{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T16:03:28Z","timestamp":1784217808335,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T00:00:00Z","timestamp":1693267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007076","name":"AIRC","doi-asserted-by":"publisher","award":["IG ID19797"],"award-info":[{"award-number":["IG ID19797"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007076","name":"AIRC","doi-asserted-by":"publisher","award":["GR-2016-02361229"],"award-info":[{"award-number":["GR-2016-02361229"]}],"id":[{"id":"10.13039\/501100007076","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"MOH","doi-asserted-by":"publisher","award":["IG ID19797"],"award-info":[{"award-number":["IG ID19797"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"MOH","doi-asserted-by":"publisher","award":["GR-2016-02361229"],"award-info":[{"award-number":["GR-2016-02361229"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Aim: DNA repair has an important role in malignant pleural mesothelioma (MPM) tumorigenesis and progression. Prognostic\/predictive biomarkers for better management of MPM patients are needed. In the present manuscript, we analyzed the expression of more than 700 genes in a cohort of MPM patients to possibly find biomarkers correlated with survival. Methods: A total of 54 MPM patients, all with epithelioid histology, whose survival follow-up and formalin-fixed paraffin-embedded tumors were available, were included in the study. Gene expression profiles were evaluated using a Nanostring platform analyzing 760 genes involved in different cellular pathways. The percentages of proliferating tumor cells positive for RAD51 and BRCA1 foci were evaluated using an immunofluorescence assay, as a readout of homologous recombination repair status. Results: Patient median survival time was 16.9 months, and based on this value, they were classified as long and short survivors (LS\/SS) with, respectively, an overall survival \u2265 and &lt;16.9 months as well as very long and very short survivors (VLS\/VSS) with an overall survival \u2265 than 33.8 and &lt; than 8.45 months. A down-regulation in the DNA damage\/repair expression score was observed in LS and VLS as compared to SS and VSS. These findings were validated by the lower number of both RAD51 and BRCA1-positive tumor cells in VLS as compared to VSS. Conclusions: The down-regulation of DNA repair signature in VLS was functionally validated by a lower % of RAD51 and BRCA1-positive tumor cells. If these data can be corroborated in a prospective trial, an easy, cost-effective test could be routinely used to better manage treatment in MPM patients.<\/jats:p>","DOI":"10.3390\/cancers15174309","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T08:51:14Z","timestamp":1693299074000},"page":"4309","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Epithelioid Mesothelioma Patients with Very Long Survival Display Defects in DNA Repair"],"prefix":"10.3390","volume":"15","author":[{"given":"Monica","family":"Ganzinelli","sequence":"first","affiliation":[{"name":"Unit of Thoracic Oncology, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7723-9974","authenticated-orcid":false,"given":"Federica","family":"Guffanti","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical Gynecological Oncology, Department of Experimental Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Ianza","sequence":"additional","affiliation":[{"name":"Oncology Department, University Health Organization Giuliano Isontina, ASUGI, Piazza Ospitale 1, 34129 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1381-0283","authenticated-orcid":false,"given":"Navid","family":"Sobhani","sequence":"additional","affiliation":[{"name":"Department of Medical, Surgical and Health Sciences, University of Trieste, 34139 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8493-1168","authenticated-orcid":false,"given":"Sergio","family":"Crovella","sequence":"additional","affiliation":[{"name":"IRCCS Burlo Garofolo, Via dell\u2019Istria 65\/1, 34137 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrizio","family":"Zanconati","sequence":"additional","affiliation":[{"name":"Department of Medical, Surgical and Health Sciences, University of Trieste, 34139 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Bottin","sequence":"additional","affiliation":[{"name":"Department of Medical, Surgical and Health Sciences, University of Trieste, 34139 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4791-768X","authenticated-orcid":false,"given":"Marco","family":"Confalonieri","sequence":"additional","affiliation":[{"name":"Department of Medical, Surgical and Health Sciences, University of Trieste, 34139 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Fumagalli","sequence":"additional","affiliation":[{"name":"Laboratory of Biology of Neurodegenerative Disorders, Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Guglielmi","sequence":"additional","affiliation":[{"name":"Oncology