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      Consensus Report of the 2015 Weinman International Conference on Mesothelioma

      , MD, PhD a , , PhD a , b , , PhD c , , MD d , , PhD e , , MD f , , MD, PhD g , , PhD h , , MD, PhD i , , PhD j , , MD k , , PhD l , , PhD m , , PhD n , , MD o , , NP p , , MD, PhD q , , PhD a , , PhD r , , PhD s , , PhD t , , DSc, FMedSci u , , Phd v , , MD w , , MD x , , MD y , , PhD a , , MD z

      Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

      Mesothelioma, BAP1, Asbestos, Erionite, Biomarkers, Genetics, Therapy

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          On November 9 and 10, 2015, the International Conference on Mesothelioma in Populations Exposed to Naturally Occurring Asbestiform Fibers was held at the University of Hawaii Cancer Center in Honolulu, Hawaii. The meeting was cosponsored by the International Association for the Study of Lung Cancer, and the agenda was designed with significant input from staff at the U.S. National Cancer Institute and National Institute of Environmental Health Sciences. A multidisciplinary group of participants presented updates reflecting a range of disciplinary perspectives, including mineralogy, geology, epidemiology, toxicology, biochemistry, molecular biology, genetics, public health, and clinical oncology. The group identified knowledge gaps that are barriers to preventing and treating malignant mesothelioma (MM) and the required next steps to address barriers. This manuscript reports the group’s efforts and focus on strategies to limit risk to the population and reduce the incidence of MM. Four main topics were explored: genetic risk, environmental exposure, biomarkers, and clinical interventions. Genetics plays a critical role in MM when the disease occurs in carriers of germline BRCA1 associated protein 1 mutations. Moreover, it appears likely that, in addition to BRCA1 associated protein 1, other yet unknown genetic variants may also influence the individual risk for development of MM, especially after exposure to asbestos and related mineral fibers. MM is an almost entirely preventable malignancy as it is most often caused by exposure to commercial asbestos or mineral fibers with asbestos-like health effects, such as erionite. In the past in North America and in Europe, the most prominent source of exposure was related to occupation. Present regulations have reduced occupational exposure in these countries; however, some people continue to be exposed to previously installed asbestos in older construction and other settings. Moreover, an increasing number of people are being exposed in rural areas that contain noncommercial asbestos, erionite, and other mineral fibers in soil or rock (termed naturally occurring asbestos [NOA]) and are being developed. Public health authorities, scientists, residents, and other affected groups must work together in the areas where exposure to asbestos, including NOA, has been documented in the environment to mitigate or reduce this exposure. Although a blood biomarker validated to be effective for use in screening and identifying MM at an early stage in asbestos/ NOA-exposed populations is not currently available, novel biomarkers presented at the meeting, such as high mobility group box 1 and fibulin-3, are promising. There was general agreement that current treatment for MM, which is based on surgery and standard chemotherapy, has a modest effect on the overall survival (OS), which remains dismal. Additionally, although much needed novel therapeutic approaches for MM are being developed and explored in clinical trials, there is a critical need to invest in prevention research, in which there is a great opportunity to reduce the incidence and mortality from MM.

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          Most cited references 121

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          BAP1 loss defines a new class of renal cell carcinoma

          The molecular pathogenesis of renal cell carcinoma (RCC) is poorly understood. Whole-genome and exome sequencing followed by innovative tumorgraft analyses (to accurately determine mutant allele ratios) identified several putative two-hit tumor suppressor genes including BAP1. BAP1, a nuclear deubiquitinase, is inactivated in 15% of clear-cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation, but not H2AK119ub1 deubiquitination. BAP1 loss sensitizes RCC cells in vitro to genotoxic stress. Interestingly, BAP1 and PBRM1 mutations anticorrelate in tumors (P=3×10−5), and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features (q=0.0007). BAP1 and PBRM1 regulate seemingly different gene expression programs, and BAP1 loss was associated with high tumor grade (q=0.0005). Our results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.
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            Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB.

