.); (H.M.)
| | - Michaela B. Kirschner
- Department of Thoracic Surgery, University Hospital Zurich, 8091 Zurich, Switzerland; (M.B.K.); (M.M.); (I.O.)
| | - Mayura Meerang
- Department of Thoracic Surgery, University Hospital Zurich, 8091 Zurich, Switzerland; (M.B.K.); (M.M.); (I.O.)
| | - Kathrin Oehl
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland (U.W.); (A.S.); (H.M.)
| | - Ulrich Wagner
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland (U.W.); (A.S.); (H.M.)
| | - Alex Soltermann
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland (U.W.); (A.S.); (H.M.)
| | - Holger Moch
- Institute of Pathology and Molecular Pathology, University Hospital Zurich, 8091 Zurich, Switzerland (U.W.); (A.S.); (H.M.)
| | - Isabelle Opitz
- Department of Thoracic Surgery, University Hospital Zurich, 8091 Zurich, Switzerland; (M.B.K.); (M.M.); (I.O.)
| | - Peter J. Wild
- Dr. Senckenberg Institute of Pathology (SIP), University Hospital Frankfurt, Goethe University, 60590 Frankfurt am Main, Germany;
- Wildlab, University Hospital Frankfurt MVZ GmbH, 60596 Frankfurt am Main, Germany
- Frankfurt Institute for Advanced Studies (FIAS), 60438 Frankfurt am Main, Germany
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Saddozai UAK, Wang F, Khattak S, Akbar MU, Badar M, Khan NH, Zhang L, Zhu W, Xie L, Li Y, Ji X, Guo X. Define the Two Molecular Subtypes of Epithelioid Malignant Pleural Mesothelioma. Cells 2022; 11:cells11182924. [PMID: 36139498 PMCID: PMC9497219 DOI: 10.3390/cells11182924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/25/2022] [Accepted: 09/08/2022] [Indexed: 11/20/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) is a fatal disease of respiratory system. Despite the availability of invasive biomarkers with promising results, there are still significant diagnostic and therapeutic challenges in the treatment of MPM. One of three main mesothelioma cell types, epithelioid mesothelioma makes up approximately 70% of all mesothelioma cases. Different observational findings are under process, but the molecular heterogeneity and pathogenesis of epithelioid malignant pleural mesothelioma (eMPM) are still not well understood. Through molecular analysis, expression profiling data were used to determine the possibility and optimal number of eMPM molecular subtypes. Next, clinicopathological characteristics and different molecular pathways of each subtype were analyzed to prospect the clinical applications and advanced mechanisms of eMPM. In this study, we identified two distinct epithelioid malignant pleural mesothelioma subtypes with distinct gene expression patterns. Subtype I eMPMs were involved in steroid hormone biosynthesis, porphyrin and chlorophyll metabolism, and drug metabolism, while subtype II eMPMs were involved in rational metabolism, tyrosine metabolism, and chemical carcinogenesis pathways. Additionally, we identified potential subtype-specific therapeutic targets, including CCNE1, EPHA3, RNF43, ROS1, and RSPO2 for subtype I and CDKN2A and RET for subtype II. Considering the need for potent diagnostic and therapeutic biomarkers for eMPM, we are anticipating that our findings will help both in exploring underlying mechanisms in the development of eMPM and in designing targeted therapy for eMPM.
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Affiliation(s)
- Umair Ali Khan Saddozai
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Fengling Wang
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Saadullah Khattak
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Muhammad Usman Akbar
- Gomal Center of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan 29050, Pakistan
| | - Muhammad Badar
- Gomal Center of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan 29050, Pakistan
| | - Nazeer Hussain Khan
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Lu Zhang
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Wan Zhu
- Department of Anesthesia, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA
| | - Longxiang Xie
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Yongqiang Li
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
| | - Xinying Ji
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
- Correspondence: (X.J.); (X.G.)
| | - Xiangqian Guo
- Department of Preventive Medicine, Institute of Bioinformatics Center, Henan Provincial Engineering Center for Tumor Molecular Medicine, School of Basic Medical Sciences, Henan University, Kaifeng 475004, China
- Correspondence: (X.J.); (X.G.)
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De Wispelaere N, Rico SD, Bauer M, Luebke AM, Kluth M, Büscheck F, Hube-Magg C, Höflmayer D, Gorbokon N, Weidemann S, Möller K, Fraune C, Bernreuther C, Simon R, Kähler C, Menz A, Hinsch A, Jacobsen F, Lebok P, Clauditz T, Sauter G, Uhlig R, Wilczak W, Steurer S, Burandt E, Krech R, Dum D, Krech T, Marx A, Minner S. High prevalence of p16 staining in malignant tumors. PLoS One 2022; 17:e0262877. [PMID: 35862385 PMCID: PMC9302831 DOI: 10.1371/journal.pone.0262877] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 01/06/2022] [Indexed: 12/26/2022] Open
Abstract
p16 (CDKN2A) is a member of the INK4 class of cell cycle inhibitors, which is often dysregulated in cancer. However, the prevalence of p16 expression in different cancer types is controversial. 15,783 samples from 124 different tumor types and 76 different normal tissue types were analyzed by immunohistochemistry in a tissue microarray format. p16 was detectable in 5,292 (45.0%) of 11,759 interpretable tumors. Except from adenohypophysis in islets of Langerhans, p16 staining was largely absent in normal tissues. In cancer, highest positivity rates were observed in uterine cervix squamous cell carcinomas (94.4%), non-invasive papillary urothelial carcinoma, pTaG2 (100%), Merkel cell carcinoma (97.7%), and small cell carcinomas of various sites of origin (54.5%-100%). All 124 tumor categories showed at least occasional p16 immunostaining. Comparison with clinico-pathological data in 128 vulvar, 149 endometrial, 295 serous ovarian, 396 pancreatic, 1365 colorectal, 284 gastric, and 1245 urinary bladder cancers, 910 breast carcinomas, 620 clear cell renal cell carcinomas, and 414 testicular germ cell tumors revealed only few statistically significant associations. Comparison of human papilloma virus (HPV) status and p16 in 497 squamous cell carcinomas of different organs revealed HPV in 80.4% of p16 positive and in 20.6% of p16 negative cancers (p<0.0001). It is concluded, that a positive and especially strong p16 immunostaining is a feature for malignancy which may be diagnostically useful in lipomatous, urothelial and possibly other tumors. The imperfect association between p16 immunostaining and HPV infection with high variability between different sites of origin challenges the use of p16 immunohistochemistry as a surrogate for HPV positivity, except in tumors of cervix uteri and the penis.
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Affiliation(s)
- Noémi De Wispelaere
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | | | - Marcus Bauer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas M. Luebke
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Doris Höflmayer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Natalia Gorbokon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sören Weidemann
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Katharina Möller
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Bernreuther
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Kähler
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Anne Menz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andrea Hinsch
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ria Uhlig
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Waldemar Wilczak
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Rainer Krech
- Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - David Dum
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - Andreas Marx
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Department of Pathology, Academic Hospital Fuerth, Fuerth Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Shah R, Klotz LV, Glade J. Current Management and Future Perspective in Pleural Mesothelioma. Cancers (Basel) 2022; 14:1044. [PMID: 35205798 PMCID: PMC8869935 DOI: 10.3390/cancers14041044] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Revised: 02/11/2022] [Accepted: 02/12/2022] [Indexed: 11/16/2022] Open
Abstract
Pleural mesothelioma is an aggressive malignancy arising from pleural mesothelial cell lining, predominantly associated with prior exposure to asbestos. The ban on asbestos use has led to its lower incidence in many countries, but globally the disease burden is expected to rise. Therefore, well-planned research is needed to develop more effective, tolerable and affordable drugs. The development of novel treatment has been too slow, with only two regimens of systemic therapy with robust phase 3 data approved formally to date. The treatment scenario for resectable disease remains controversial. However, recent developments in the understanding of disease and clinical trials have been encouraging, and may add better treatment options in the coming years. In this review, we discuss the current treatment options for pleural mesothelioma and shed light on some recent studies and ongoing trials.
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Affiliation(s)
- Rajiv Shah
- Department of Thoracic Oncology, Thoraxklinik, Heidelberg University Hospital, 69126 Heidelberg, Germany
| | - Laura V. Klotz
- Department of Thoracic Surgery, Thoraxklinik, Heidelberg University Hospital, 69126 Heidelberg, Germany;
| | - Julia Glade
- Institute for Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany;
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Štrbac D, Dolžan V. Novel and Future Treatment Options in Mesothelioma: A Systematic Review. Int J Mol Sci 2022; 23:1975. [PMID: 35216091 PMCID: PMC8874564 DOI: 10.3390/ijms23041975] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 01/30/2022] [Accepted: 02/03/2022] [Indexed: 12/23/2022] Open
Abstract
Mesothelioma is a rare tumor, frequently associated with asbestos exposure, arising from pleura and peritoneum. Traditionally, diagnosis and treatment have been difficult in a clinical setting. The treatment is based on a trimodal approach involving surgery, chemotherapy, and radiotherapy. The introduction of chemotherapy improved the overall survival. However, the regimen of pemetrexed/cisplatin doublet has not been changed as a standard treatment since 2004. Novel combinations of ipilimumab and nivolumab have only been approved for clinical use in late 2020. The aim of this review was to systematically summarize findings on novel treatment options in mesothelioma. We searched available medical databases online, such as PubMed and Clinicaltrials.gov, to systematically review the literature on novel approaches in immunotherapy, vaccines, and Chimeric Antigen Receptor (CAR)-T cell therapy in mesothelioma. We manually screened 1127 articles on PubMed and 450 trials on ClinicalTrials.gov, and 24 papers and 12 clinical trials published in the last ten years were included in this review. Immunotherapy that was swiftly introduced to treat other thoracic malignancies was slow to reach desirable survival endpoints in mesothelioma, possibly due to limited patient numbers. Novel treatment approaches, such as CAR-T cell therapy, are being investigated. As the incidence of mesothelioma is still rising globally, novel treatment options based on a better understanding of the tumor microenvironment and the genetic drivers that modulate it are needed to support future precision-based therapies.
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Affiliation(s)
| | - Vita Dolžan
- Pharmacogenetics Laboratory, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
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Vandenhoeck J, van Meerbeeck JP, Fransen E, Raskin J, Van Camp G, Op de Beeck K, Lamote K. DNA Methylation as a Diagnostic Biomarker for Malignant Mesothelioma: A Systematic Review and Meta-Analysis. J Thorac Oncol 2021; 16:1461-1478. [PMID: 34082107 DOI: 10.1016/j.jtho.2021.05.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 05/03/2021] [Accepted: 05/26/2021] [Indexed: 01/02/2023]
Abstract
Malignant mesothelioma is an aggressive cancer type linked to asbestos exposure. Because of several intrinsic challenges, mesothelioma is often diagnosed in an advanced disease stage. Therefore, there is a need for diagnostic biomarkers that may contribute to early detection. Recently, the epigenome of tumors is being extensively investigated to identify biomarkers. This manuscript is a systematic review summarizing the state-of-the-art research investigating DNA methylation in mesothelioma. Four literature databases (PubMed, Scopus, Web of Science, MEDLINE) were systematically searched for studies investigating DNA methylation in mesothelioma up to October 16, 2020. A meta-analysis was performed per gene investigated in at least two independent studies. A total of 53 studies investigated DNA methylation of 97 genes in mesothelioma and are described in a qualitative overview. Furthermore, ten studies investigating 13 genes (APC, CDH1, CDKN2A, DAPK, ESR1, MGMT, miR-34b/c, PGR, RARβ, RASSF1, SFRP1, SFRP4, WIF1) were included in the quantitative meta-analysis. In this meta-analysis, the APC gene is significantly hypomethylated in mesothelioma, whereas CDH1, ESR1, miR-34b/c, PGR, RARβ, SFRP1, and WIF1 are significantly hypermethylated in mesothelioma. The three genes that are the most appropriate candidate biomarkers from this meta-analysis are APC, miR-34b/c, and WIF1. Nevertheless, both study number and study objects comprised in this meta-analysis are too low to draw final conclusions on their clinical applications. The elucidation of the genome-wide DNA methylation profile of mesothelioma is desirable in the future, using a standardized genome-wide methylation analysis approach. The most informative CpG sites from this signature could then form the basis of a panel of highly sensitive and specific biomarkers that can be used for the diagnosis of mesothelioma and even for the screening of an at high-risk population of asbestos-exposed individuals.
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Affiliation(s)
- Janah Vandenhoeck
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium; Centre for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijk, Belgium
| | - Jan P van Meerbeeck
- Department of Thoracic Oncology, Antwerp University Hospital, Edegem, Belgium; Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Wilrijk, Belgium; Infla-Med Centre of Excellence, University of Antwerp, Wilrijk, Belgium
| | - Erik Fransen
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium; StatUa Centre for Statistics, University of Antwerp, Antwerp, Belgium
| | - Jo Raskin
- Department of Thoracic Oncology, Antwerp University Hospital, Edegem, Belgium
| | - Guy Van Camp
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium; Centre for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijk, Belgium
| | - Ken Op de Beeck
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium; Centre for Oncological Research, University of Antwerp and Antwerp University Hospital, Wilrijk, Belgium
| | - Kevin Lamote
- Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Wilrijk, Belgium; Infla-Med Centre of Excellence, University of Antwerp, Wilrijk, Belgium; Department of Pulmonology, Antwerp University Hospital, Edegem, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
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10
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Pezzuto F, Serio G, Fortarezza F, Scattone A, Caporusso C, Punzi A, Cavone D, Pennella A, Marzullo A, Vimercati L. Prognostic Value of Ki67 Percentage, WT-1 Expression and p16/CDKN2A Deletion in Diffuse Malignant Peritoneal Mesothelioma: A Single-Centre Cohort Study. Diagnostics (Basel) 2020; 10:diagnostics10060386. [PMID: 32526924 PMCID: PMC7345555 DOI: 10.3390/diagnostics10060386] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 06/03/2020] [Accepted: 06/05/2020] [Indexed: 12/29/2022] Open
Abstract
Diffuse malignant peritoneal mesothelioma (DMPM) is a rare malignant neoplasm with a poor survival. Although some advances in knowledge have been obtained for the pleural form, much less is known about DMPM. Advantages in terms of prognosis are still limited and strong efforts need to be made. The aim of our study was to correlate several histological and molecular factors with survival in a large cohort of 45 DMPMs. We evaluated histotype, nuclear grade, mitotic count, necrosis, inflammation, desmoplastic reaction, Ki67 percentage, WT-1 expression, p16 protein by immunohistochemistry and CDKN2A deletion by FISH. Our results showed that epithelioid histotype, nuclear grade 2, mitotic count ≤5 x mm2, absence of desmoplasia and p16/CDKN2A deletion, low Ki67 value, and high WT-1 expression were correlated with the most prolonged survival (p = 0.0001). Moreover, p16 loss in immunohistochemistry reflected CDKN2A deletion detected with FISH, and both were correlated with the worst survival (p = 0.0001). At multivariate analysis, Ki67 value, WT-1 expression and p16/CDKN2A deletion emerged as independent prognostic factors (p = 0.01, p = 0.0001 and p = 0.01, respectively). These parameters are easy to analyse at the time of DMPM diagnosis and may support better patient stratification, prediction of treatment effectiveness and therapeutic optimization.
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Affiliation(s)
- Federica Pezzuto
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy;
- Correspondence: (F.P.); (G.S.)
| | - Gabriella Serio
- Pathology Division, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (C.C.); (A.P.); (A.M.)
- Correspondence: (F.P.); (G.S.)
| | - Francesco Fortarezza
- Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padova, 35128 Padova, Italy;
| | - Anna Scattone
- Pathology Division, IRCCS National Cancer Institute “Giovanni Paolo II”, 70124 Bari, Italy;
| | - Concetta Caporusso
- Pathology Division, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (C.C.); (A.P.); (A.M.)
| | - Alessandra Punzi
- Pathology Division, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (C.C.); (A.P.); (A.M.)
| | - Domenica Cavone
- Occupational Health Division, Department of Interdisciplinary Medicine, University of Bari, 70124 Bari, Italy; (D.C.); (L.V.)
| | - Antonio Pennella
- Pathology Division, Department of Surgery, University of Foggia, 71122 Foggia, Italy;
| | - Andrea Marzullo
- Pathology Division, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; (C.C.); (A.P.); (A.M.)
| | - Luigi Vimercati
- Occupational Health Division, Department of Interdisciplinary Medicine, University of Bari, 70124 Bari, Italy; (D.C.); (L.V.)
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Abstract
Mesothelioma is a rare neoplasm that arises from mesothelial cells lining body cavities including the pleura, pericardium, peritoneum, and tunica vaginalis. Most malignant mesotheliomas occur in the chest and are frequently associated with a history of asbestos exposure. The diagnosis of malignant mesothelioma is challenging and fraught with pitfalls, particularly in small biopsies. This article highlights what the pathologist needs to know regarding the clinical and radiographic presentation of mesothelioma, histologic features including subtypes and variants, and recent advances in immunohistochemical markers and molecular testing.