            Polycomb group (PcG) proteins are transcriptional repressors that control processes ranging from the maintenance of cell fate decisions and stem cell pluripotency in animals to the control of flowering time in plants. In Drosophila, genetic studies identified more than 15 different PcG proteins that are required to repress homeotic (HOX) and other developmental regulator genes in cells where they must stay inactive. Biochemical analyses established that these PcG proteins exist in distinct multiprotein complexes that bind to and modify chromatin of target genes. Among those, Polycomb repressive complex 1 (PRC1) and the related dRing-associated factors (dRAF) complex contain an E3 ligase activity for monoubiquitination of histone H2A (refs 1-4). Here we show that the uncharacterized Drosophila PcG gene calypso encodes the ubiquitin carboxy-terminal hydrolase BAP1. Biochemically purified Calypso exists in a complex with the PcG protein ASX, and this complex, named Polycomb repressive deubiquitinase (PR-DUB), is bound at PcG target genes in Drosophila. Reconstituted recombinant Drosophila and human PR-DUB complexes remove monoubiquitin from H2A but not from H2B in nucleosomes. Drosophila mutants lacking PR-DUB show a strong increase in the levels of monoubiquitinated H2A. A mutation that disrupts the catalytic activity of Calypso, or absence of the ASX subunit abolishes H2A deubiquitination in vitro and HOX gene repression in vivo. Polycomb gene silencing may thus entail a dynamic balance between H2A ubiquitination by PRC1 and dRAF, and H2A deubiquitination by PR-DUB.
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              Guidelines of the European Respiratory Society and the European Society of Thoracic Surgeons for the management of malignant pleural mesothelioma.

              Malignant pleural mesothelioma (MPM) is a rare tumour but with increasing incidence and a poor prognosis. In 2008, the European Respiratory Society/European Society of Thoracic Surgeons Task Force brought together experts to propose practical and up-to-dated guidelines on the management of MPM. To obtain an earlier and reliable diagnosis of MPM, the experts recommend performing thoracoscopy, except in cases of pre-operative contraindication or pleural symphysis. The standard staining procedures are insufficient in approximately 10% of cases. Therefore, we propose using specific immunohistochemistry markers on pleural biopsies. In the absence of a uniform, robust and validated staging system, we advice use of the most recent TNM based classification, and propose a three step pre-treatment assessment. Patient's performance status and histological subtype are currently the only prognostic factors of clinical importance in the management of MPM. Other potential parameters should be recorded at baseline and reported in clinical trials. MPM exhibits a high resistance to chemotherapy and only a few patients are candidates for radical surgery. New therapies and strategies have been reviewed. Because of limited data on the best combination treatment, we emphasise that patients who are considered candidates for a multimodal approach should be included in a prospective trial at a specialised centre.

                Author and article information

                J Thorac Oncol
                J Thorac Oncol
                Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
                28 June 2017
                August 2016
                10 August 2017
                : 11
                : 8
                : 1246-1262
                [a ]Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, Hawaii
                [b ]Samuel Oschin Comprehensive Cancer Institute and Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
                [c ]Center for Global Health, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
                [d ]National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
                [e ]Center to Reduce Cancer Health Disparities, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
                [f ]Respiratory Health Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia
                [g ]Mayo Clinic, Rochester, Minnesota
                [h ]ERIM, University of New Caledonia, Noumea, New Caledonia
                [i ]Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York
                [j ]Department of Geoscience, University of Nevada Las Vegas, Las Vegas, Nevada
                [k ]Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
                [l ]Chemical and Biochemical Engineering Department and Center for Global and Regional Environmental Research, University of Iowa, Iowa City, Iowa
                [m ]Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina
                [n ]Chemical/Earth Sciences Department, University of Modena, Modena, Italy
                [o ]Thoracic Oncology Branch, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland
                [p ]Mesothelioma Applied Research Foundation, Alexandria, Virginia
                [q ]University of Colorado Cancer Center, Denver, Colorado
                [r ]Cancer Research Institute, Zhejiang Cancer Hospital and Key Laboratory of Diagnosis and Treatment Technology on Thoracic Oncology of Zhejiang, Hangzhou, People’s Republic of China
                [s ]National Toxicology Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina
                [t ]Cardiothoracic Surgery, New York University Langone Medical Center, New York, New York
                [u ]Cancer Research UK, London School of Hygiene and Tropical Medicine, London, United Kingdom
                [v ]Department of Public Health and Pediatrics, University of Turin, Turin, Italy
                [w ]Notre Dame Integrated Imaging Facility, Notre Dame University, Notre Dame, Indiana
                [x ]Department of Thoracic and Head and Neck Medical Oncology, Division of Cancer Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
                [y ]Thoracic Surgery, University of California at San Francisco, San Francisco, California
                [z ]Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
                Author notes
                [* ]Address for correspondence: Michele Carbone, MD, PhD, University of Hawaii Cancer Center, 701 Ilalo St., Room #437, Honolulu, HI 96813. mcarbone@ 123456cc.hawaii.edu

                This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/).


                genetics, mesothelioma, bap1, asbestos, erionite, biomarkers, therapy


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