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12
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The importance of FISH signal cut-off values for 9p21 deletion in malignant pleural mesothelioma: Is it underestimated? Pathol Res Pract 2019; 215:152377. [DOI: 10.1016/j.prp.2019.03.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 02/09/2019] [Accepted: 03/02/2019] [Indexed: 11/17/2022]
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13
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Kettunen E, Savukoski S, Salmenkivi K, Böhling T, Vanhala E, Kuosma E, Anttila S, Wolff H. CDKN2A copy number and p16 expression in malignant pleural mesothelioma in relation to asbestos exposure. BMC Cancer 2019; 19:507. [PMID: 31138176 PMCID: PMC6537412 DOI: 10.1186/s12885-019-5652-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 04/29/2019] [Indexed: 11/12/2022] Open
Abstract
Background Deletion of the CDKN2A locus is centrally involved in the development of several malignancies. In malignant pleural mesothelioma (MPM), it is one of the most frequently reported genomic alteration. MPM is strongly associated with a patients’ asbestos exposure. However, the status of CDKN2A and the expression of the corresponding protein, p16, in relation to MPM patient’s asbestos exposure is poorly known. Copy number alterations in 2p16, 9q33.1 and 19p13 have earlier been shown to accumulate in lung cancer in relation to asbestos exposure but their status in MPM is unclear. Methods We studied DNA copy numbers for CDKN2A using fluorescence in situ hybridization (FISH) and p16 expression by immunohistochemistry (IHC) in 92 MPM patients, 75 of which with known asbestos exposure status. We also studied, in MPM, copy number alterations in 2p16, 9q33.1 and 19p13 by FISH. Results We were unable to detect an association between p16 expression and pulmonary asbestos fiber count in MPM tumor cells. However, significantly more MPM patients with high pulmonary asbestos fiber count (> 1 million fibers per gram [f/g]) had stromal p16 immunoreactivity than MPM of patients with low exposure (≤ 0.5 million f/g) (51.4% vs 16.7%; p = 0.035, Chi-Square). We found that an abnormal copy number of CDKN2A in MPM tumor cells associated with a high pulmonary asbestos fiber count (p = 0.044, Fisher’s Exact test, two-tailed). In contrast to our earlier findings in asbestos associated lung cancer, DNA copy number changes in 2p16, 9q33 and 19p13 were not frequent in MPM although single cases with variable copy numbers on those regions were seen. Conclusions We found two instances where the gene locus CDKN2A or its corresponding protein expression, is associated with high asbestos exposure levels. This suggests that there may be biological differences between the mesotheliomas with high pulmonary asbestos fiber count and those with low fiber count. Electronic supplementary material The online version of this article (10.1186/s12885-019-5652-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Eeva Kettunen
- Research and Service Centre for Occupational Safety, Finnish Institute of Occupational Health, PO Box 40, FI-00032 Työterveyslaitos, Helsinki, Finland.
| | - Sauli Savukoski
- Research and Service Centre for Occupational Safety, Finnish Institute of Occupational Health, PO Box 40, FI-00032 Työterveyslaitos, Helsinki, Finland
| | - Kaisa Salmenkivi
- Department of Pathology, University of Helsinki, and HUSLAB, Helsinki University Hospital, 00029 HUS, Helsinki, Finland
| | - Tom Böhling
- Department of Pathology, University of Helsinki, and HUSLAB, Helsinki University Hospital, 00029 HUS, Helsinki, Finland
| | - Esa Vanhala
- Research and Service Centre for Occupational Safety, Finnish Institute of Occupational Health, PO Box 40, FI-00032 Työterveyslaitos, Helsinki, Finland
| | - Eeva Kuosma
- Research and Service Centre for Occupational Safety, Finnish Institute of Occupational Health, PO Box 40, FI-00032 Työterveyslaitos, Helsinki, Finland
| | - Sisko Anttila
- Research and Service Centre for Occupational Safety, Finnish Institute of Occupational Health, PO Box 40, FI-00032 Työterveyslaitos, Helsinki, Finland.,Department of Pathology, University of Helsinki, and HUSLAB, Helsinki University Hospital, 00029 HUS, Helsinki, Finland
| | - Henrik Wolff
- Research and Service Centre for Occupational Safety, Finnish Institute of Occupational Health, PO Box 40, FI-00032 Työterveyslaitos, Helsinki, Finland
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14
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Wahiduzzaman M, Karnan S, Ota A, Hanamura I, Murakami H, Inoko A, Rahman ML, Hyodo T, Konishi H, Tsuzuki S, Hosokawa Y. Establishment and characterization of CRISPR/Cas9-mediated NF2 -/- human mesothelial cell line: Molecular insight into fibroblast growth factor receptor 2 in malignant pleural mesothelioma. Cancer Sci 2018; 110:180-193. [PMID: 30417500 PMCID: PMC6317947 DOI: 10.1111/cas.13871] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 11/06/2018] [Accepted: 11/06/2018] [Indexed: 12/12/2022] Open
Abstract
Malignant pleural mesothelioma (MPM), a highly refractory tumor, is currently incurable due to the lack of an early diagnosis method and medication, both of which are urgently needed to improve the survival and/or quality of life of patients. NF2 is a tumor suppressor gene and is frequently mutated in MPM. Using a CRISPR/Cas9 system, we generated an NF2‐knockout human mesothelial cell line, MeT‐5A (NF2‐KO). In NF2‐KO cell clones, cell growth, clonogenic activity, migration activity, and invasion activity significantly increased compared with those in NF2‐WT cell clones. Complementary DNA microarray analysis clearly revealed the differences in global gene expression profile between NF2‐WT and NF2‐KO cell clones. Quantitative PCR analysis and western blot analysis showed that the upregulation of fibroblast growth factor receptor 2 (FGFR2) was concomitant with the increases in phosphorylation levels of JNK, c‐Jun, and retinoblastoma (Rb) in NF2‐KO cell clones. These increases were all abrogated by the exogenous expression of NF2 in the NF2‐KO clone. In addition, the disruption of FGFR2 in the NF2‐KO cell clone suppressed cell proliferation as well as the phosphorylation levels of JNK, c‐Jun, and Rb. Notably, FGFR2 was found to be highly expressed in NF2‐negative human mesothelioma tissues (11/12 cases, 91.7%) but less expressed in NF2‐positive tissues. Collectively, these findings suggest that NF2 deficiency might play a role in the tumorigenesis of human mesothelium through mediating FGFR2 expression; FGFR2 would be a candidate molecule to develop therapeutic and diagnostic strategies for targeting MPM with NF2 loss.
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Affiliation(s)
- Md Wahiduzzaman
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Sivasundaram Karnan
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Akinobu Ota
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Ichiro Hanamura
- Division of Hematology, Department of Internal Medicine, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Hideki Murakami
- Department of Pathology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Akihito Inoko
- Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan
| | - Md Lutfur Rahman
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Toshinori Hyodo
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Hiroyuki Konishi
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Shinobu Tsuzuki
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yoshitaka Hosokawa
- Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan
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15
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Suzuki R, Amatya VJ, Kushitani K, Kai Y, Kambara T, Takeshima Y. miR-182 and miR-183 Promote Cell Proliferation and Invasion by Targeting FOXO1 in Mesothelioma. Front Oncol 2018; 8:446. [PMID: 30406026 PMCID: PMC6204457 DOI: 10.3389/fonc.2018.00446] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 09/24/2018] [Indexed: 12/14/2022] Open
Abstract
Dysregulation of miR-182 and miR-183 has been implicated in the progression of several human cancers. Our previous study showed that miR-182 and miR-183 are upregulated in malignant mesothelioma. However, their biological functions remain unclear. We performed in-situ hybridization to analyze the expression of miR-182 and miR-183 in human tissues. Functional analysis was performed by treatment of two mesothelioma cell lines (ACC-MESO1 and CRL-5915) with miR-182 and miR-183 inhibitors. RT-PCR and western blot analysis were conducted to analyze the expression of FOXO1, a known target of both miR-182 and miR-183. Mesothelioma cells treated with FOXO1 siRNA and miR-182/183 inhibitors were also analyzed by evaluating cell proliferation and invasion, as well as expression of FOXO1 and its downstream targets. We confirmed miR-182 expression in 25/29 cases and miR-183 expression in 29/29 cases of human mesothelioma tissue by in-situ hybridization. Notably, inhibition of miR-182 or miR-183 reduced cell proliferation, invasion, migration, and adhesion abilities of mesothelioma cells. Surprisingly, transfection with both miR-182 and miR-183 inhibitors showed even more effects on cell progression. Furthermore, FOXO1 was identified as a target of miR-182 and miR-183 in mesothelioma cells. Inhibition of miR-182 and miR-183 reduced cell proliferation ability via upregulation of FOXO1 and its downstream targets, namely, p27. Moreover, inhibition of miR-182 and miR-183 reduced the cell invasion properties of mesothelioma cells. Our findings indicated that miR-182 and miR-183 promote mesothelioma cell progression via downregulation of FOXO1 and p27. Targeting the miR-182/183—FOXO1 axis could serve as a novel treatment against malignant mesothelioma.
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Affiliation(s)
- Rui Suzuki
- Department of Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Vishwa Jeet Amatya
- Department of Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kei Kushitani
- Department of Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuichiro Kai
- Department of Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.,Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan
| | - Takahiro Kambara
- Department of Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yukio Takeshima
- Department of Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
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16
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Hylebos M, Van Camp G, Vandeweyer G, Fransen E, Beyens M, Cornelissen R, Suls A, Pauwels P, van Meerbeeck JP, Op de Beeck K. Large-scale copy number analysis reveals variations in genes not previously associated with malignant pleural mesothelioma. Oncotarget 2017; 8:113673-113686. [PMID: 29371938 PMCID: PMC5768355 DOI: 10.18632/oncotarget.22817] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 11/15/2017] [Indexed: 12/29/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive tumor that is often causally associated with asbestos exposure. Comparative genomic hybridization techniques and arrays demonstrated a complex set of copy number variations (CNVs) in the MPM-genome. These techniques however have a limited resolution, throughput and flexibility compared to next-generation sequencing platforms. In this study, the presence of CNVs in the MPM-genome was investigated using an MPM-cohort (N = 85) for which genomic microarray data are available through ‘The Cancer Genome Atlas’ (TCGA). To validate these results, the genomes of MPMs and matched normal samples (N = 21) were analyzed using low-pass whole genome sequencing on an ‘Illumina HiSeq’ platform. CNVs were detected using in-house developed analysis pipelines and frequencies of copy number loss and gain were calculated. In both datasets, losses on chromosomes 1, 3, 4, 6, 9, 13 and 22 and gains on chromosomes 1, 5, 7 and 17 were found in at least 25% and 15% of MPMs, respectively. Besides the well-known MPM-associated genes, CDKN2A, NF2 and BAP1, other interesting cancer-associated genes were listed as frequently involved in a copy number loss (e.g. EP300, SETD2 and PBRM1). Moreover, four cancer-associated genes showed a high frequency of copy number gain in both datasets (i.e. TERT, FCGR2B, CD79B and PRKAR1A). A statistically significant association between overall survival and the presence of copy number loss in the CDKN2A-containing region was observed in the TCGA-set. In conclusion, recurrent CNVs were detected in both datasets, occurring in regions harboring known MPM-associated genes and genes not previously linked to MPM.
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Affiliation(s)
- Marieke Hylebos
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Antwerp, Belgium.,Center for Oncological Research, University of Antwerp, 2610 Antwerp, Belgium
| | - Guy Van Camp
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Antwerp, Belgium.,Center for Oncological Research, University of Antwerp, 2610 Antwerp, Belgium
| | - Geert Vandeweyer
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Antwerp, Belgium
| | - Erik Fransen
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Antwerp, Belgium.,StatUa Center for Statistics, University of Antwerp, 2610 Antwerp, Belgium
| | - Matthias Beyens
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Antwerp, Belgium.,Center for Oncological Research, University of Antwerp, 2610 Antwerp, Belgium
| | - Robin Cornelissen
- Department of Pulmonary Medicine, Erasmus Medical Center Cancer Institute, 3015 Rotterdam, The Netherlands
| | - Arvid Suls
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Antwerp, Belgium
| | - Patrick Pauwels
- Center for Oncological Research, University of Antwerp, 2610 Antwerp, Belgium.,Laboratory of Pathology, Antwerp University Hospital, 2650 Antwerp, Belgium
| | - Jan P van Meerbeeck
- Center for Oncological Research, University of Antwerp, 2610 Antwerp, Belgium.,Thoracic Oncology, Antwerp University Hospital, 2650 Antwerp, Belgium
| | - Ken Op de Beeck
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, 2650 Antwerp, Belgium.,Center for Oncological Research, University of Antwerp, 2610 Antwerp, Belgium
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17
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Ghosh M, Öner D, Poels K, Tabish AM, Vlaanderen J, Pronk A, Kuijpers E, Lan Q, Vermeulen R, Bekaert B, Hoet PH, Godderis L. Changes in DNA methylation induced by multi-walled carbon nanotube exposure in the workplace. Nanotoxicology 2017; 11:1195-1210. [PMID: 29191063 DOI: 10.1080/17435390.2017.1406169] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
This study was designed to assess the epigenetic alterations in blood cells, induced by occupational exposure to multi-wall carbon nanotubes (MWCNT). The study population comprised of MWCNT-exposed workers (n=24) and unexposed controls (n=43) from the same workplace. We measured global DNA methylation/hydroxymethylation levels on the 5th cytosine residues using a validated liquid chromatography tandem-mass spectrometry (LC-MS/MS) method. Sequence-specific methylation of LINE1 retrotransposable element 1 (L1RE1) elements, and promoter regions of functionally important genes associated with epigenetic regulation [DNA methyltransferase-1 (DNMT1) and histone deacetylase 4 (HDAC4)], DNA damage/repair and cell cycle pathways [nuclear protein, coactivator of histone transcription/ATM serine/threonine kinase (NPAT/ATM)], and a potential transforming growth factor beta (TGF-β) repressor [SKI proto-oncogene (SKI)] were studied using bisulfite pyrosequencing. Analysis of global DNA methylation levels and hydroxymethylation did not reveal significant difference between the MWCNT-exposed and control groups. No significant changes in Cytosine-phosphate-Guanine (CpG) site methylation were observed for the LINE1 (L1RE1) elements. Further analysis of gene-specific DNA methylation showed a significant change in methylation for DNMT1, ATM, SKI, and HDAC4 promoter CpGs in MWCNT-exposed workers. Since DNA methylation plays an important role in silencing/regulation of the genes, and many of these genes have been associated with occupational and smoking-induced diseases and cancer (risk), aberrant methylation of these genes might have a potential effect in MWCNT-exposed workers.
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Affiliation(s)
- Manosij Ghosh
- a Department of Public Health and Primary Care, Centre Environment & Health , KU Leuven , Leuven , Belgium
| | - Deniz Öner
- a Department of Public Health and Primary Care, Centre Environment & Health , KU Leuven , Leuven , Belgium
| | - Katrien Poels
- a Department of Public Health and Primary Care, Centre Environment & Health , KU Leuven , Leuven , Belgium
| | - Ali M Tabish
- a Department of Public Health and Primary Care, Centre Environment & Health , KU Leuven , Leuven , Belgium
| | - Jelle Vlaanderen
- b Division of Environmental Epidemiology, Institute for Risk Assessment Sciences , Utrecht University , Utrecht , The Netherlands
| | - Anjoeka Pronk
- c TNO, Netherlands Organisation for Applied Scientific Research , Zeist , The Netherlands
| | - Eelco Kuijpers
- c TNO, Netherlands Organisation for Applied Scientific Research , Zeist , The Netherlands
| | - Qing Lan
- d Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics , National Cancer Institute , Bethesda , MD , USA
| | - Roel Vermeulen
- b Division of Environmental Epidemiology, Institute for Risk Assessment Sciences , Utrecht University , Utrecht , The Netherlands
| | - Bram Bekaert
- e Department of Forensic Medicine, Laboratory of Forensic Genetics and Molecular Archaeology , University Hospitals Leuven , Leuven , Belgium
| | - Peter Hm Hoet
- a Department of Public Health and Primary Care, Centre Environment & Health , KU Leuven , Leuven , Belgium
| | - Lode Godderis
- a Department of Public Health and Primary Care, Centre Environment & Health , KU Leuven , Leuven , Belgium.,f External Service for Prevention and Protection at Work , Idewe , Heverlee , Belgium
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18
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Sobhani N, Corona SP, Bonazza D, Ianza A, Pivetta T, Roviello G, Cortale M, Guglielmi A, Zanconati F, Generali D. Advances in systemic therapy for malignant mesothelioma: future perspectives. Future Oncol 2017; 13:2083-2101. [PMID: 28984470 DOI: 10.2217/fon-2017-0224] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 06/29/2017] [Indexed: 11/21/2022] Open
Abstract
Malignant mesothelioma is a rare and aggressive form of cancer affecting the mesothelium. This mainly occupational disease is becoming more common in those countries where asbestos has been used for industrial applications. Notwithstanding the progress made in the field, patients do not survive more than 12 months on average with standard treatment. With the advent of next generation sequencing, it is now possible to study the mutational landscape of each tumor with the aim of identifying the genetic aberrations driving tumorigenesis. This review encompasses the latest research in the field, with particular attention to new chemotherapy combinatorial regimens, molecular targets and immunotherapies, providing a comprehensive picture of the current and future treatment options for malignant mesothelioma patients.
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Affiliation(s)
- Navid Sobhani
- Department of Medical, Surgical, & Health Sciences, University of Trieste, Piazza Ospitale 1 34129 Trieste, Italy
- Department of Medical, Surgical, & Health Sciences, Teaching Hospital of Cattinara, University of Trieste, Via Fiume 447, 34129 Trieste, Italy
| | - Silvia Paola Corona
- Department of Radiation Oncology, Peter MacCallum Cancer Center, Moorabbin Campus, 823-865 Centre Rd, Bentleigh East VIC 3165, Australia
| | - Deborah Bonazza
- Department of Medical, Surgical, & Health Sciences, Teaching Hospital of Cattinara, University of Trieste, Via Fiume 447, 34129 Trieste, Italy
| | - Anna Ianza
- Department of Medical, Surgical, & Health Sciences, University of Trieste, Piazza Ospitale 1 34129 Trieste, Italy
| | - Tania Pivetta
- Department of Medical, Surgical, & Health Sciences, Teaching Hospital of Cattinara, University of Trieste, Via Fiume 447, 34129 Trieste, Italy
| | | | - Maurizio Cortale
- Department of Medical, Surgical, & Health Sciences, Teaching Hospital of Cattinara, University of Trieste, Via Fiume 447, 34129 Trieste, Italy
| | - Alessandra Guglielmi
- Department of Medical, Surgical, & Health Sciences, University of Trieste, Piazza Ospitale 1 34129 Trieste, Italy
| | - Fabrizio Zanconati
- Department of Medical, Surgical, & Health Sciences, Teaching Hospital of Cattinara, University of Trieste, Via Fiume 447, 34129 Trieste, Italy
| | - Daniele Generali
- Department of Medical, Surgical, & Health Sciences, University of Trieste, Piazza Ospitale 1 34129 Trieste, Italy
- Breast Cancer Unit, ASST Cremona, Viale Concordia 1, 26100, Cremona, Italy
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19
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Mossman BT. Cell Signaling and Epigenetic Mechanisms in Mesothelioma. ASBESTOS AND MESOTHELIOMA 2017. [DOI: 10.1007/978-3-319-53560-9_10] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
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20
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McGregor SM, McElherne J, Minor A, Keller-Ramey J, Dunning R, Husain AN, Vigneswaran W, Fitzpatrick C, Krausz T. BAP1 immunohistochemistry has limited prognostic utility as a complement of CDKN2A (p16) fluorescence in situ hybridization in malignant pleural mesothelioma. Hum Pathol 2016; 60:86-94. [PMID: 27771374 DOI: 10.1016/j.humpath.2016.09.026] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2016] [Revised: 09/07/2016] [Accepted: 09/22/2016] [Indexed: 11/27/2022]
Abstract
BRCA-associated protein 1 (BAP1) immunohistochemistry (IHC) and CDKN2A (p16) fluorescence in situ hybridization (FISH) have shown clinical utility in confirming the diagnosis of malignant pleural mesothelioma (MPM), but the role for using these 2 markers to guide clinical management is not yet clear. Although p16 loss is predictive of poor prognosis, there is controversy as to whether BAP1 loss is predictive of a more favorable prognosis; how these results interact with one another has not been explored. We performed CDKN2A FISH on a previously published tissue microarray on which we had performed BAP1 IHC, revealing combined BAP1/p16 status for 93 MPM cases. As expected, BAP1 IHC in combination with CDKN2A FISH resulted in high sensitivity (84%) and specificity (100%) for MPM, and p16 loss was an independent predictor of poor survival (hazard ratio, 2.2553; P = .0135). There was no association between BAP1 loss and p16 loss, as 26%, 28%, 30%, and 16% of overall cases demonstrated loss of BAP1 alone, loss of p16 alone, loss of both BAP1 and p16, or neither abnormality, respectively. Although multivariate analysis demonstrated that BAP1 IHC is not an independent predictor of prognosis, when viewed in combination with homozygous CDKN2A deletion, risk stratification was evident. More specifically, patients with CDKN2A disomy and loss of BAP1 expression had improved outcomes compared with those with CDKN2A disomy and retained BAP1 expression (hazard ratio, 0.2286; P = .0017), and this finding was notably evident among epithelioid cases. We conclude that BAP1 IHC provides prognostic information within the context of CDKN2A FISH that may have clinical utility beyond diagnosis.
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Affiliation(s)
- Stephanie M McGregor
- Department of Pathology, University of Chicago Medicine, Chicago, IL 60637; Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI 53792.
| | - James McElherne
- Department of Pathology, University of Chicago Medicine, Chicago, IL 60637.
| | - Agata Minor
- Department of Pathology, University of Chicago Medicine, Chicago, IL 60637.
| | | | - Ryan Dunning
- Department of Pathology, University of Chicago Medicine, Chicago, IL 60637.
| | - Aliya N Husain
- Department of Pathology, University of Chicago Medicine, Chicago, IL 60637.
| | | | - Carrie Fitzpatrick
- Department of Pathology, University of Chicago Medicine, Chicago, IL 60637.
| | - Thomas Krausz
- Department of Pathology, University of Chicago Medicine, Chicago, IL 60637.
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21
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Low homozygous/high heterozygous deletion status by p16 FISH correlates with a better prognostic group than high homozygous deletion status in malignant pleural mesothelioma. Lung Cancer 2016; 99:155-61. [DOI: 10.1016/j.lungcan.2016.07.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Accepted: 07/11/2016] [Indexed: 11/27/2022]
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22
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Alterations of p14 ARF , p15 INK4b , and p16 INK4a Genes in Primary Laryngeal Squamous Cell Carcinoma. Pathol Oncol Res 2016; 23:63-71. [PMID: 27377733 DOI: 10.1007/s12253-016-0083-4] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Accepted: 06/28/2016] [Indexed: 10/21/2022]
Abstract
The 9p21 gene cluster, harboring growth suppressive genes p14 ARF , p15 INK4b , and p16 INK4a , is one of the major aberration hotspots in head and neck cancers. We try to elucidate specific aberrations affecting this region, throughout methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay. Methylation of the gene was investigated by MS-MLPA in a well-characterized series of 27 laryngeal squamous cell carcinomas and 20 samples of healthy mucosa. Aberrant promoter hypermethylation was confirmed using and methylation-specific. All samples studied except 3 (11 %) presented losses at 9p21 segment. The most common finding was the small deletion (exon 1α) of the p16 INK4a locus (44 %). Deletion of the 9p21 gene cluster was identified in 5 cases (18 %). We only found methylation in 8 samples (30 %) for p15 IK4b -exon 1. Promoter methylation of p14 ARF , p15 IK4b and p16 INK4a was not detected in any tumor sample. Methylation-specific polymerase chain reaction confirmed the results. Our data indicate that there may be a subgroup of patients in which epigenetic regulation of 9p21 segment might have little relevance. Nevertheless, MS-MLPA could not be suitable for the study of methylation at this region and further research is required.
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The prognostic significance of BAP1, NF2, and CDKN2A in malignant peritoneal mesothelioma. Mod Pathol 2016; 29:14-24. [PMID: 26493618 DOI: 10.1038/modpathol.2015.121] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 09/06/2015] [Accepted: 09/13/2015] [Indexed: 12/17/2022]
Abstract
Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for patients with malignant peritoneal mesothelioma has resulted in improved disease control and increased survival. Despite these results, there are significant perioperative risks associated with this aggressive procedure that necessitate consideration of prognostic markers during patient selection. The molecular pathogenesis of peritoneal mesothelioma remains relatively unknown, but extrapolation of findings from their pleural counterpart would suggest frequent alterations in CDKN2A, NF2, and BAP1. Homozygous deletions in CDKN2A portend a worse overall survival in peritoneal mesothelioma. However, the prevalence and prognostic significance of NF2 and BAP1 abnormalities has not been studied. Dual-color fluorescence in situ hybridization using CDKN2A and NF2 locus-specific probes and BAP1 immunohistochemistry identified homozygous CDKN2A deletions (n=25, 29%), hemizygous NF2 loss (n=30, 35%), and/or loss of BAP1 protein expression (n=49, 57%) in 68 of 86 (79%) peritoneal mesotheliomas. Homozygous CDKN2A deletions or hemizygous NF2 loss correlated with shorter progression-free survival (P<0.02) and poor overall survival (P<0.03). Moreover, the significance of these findings was cumulative. Patients harboring both homozygous CDKN2A deletions and hemizygous NF2 loss had a 2-year progression-free survival rate of 9% with a median of 6 months (P<0.01) and overall survival rate of 18% with a median of 8 months (P<0.01). By multivariate analysis, combined homozygous CDKN2A deletions and hemizygous NF2 loss was a negative prognostic factor for both progression-free survival and overall survival, independent of patient age, peritoneal cancer index, completeness of cytoreduction, and extent of invasion. In contrast, loss of BAP1 was not associated with clinical outcome. In summary, homozygous deletions in CDKN2A and hemizygous loss of NF2 as detected by fluorescence in situ hybridization would confer a poor clinical outcome and may guide future treatment decisions for patients with peritoneal mesothelioma.
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Suzawa K, Yamamoto H, Murakami T, Katayama H, Furukawa M, Shien K, Hashida S, Okabe K, Aoe K, Soh J, Asano H, Tsukuda K, Mimura Y, Toyooka S, Miyoshi S. Establishment and molecular characterization of cell lines from Japanese patients with malignant pleural mesothelioma. Oncol Lett 2015; 11:705-712. [PMID: 26870271 DOI: 10.3892/ol.2015.3955] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Accepted: 09/14/2015] [Indexed: 11/06/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) is an aggressive disease that is resistant to conventional therapies. Cell lines are useful models for studying the biological characteristics of tumors; therefore, the establishment of MPM cell lines is valuable for exploring novel therapeutic strategies for MPM. In the present study, 4 MPM cell lines (YUMC8, YUMC44, YUMC63, and YUMC64) were established, which consisted of 2 epithelioid and 2 sarcomatoid mesothelioma histological subtypes, from Japanese patients with MPM. The DNA methylation status, mutations, copy number gains, protein expression of representative genes, and the sensitivity to several drugs were examined in these 4 cell lines. Methylation of P16 was demonstrated in 3/4 cell lines, in which the protein expression of p16 was lost. Methylation of RASSF1A was observed in 3/4 cell lines. Copy number gains of EGFR, HER2 or MET were not detected in the 4 cell lines. Mutations in various genes, including EGFR, KRAS, HER2, BRAF, and PIK3CA, which are frequently detected in non-small cell lung cancer, were not detected in the 4 cell lines. microRNA-34b/c is a direct transcriptional target of p53 and is often silenced in MPM by promoter methylation. In the present study, miR-34b/c was heavily methylated in 2/4 established MPM cell lines. For cell adhesion molecules, E-cadherin expression was detected in the 2 epithelioid MPM cell lines, whereas N-cadherin expression was detected in all 4 established cell lines by western blotting. Vimentin was strongly expressed in the 2 sarcomatoid MPM cell lines. None of the established MPM cell lines demonstrated significant responses to the drugs tested, including NVP-AUY922, 17-DMAG, Trichostatin A, and Vorinostat. Although novel molecular findings were not observed in the current characterization of these MPM cell lines, these lines will be useful for future extensive analyses of the biological behavior of MPM and the development of novel therapeutic strategies.
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Affiliation(s)
- Ken Suzawa
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Hiromasa Yamamoto
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; Department of Thoracic Surgery, National Hospital Organization Yamaguchi-Ube Medical Center, Ube, Yamaguchi 755-0241, Japan; Department of Clinical Research, National Hospital Organization Yamaguchi-Ube Medical Center, Ube, Yamaguchi 755-0241, Japan
| | - Tomoyuki Murakami
- Department of Clinical Research, National Hospital Organization Yamaguchi-Ube Medical Center, Ube, Yamaguchi 755-0241, Japan
| | - Hideki Katayama
- Department of Clinical Research, National Hospital Organization Yamaguchi-Ube Medical Center, Ube, Yamaguchi 755-0241, Japan; Department of Medical Oncology, National Hospital Organization Yamaguchi-Ube Medical Center, Ube, Yamaguchi 755-0241, Japan
| | - Masashi Furukawa
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Kazuhiko Shien
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Shinsuke Hashida
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Kazunori Okabe
- Department of Thoracic Surgery, National Hospital Organization Yamaguchi-Ube Medical Center, Ube, Yamaguchi 755-0241, Japan; Department of Clinical Research, National Hospital Organization Yamaguchi-Ube Medical Center, Ube, Yamaguchi 755-0241, Japan
| | - Keisuke Aoe
- Department of Clinical Research, National Hospital Organization Yamaguchi-Ube Medical Center, Ube, Yamaguchi 755-0241, Japan; Department of Medical Oncology, National Hospital Organization Yamaguchi-Ube Medical Center, Ube, Yamaguchi 755-0241, Japan
| | - Junichi Soh
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Hiroaki Asano
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Kazunori Tsukuda
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Yusuke Mimura
- Department of Clinical Research, National Hospital Organization Yamaguchi-Ube Medical Center, Ube, Yamaguchi 755-0241, Japan
| | - Shinichi Toyooka
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan; Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Shinichiro Miyoshi
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
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Furukawa M, Toyooka S, Hayashi T, Yamamoto H, Fujimoto N, Soh J, Hashida S, Shien K, Asano H, Aoe K, Okabe K, Pass HI, Tsukuda K, Kishimoto T, Miyoshi S. DNA copy number gains in malignant pleural mesothelioma. Oncol Lett 2015; 10:3274-3278. [PMID: 26722325 DOI: 10.3892/ol.2015.3652] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 07/30/2015] [Indexed: 12/18/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with an extremely poor prognosis. The incidence of MPM is increasing as a result of widespread exposure to asbestos. The molecular pathogenesis of MPM remains unclear. The present study analyzed the frequency of various genomic copy number gains (CNGs) in MPM using reverse transcription-quantitative polymerase chain reaction. A total of 83 primary MPMs and 53 primary lung adenocarcinomas were analyzed to compare the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2. In MPM, the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2 were detected in 12 (14.5%), 8 (9.6%), 5 (6.0%), 4 (4.8%) and 1 (1.2%) of the samples, respectively. In lung adenocarcinomas, the CNGs of EGFR, KRAS, MET, FGFR1 and SOX2 were detected in 21 (39.6%), 12 (22.6%), 5 (9.4%), 10 (18.9%) and 0 (0.0%) of the samples, respectively. The CNGs of EGFR, KRAS and FGFR1 were significantly less frequent in the MPMs compared with the lung adenocarcinomas (P=0.0018, 0.048 and 0.018, respectively). Overall, the MPMs exhibited these CNGs less frequently compared with the lung adenocarcinomas (P=0.0002). The differences in CNGs between the two tumor types suggested that they are genetically different.
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Affiliation(s)
- Masashi Furukawa
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan
| | - Shinichi Toyooka
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan ; Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan
| | - Tatsuro Hayashi
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan ; Department of Thoracic Surgery, National Hospital Organization Yamaguchi-Ube Medical Center, Ube, Yamaguchi 755-0241, Japan
| | - Hiromasa Yamamoto
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan ; Department of Thoracic Surgery, National Hospital Organization Yamaguchi-Ube Medical Center, Ube, Yamaguchi 755-0241, Japan
| | - Nobukazu Fujimoto
- Department of Internal Medicine, Okayama Rosai Hospital, Okayama, Okayama 702-8055, Japan
| | - Junichi Soh
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan
| | - Shinsuke Hashida
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan ; Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan
| | - Kazuhiko Shien
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan ; Department of Clinical Genomic Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan
| | - Hiroaki Asano
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan
| | - Keisuke Aoe
- Department of Medical Oncology, National Hospital Organization Yamaguchi-Ube Medical Center, Ube, Yamaguchi 755-0241, Japan
| | - Kazunori Okabe
- Department of Thoracic Surgery, National Hospital Organization Yamaguchi-Ube Medical Center, Ube, Yamaguchi 755-0241, Japan
| | - Harvey I Pass
- Division of Thoracic Surgery, Department of Cardiothoracic Surgery, New York University Langone Medical Center, NY 10016, USA
| | - Kazunori Tsukuda
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan
| | - Takumi Kishimoto
- Department of Internal Medicine, Okayama Rosai Hospital, Okayama, Okayama 702-8055, Japan
| | - Shinichiro Miyoshi
- Department of Thoracic, Breast and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Okayama 700-8558, Japan
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Differential p16/INK4A cyclin-dependent kinase inhibitor expression correlates with chemotherapy efficacy in a cohort of 88 malignant pleural mesothelioma patients. Br J Cancer 2015; 113:69-75. [PMID: 26057448 PMCID: PMC4647524 DOI: 10.1038/bjc.2015.187] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 04/21/2015] [Accepted: 04/28/2015] [Indexed: 12/25/2022] Open
Abstract
Background: Malignant pleural mesothelioma (MPM) is a rare and essentially incurable malignancy most often linked with occupational exposure to asbestos fibres. In common with other malignancies, the development and progression of MPM is associated with extensive dysregulation of cell cycle checkpoint proteins that modulate cell proliferation, apoptosis, DNA repair and senescence. Methods: The expression of cyclin-dependent kinase inhibitor p16/INK4A was evaluated by immunohistochemistry using tumour biopsy specimens from 88 MPM cases and a semi-quantitative score for p16/INK4A expression was obtained. Post-diagnosis survival and the survival benefit of chemotherapeutic intervention was correlated with p16/INK4A expression. Results: A low, intermediate and high score for p16/INK4A expression was observed for 45 (51.1%), 28 (31.8%) and 15 (17.1%) of the MPM cases, respectively. Those cases with intermediate or high p16/INK4A tumour expression had a significantly better post-diagnosis survival than those cases whose tumours lost p16 expression (log-rank P<0.001). Those patients with sustained p16/INK4A expression who received chemotherapy also had a better survival than those treated patients whose tumours had lost p16/INK4A expression (log-rank P<0.001). Conclusions: Sustained p16/INK4A expression predicts better post-diagnosis survival in MPM and also better survival following chemotherapeutic intervention.
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Zucali PA, De Vincenzo F, Simonelli M, Santoro A. Future developments in the management of malignant pleural mesothelioma. Expert Rev Anticancer Ther 2014; 9:453-67. [DOI: 10.1586/era.09.2] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Tarakji B, Altamimi MA, Baroudi K, Nassain MZ, Alenzi FQ. Immunohistochemical expression of p16 in Carcinoma Ex-pleomorphic Adenoma (undifferentiated and Adenocarcinoma Types). J Clin Diagn Res 2013; 7:3054-6. [PMID: 24551726 DOI: 10.7860/jcdr/2013/7380.3851] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Accepted: 10/27/2013] [Indexed: 11/24/2022]
Abstract
OBJECTIVE This study was aimed at characterizing alterations in the immunohistochemical expression of p16 in carcinoma ex-pleomorphic adenomas. STUDY DESIGN A selected series of 27 cases of carcinoma ex-pleomorphic adenomas were examined. RESULTS The results showed that p16 expression in non tumour duct cells was strongly positive nuclear staining in 23 (85%) cases out of 27 cases, that 3 (11.1%) had moderate staining, and that 1 (3.7%) had weak staining. p16 expression in carcinoma ex-pleomorphic adenomas was indicated as a negative nuclear staining in 22 (81.4%) cases out of 27cases, and 5 (18.5%) cases expressed moderate staining. CONCLUSION This study suggests that alteration of p16 expression is detected in carcinoma ex-pleomorphic adenomas. p16 has a role in development of carcinoma ex-pleomorphic adenomas.
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Affiliation(s)
- Bassel Tarakji
- Faculty, Head of Department of Oral Maxillofacial Sciences, Alfarabi College of Dentistry and Nursing , Kingdom of Saudi Arabia, Riyadh
| | - Mohammed Alsakran Altamimi
- Faculty, Department of Restorative Dental Sciences, Alfarabi College of Dentistry and Nursing , Kingdom of Saudi Arabia, Riyadh
| | - Kusai Baroudi
- Faculty, Department of Restorative Dental Sciences, Alfarabi College of Dentistry and Nursing , Kingdom of Saudi Arabia, Riyadh
| | - Mohammad Z Nassain
- Faculty, Department of Restorative Dental Sciences, Alfarabi College of Dentistry and Nursing , Kingdom of Saudi Arabia, Riyadh
| | - Faris Q Alenzi
- Faculty, College of Applied Medical Sciences, Prince Salman University , Al-Kharj, Saudi Arabia
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Cheng J, Fan XM. Role of cyclooxygenase-2 in gastric cancer development and progression. World J Gastroenterol 2013; 19:7361-7368. [PMID: 24259966 PMCID: PMC3831217 DOI: 10.3748/wjg.v19.i42.7361] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2013] [Revised: 09/12/2013] [Accepted: 09/29/2013] [Indexed: 02/06/2023] Open
Abstract
Although the incidence of gastric cancer has been declining in recent decades, it remains a major public health issue as the second leading cause of cancer death worldwide. In China, gastric cancer is still the main cause of death in patients with malignant tumors. Most patients are diagnosed at an advanced stage and mortality is high. Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in prostanoid synthesis and plays an important role in the development and progression of gastric cancer. The expression of COX-2 in gastric cancer is upregulated and its molecular mechanisms have been investigated. Helicobacter pylori infection, tumor suppressor gene mutation and the activation of nuclear factor-kappa B may be responsible for the elevated expression of COX-2 in gastric cancer. The mechanisms of COX-2 in the development and progression of gastric cancer are probably through promoting the proliferation of gastric cancer cells, while inhibiting apoptosis, assisting angiogenesis and lymphatic metastasis, and participating in cancer invasion and immunosuppression. This review is intended to discuss, comment and summarize recent research progress on the role of COX-2 in gastric cancer development and progression, and elucidate the molecular mechanisms which might be involved in the carcinogenesis.
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Wu D, Hiroshima K, Matsumoto S, Nabeshima K, Yusa T, Ozaki D, Fujino M, Yamakawa H, Nakatani Y, Tada Y, Shimada H, Tagawa M. Diagnostic usefulness of p16/CDKN2A FISH in distinguishing between sarcomatoid mesothelioma and fibrous pleuritis. Am J Clin Pathol 2013; 139:39-46. [PMID: 23270897 DOI: 10.1309/ajcpt94jvwihbkrd] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Abstract
The distinction between sarcomatoid mesothelioma and fibrous pleuritis is difficult based on histology, especially when the amount of tumor tissue examined via biopsy is small and immunohistochemical examination is inconclusive. We studied the usefulness of deletion of p16 with fluorescence in situ hybridization (FISH) and p16 hypermethylation with polymerase chain reaction for the diagnosis and prognosis of malignant pleural mesothelioma (MPM). We analyzed 50 MPMs, including 22 sarcomatoid mesothelioma cases and 10 fibrous pleuritis cases. We set the cutoff value of homozygous deletion pattern as 14.4% based on FISH signaling patterns using samples of fibrous pleuritis. The percentage of homozygous deletion pattern was higher than 14.4% in 55.6% of the epithelioid mesotheliomas (10/18) and in all of the sarcomatoid mesotheliomas (22/22). Methylation of p16 was observed in 7 (20.6%) of 34 informative cases. p16 FISH analysis can be a reliable test for distinguishing between sarcomatoid mesothelioma and fibrous pleuritis and a prognostic factor for MPM.
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Affiliation(s)
- Di Wu
- Department of Pathology, Tokyo Women’s Medical University Yachiyo Medical Center, Yachiyo, Japan
| | - Kenzo Hiroshima
- Department of Pathology, Tokyo Women’s Medical University Yachiyo Medical Center, Yachiyo, Japan
| | | | | | - Toshikazu Yusa
- Department of Thoracic Surgery, Chiba Rosai Hospital, Ichihara, Japan
| | - Daisuke Ozaki
- Department of Pathology, Chiba Rosai Hospital, Ichihara, Japan
| | - Michio Fujino
- Department of Thoracic Surgery, Chiba Medical Center, Chiba, Japan
| | - Hisami Yamakawa
- Department of Thoracic Surgery, Yarita Hospital, Ichihara, Japan
| | - Yukio Nakatani
- Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yuji Tada
- Department of Respirology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hideaki Shimada
- Department of Surgery, School of Medicine, Toho University, Tokyo, Japan
| | - Masatoshi Tagawa
- Division of Pathology and Cell Therapy, Chiba Cancer Center Research Institute, Chiba, Japan
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Ambrogi V, Mineo TC. Clinical and biologic prognostic factors in malignant pleural mesothelioma. Thorac Cancer 2012; 3:289-302. [PMID: 28920270 DOI: 10.1111/j.1759-7714.2012.00127.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Malignant pleural mesothelioma is an extremely aggressive neoplasm of the pleura mainly attributable to asbestos exposure. Conventional medical, physical, and surgical treatments and their combinations are basically ineffective and just a few subjects experience some benefit. No definite guidelines can be provided in patient selection and therapeutic strategies. Currently, malignant pleural mesothelioma therapy is guided by clinical stage and patient characteristics, which are quite unreliable, rather than by the histological or molecular features of the tumor. In the present review the impact on prognosis of classic (i.e. etiology, age, gender, histology, staging), as well as relatively new clinical factors such as quality of life, positron emission tomography assessment, and occult residual disease, are firstly evaluated. In the second section of the review several biological variables and genetic markers, which have been recently recognized as the bases of the disease onset and development, are listed and discussed. There are serum and tissue markers. The latter are mainly related to cell cycle regulation, apoptosis, and growth factor pathways. These novel factors may play an important role in defining the prognosis of the disease and, subsequently, may have a place in addressing therapy.
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Affiliation(s)
- Vincenzo Ambrogi
- Department of Thoracic Surgery, Tor Vergata University, Rome, Italy
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- Department of Thoracic Surgery, Tor Vergata University, Rome, Italy
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Amatya VJ, Takeshima Y, Aoe K, Fujimoto N, Okamoto T, Yamada T, Kishimoto T, Morimoto C, Inai K. CD9 expression as a favorable prognostic marker for patients with malignant mesothelioma. Oncol Rep 2012; 29:21-8. [PMID: 23128478 PMCID: PMC3583601 DOI: 10.3892/or.2012.2116] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Accepted: 10/02/2012] [Indexed: 11/25/2022] Open
Abstract
CD9 is involved in cell growth, adhesion and motility and its expression is reported to be of prognostic significance in various types of human malignancies. We found increased cell migration in the mesothelioma cell lines MSTO-211H and TUM1 following in vitro shRNA-mediated knockdown of CD9 expression. We investigated CD9 expression in 112 malignant pleural mesotheliomas. CD9 expression was observed in 62 of 71 epithelioid, 13 of 20 biphasic and only 1 of 21 sarcomatoid mesotheliomas. Among the epithelioid mesotheliomas (EMs), CD9 expression was observed in all of the 33 cases with a differentiated type (EM-D) and in 29 of the 38 cases with a less-differentiated type (EM-LD). Patients with CD9 expression showed higher 1- and 2-year survival rates (63 and 25%) compared to the patients without CD9 expression (39 and 11%). Univariate analysis revealed that patients with CD9 expression demonstrated a more favorable survival (P=0.0025) along with other clinicopathological factors, including age younger than 60 years, IMIG stage I–II, epithelioid histology, EM-D and patients who underwent extrapleural pneumonectomy or received chemotherapy. Multivariate analysis identified CD9 expression as an independent prognostic factor with a hazard ratio (HR) of 1.99 in the analysis of all mesotheliomas (P=0.0261) and an HR of 2.60 in the analysis of EMs (P=0.0376). CD9 expression is an independent favorable prognostic marker of malignant mesothelioma.
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Affiliation(s)
- Vishwa Jeet Amatya
- Department of Pathology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.
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Aberrant expression of cell cycle regulatory genes predicts overall and disease free survival in malignant pleural mesothelioma patients. Exp Mol Pathol 2012; 93:154-61. [DOI: 10.1016/j.yexmp.2012.04.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2012] [Revised: 03/05/2012] [Accepted: 04/02/2012] [Indexed: 01/15/2023]
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Fujii M, Fujimoto N, Hiraki A, Gemba K, Aoe K, Umemura S, Katayama H, Takigawa N, Kiura K, Tanimoto M, Kishimoto T. Aberrant DNA methylation profile in pleural fluid for differential diagnosis of malignant pleural mesothelioma. Cancer Sci 2012; 103:510-4. [PMID: 22146010 DOI: 10.1111/j.1349-7006.2011.02180.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Malignant pleural mesothelioma (MPM) usually develops pleural fluid. We investigated the value of DNA methylation in the pleural fluid for differentiating MPM from lung cancer (LC). Pleural fluid was collected from 39 patients with MPM, 46 with LC, 25 with benign asbestos pleurisy (BAP) and 30 with other causes. The methylation of O(6)-methylguanine-DNA methyltransferase (MGMT), p16(INK4a) , ras association domain family 1A (RASSF1A), death-associated protein kinase (DAPK), and retinoic acid receptor β (RARβ) was examined using quantitative real-time PCR. DNA methylation of RASSF1A, p16(INK4a), RARβ, MGMT and DAPK was detected in 12 (30.8%), 3 (7.7%), 11 (28.2%), 0 (0.0%) and five patients (12.8%) with MPM, and in 22 (47.8%), 14 (30.4%), 24 (52.2%), 1 (2.2%) and six patients (13.0%) with LC, respectively. The mean methylation ratios of RASSF1A, p16(INK4a) and RARβ were 0.37 (range 0.0-2.84), 0.11 (0.0-2.67) and 0.44 (0.0-3.32) in MPM, and 0.87 (0.0-3.14), 1.16 (0.0-5.35) and 1.69 (0.0-6.49) in LC, respectively. The methylation ratios for the three genes were significantly higher in LC than in MPM (RASSF1A, P = 0.039; p16(INK4a), P = 0.005; and RARβ, P = 0.002). Patients with methylation in at least one gene were 3.51 (95% confidence interval, 1.09-11.34) times more likely to have LC. Hypermethylation seemed no greater with MPM than with BAP. Extended exposure to asbestos (≧30 years) was correlated with an increased methylation frequency (P = 0.020). Hypermethylation of tumor suppressor genes in pleural fluid DNA has the potential to be a valuable marker for differentiating MPM from LC.
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Affiliation(s)
- Masanori Fujii
- Department of Respiratory Medicine, Okayama Rosai Hospital, Okayama, Japan
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Demokan S, Chuang A, Suoğlu Y, Ulusan M, Yalnız Z, Califano JA, Dalay N. Promoter methylation and loss of p16(INK4a) gene expression in head and neck cancer. Head Neck 2011; 34:1470-5. [PMID: 22106032 DOI: 10.1002/hed.21949] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2011] [Revised: 07/25/2011] [Accepted: 09/05/2011] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Silencing of tumor suppressor genes plays a vital role in head and neck carcinogenesis. In this study we aimed to evaluate aberrant p16(INK4a) gene promoter methylation in patients with head and neck cancer. METHODS Methylation of the gene was investigated by bisulfite modification/methylation-specific polymerase chain reaction and gene expression levels were analyzed by quantitative reverse transcription-polymerase chain reaction in tumors and matched normal tissue samples from Turkish patients with head and neck cancer. RESULTS The promoter region of the p16(INK4a) gene was methylated in 67.5% and 28.6% of the primary tumors and the corresponding normal tissue, respectively. This difference was highly significant. In concordance, p16(INK4a) gene expression was downregulated in 67.5% of the tumor samples. Methylation and the absence of expression in the tumors were observed in 48% of the patients. CONCLUSIONS Our data indicate that methylation of the p16(INK4a) gene is a frequent event in primary head and neck cancer and that it plays a major role in the silencing of p16(INK4a) gene expression during tumor development.
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Affiliation(s)
- Semra Demokan
- Department of Basic Oncology, Oncology Institute, Istanbul University, Istanbul, Turkey
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Zucali PA, Ceresoli GL, De Vincenzo F, Simonelli M, Lorenzi E, Gianoncelli L, Santoro A. Advances in the biology of malignant pleural mesothelioma. Cancer Treat Rev 2011; 37:543-58. [PMID: 21288646 DOI: 10.1016/j.ctrv.2011.01.001] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2010] [Revised: 12/29/2010] [Accepted: 01/06/2011] [Indexed: 01/07/2023]
Abstract
Malignant pleural mesothelioma is a highly aggressive cancer with a very poor prognosis. Although the mechanism of carcinogenesis is not fully understood, approximately 80% of malignant pleural mesothelioma can be attributed to asbestos fiber exposure. This disease is largely unresponsive to conventional chemotherapy or radiotherapy, and most patients die within 10-17 months of their first symptoms. Currently, malignant pleural mesothelioma therapy is guided by clinical stage and patient characteristics rather than by the histological or molecular features of the tumor. Several molecular pathways involved in malignant pleural mesothelioma have been identified; these include cell cycle regulation, apoptosis, growth factor pathways, and angiogenesis. Unfortunately, several agents targeting these processes, including erlotinib, gefitinib, and imatinib, have proven ineffective in clinical trials. A greater understanding of the molecular pathways involved in malignant pleural mesothelioma is needed to develop better diagnostics, therapeutics, and preventative measures. Moreover, understanding the biological basis of mesothelioma progression may facilitate personalized treatment approaches, and early identification of poor prognostic indicators may help reduce the heterogeneity of the clinical response. This paper reviews advances in the molecular biology of malignant pleural mesothelioma in terms of pathogenesis, the major molecular pathways and the associated therapeutic strategies, and the roles of biomarkers.
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Affiliation(s)
- P A Zucali
- Department of Medical Oncology, Istituto Clinico Humanitas, Via Manzoni 56, 20089 Rozzano, Milan, Italy.
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Affiliation(s)
- Dean A Fennell
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, BT9 7BL, Northern Ireland, UK.
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CDKN2A and MTAP deletions in peritoneal mesotheliomas are correlated with loss of p16 protein expression and poor survival. Mod Pathol 2010; 23:531-8. [PMID: 20081810 DOI: 10.1038/modpathol.2009.186] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Homozygous deletion of CDKN2A (p16) is one of the most common genetic alterations in pleural mesotheliomas, occurring in up to 74% of cases. MTAP resides in the same gene cluster of the 9p21 region and is co-deleted in the majority of CDKN2A deleted cases. This study examines the genetic alterations in peritoneal mesotheliomas, which may have a different pathogenesis than their pleural counterparts. Twenty-six cases of peritoneal mesotheliomas in a triplicate tissue microarray were studied. Dual-color fluorescence in situ hybridization was performed with CDKN2A and MTAP locus-specific probes. Nine of 26 (35%) peritoneal mesotheliomas had homozygous deletion of CDKN2A; MTAP was co-deleted in every case. All cases with CDKN2A deletions had loss of p16 protein expression; five cases had loss of p16 protein without evidence of CDKN2A deletions. All patients with CDKN2A deletions were men (P, NS) and were significantly older (mean, 63 years) than the patients with no deletions (mean, 52 years) (P=0.033, t-test). An association with asbestos exposure could not be proved in this study. Similar to pleural mesotheliomas, patients with CDKN2A deletions and loss of p16 protein expression had worse overall and disease-specific survival (P=0.010 and 0.006, respectively; Kaplan-Meier log rank). Detection of CDKN2A-MTAP co-deletion in peritoneal mesotheliomas, coupled with a p16 immunohistochemical stain as an inexpensive screening tool, can help identify those patients who may have an unfavorable outcome after aggressive cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy and those who may respond to targeted therapy of the MTAP pathway.
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Abstract
Malignant mesothelioma (MM) is a rare primary malignant tumor of the surface serosal cells. The diagnosis of MM is challenging with a broad differential diagnosis. For many decades, studies have focused on distinguishing MM from other types of cancer; however, benign mesothelial cell hyperplasia, especially in small biopsies, has emerged as a major problem. The features of pleural lesions are somewhat different from peritoneal diseases, and this article primarily focuses on pleural diseases. Thorough interpretation and correlation of clinical, radiologic, and pathologic findings are essential for a correct diagnosis.
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Affiliation(s)
- E Handan Zeren
- Department of Pathology, Faculty of Medicine, Çukurova University, Adana 01330, Turkey; Department of Pathology, Acıbadem Medical Group, Maslak Hospital, Büyükdere Caddesi 40, Istanbul 34457, Turkey.
| | - Funda Demirag
- Department of Pathology, Atatürk Chest Diseases and Chest Surgery Education and Research Hospital, Ankara 06280, Turkey
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Bowman RV, Wright CM, Davidson MR, Francis SMS, Yang IA, Fong KM. Epigenomic targets for the treatment of respiratory disease. Expert Opin Ther Targets 2009; 13:625-40. [PMID: 19409032 DOI: 10.1517/14728220902926119] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND A number of processes lead to epigenetic and epigenomic modifications. OBJECTIVE To address the importance of epigenomics in respiratory disease. METHODS Studies of epigenomics were analysed in relation to chronic respiratory diseases. RESULTS/CONCLUSION In lung cancer and mesothelioma, a number of genes involved in carcinogenesis have been demonstrated to be hypermethylated, implicating epigenomic changes in the aetiology of these cancers. Hypermethylated genes have also been associated with lung cancer recurrence, indicating epigenomic regulation of metastasis. In airway diseases, modulation of histone function may activate inflammatory mechanisms in chronic obstructive pulmonary disease patients and lead to relative steroid resistance. There is emerging evidence for the role of epigenetic changes in chronic lung diseases such as asthma, including responses to environmental exposures in utero and to the effects of air pollution. Insight into epigenomics will lead to the development of novel biomarkers and treatment targets in respiratory diseases.
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Affiliation(s)
- Rayleen V Bowman
- The Prince Charles Hospital, Department of Thoracic Medicine, Brisbane, Australia.
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