Department, University Health Organization Giuliano Isontina, ASUGI, Piazza Ospitale 1, 34129 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6002-1530","authenticated-orcid":false,"given":"Daniele","family":"Generali","sequence":"additional","affiliation":[{"name":"Oncology Department, University Health Organization Giuliano Isontina, ASUGI, Piazza Ospitale 1, 34129 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9749-434X","authenticated-orcid":false,"given":"Giovanna","family":"Damia","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical Gynecological Oncology, Department of Experimental Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"238","DOI":"10.21037\/atm.2017.04.29","article-title":"Mesothelioma: Recent highlights","volume":"5","author":"Carbone","year":"2017","journal-title":"Ann. Transl. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1702384","DOI":"10.1183\/13993003.02384-2017","article-title":"Variation in incidence trends of malignant pleural mesothelioma in Europe","volume":"51","author":"Ahmed","year":"2018","journal-title":"Eur. Respir. J."},{"key":"ref_3","first-page":"1","article-title":"An Update on Emerging Therapeutic Options for Malignant Pleural Mesothelioma","volume":"13","author":"Davis","year":"2022","journal-title":"Lung Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Rondon, L., Fu, R., and Patel, M.R. (2023). Success of Checkpoint Blockade Paves the Way for Novel Immune Therapy in Malignant Pleural Mesothelioma. Cancers, 15.","DOI":"10.3390\/cancers15112940"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.celrep.2018.03.076","article-title":"Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas","volume":"23","author":"Knijnenburg","year":"2018","journal-title":"Cell Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1186\/s12935-022-02597-9","article-title":"DNA repair and damage pathways in mesothelioma development and therapy","volume":"22","author":"Malakoti","year":"2022","journal-title":"Cancer Cell Int."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Panou, V., and Roe, O.D. (2020). Inherited Genetic Mutations and Polymorphisms in Malignant Mesothelioma: A Comprehensive Review. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21124327"},{"key":"ref_8","first-page":"4236","article-title":"Inherited predisposition to malignant mesothelioma: Germline BAP1 mutations and beyond","volume":"25","author":"Pagliuca","year":"2021","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9008","DOI":"10.1073\/pnas.1821510116","article-title":"Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy","volume":"116","author":"Hassan","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.jtho.2019.12.111","article-title":"Novel Germline Mutations in DNA Damage Repair in Patients with Malignant Pleural Mesotheliomas","volume":"15","author":"Guo","year":"2020","journal-title":"J. Thorac. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.ejca.2021.12.023","article-title":"Malignant pleural mesothelioma: Germline variants in DNA repair genes may steer tailored treatment","volume":"163","author":"Sculco","year":"2022","journal-title":"Eur. J. Cancer"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1158\/2159-8290.CD-15-0714","article-title":"Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer","volume":"5","author":"Konstantinopoulos","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1007\/s11523-023-00970-w","article-title":"PARP Inhibitors in Ovarian Cancer: A Review","volume":"18","author":"Krivak","year":"2023","journal-title":"Target. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.1200\/JCO.2018.78.5204","article-title":"Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma","volume":"36","author":"Panou","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_15","first-page":"100231","article-title":"Phase 2 Study of Olaparib in Malignant Mesothelioma and Correlation of Efficacy with Germline or Somatic Mutations in BAP1 Gene","volume":"2","author":"Ghafoor","year":"2021","journal-title":"JTO Clin. Res. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/S2213-2600(20)30390-8","article-title":"Rucaparib in patients with BAP1-deficient or BRCA1-deficient mesothelioma (MiST1): An open-label, single-arm, phase 2a clinical trial","volume":"9","author":"King","year":"2021","journal-title":"Lancet Respir. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1002\/gcc.22670","article-title":"Sensitivity to asbestos is increased in patients with mesothelioma and pathogenic germline variants in BAP1 or other DNA repair genes","volume":"57","author":"Betti","year":"2018","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1093\/carcin\/bgu227","article-title":"Mesothelioma patients with germline BAP1 mutations have 7-fold improved long-term survival","volume":"36","author":"Baumann","year":"2015","journal-title":"Carcinogenesis"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/s13073-019-0620-3","article-title":"BAP1 haploinsufficiency predicts a distinct immunogenic class of malignant peritoneal mesothelioma","volume":"11","author":"Shrestha","year":"2019","journal-title":"Genome Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Thomas, M., Dubacq, C., Rabut, E., Lopez, B.S., and Guirouilh-Barbat, J. (2023). Noncanonical Roles of RAD51. Cells, 12.","DOI":"10.3390\/cells12081169"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1016\/j.ygyno.2020.08.035","article-title":"Homologous recombination deficiency real-time clinical assays, ready or not?","volume":"159","author":"Fuh","year":"2020","journal-title":"Gynecol. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1038\/s41416-021-01609-1","article-title":"Basal expression of RAD51 foci predicts olaparib response in patient-derived ovarian cancer xenografts","volume":"126","author":"Guffanti","year":"2022","journal-title":"Br. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1646","DOI":"10.1158\/0008-5472.CAN-21-2409","article-title":"Preclinical In Vivo Validation of the RAD51 Test for Identification of Homologous Recombination-Deficient Tumors and Patient Stratification","volume":"82","author":"Pellegrino","year":"2022","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.1093\/bioinformatics\/bts188","article-title":"NanoStringNorm: An extensible R package for the pre-processing of NanoString mRNA and miRNA data","volume":"28","author":"Waggott","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_25","unstructured":"(2023, August 20). Available online: http:\/\/media.aiom.it\/userfiles\/files\/doc\/LG\/2017_LGAIOM_Mesotelioma.pdf."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"102948","DOI":"10.1016\/j.dnarep.2020.102948","article-title":"Roles for MDC1 in cancer development and treatment","volume":"95","author":"Ruff","year":"2020","journal-title":"DNA Repair"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"111935","DOI":"10.1016\/j.yexcr.2020.111935","article-title":"Pleiotropic roles of tankyrase\/PARP proteins in the establishment and maintenance of human naive pluripotency","volume":"390","author":"Zimmerlin","year":"2020","journal-title":"Exp. Cell Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1056\/NEJMra1912719","article-title":"Perspectives on the Treatment of Malignant Pleural Mesothelioma","volume":"385","author":"Janes","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1743-8977-7-5","article-title":"Asbestos, carbon nanotubes and the pleural mesothelium: A review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesothelioma","volume":"7","author":"Donaldson","year":"2010","journal-title":"Part. Fibre Toxicol."},{"key":"ref_30","first-page":"5922","article-title":"Role of oxyradicals in mutagenicity and DNA damage induced by crocidolite asbestos in mammalian cells","volume":"59","author":"Xu","year":"1999","journal-title":"Cancer Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"660039","DOI":"10.3389\/fonc.2021.660039","article-title":"Tumor Immune Microenvironment and Genetic Alterations in Mesothelioma","volume":"11","author":"Hiltbrunner","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.canlet.2017.06.028","article-title":"Germline mutations in DNA repair genes predispose asbestos-exposed patients to malignant pleural mesothelioma","volume":"405","author":"Betti","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"100744","DOI":"10.1016\/j.drup.2021.100744","article-title":"Overcoming PARPi resistance: Preclinical and clinical evidence in ovarian cancer","volume":"55","author":"Chiappa","year":"2021","journal-title":"Drug Resist. Updat."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Borchert, S., Wessolly, M., Schmeller, J., Mairinger, E., Kollmeier, J., Hager, T., Mairinger, T., Herold, T., Christoph, D.C., and Walter, R.F.H. (2019). Gene expression profiling of homologous recombination repair pathway indicates susceptibility for olaparib treatment in malignant pleural mesothelioma in vitro. BMC Cancer, 19.","DOI":"10.1186\/s12885-019-5314-0"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2134","DOI":"10.1007\/s00268-017-4424-6","article-title":"A Nomogram to Predict Prognosis in Malignant Pleural Mesothelioma","volume":"42","author":"Wang","year":"2018","journal-title":"World J. Surg."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Mannarino, L., Paracchini, L., Pezzuto, F., Olteanu, G.E., Moracci, L., Vedovelli, L., De Simone, I., Bosetti, C., Lupi, M., and Amodeo, R. (2022). Epithelioid Pleural Mesothelioma Is Characterized by Tertiary Lymphoid Structures in Long Survivors: Results from the MATCH Study. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105786"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"838","DOI":"10.3892\/or.2020.7669","article-title":"Connective tissue growth factor produced by cancer-associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma","volume":"44","author":"Ohara","year":"2020","journal-title":"Oncol. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.ebiom.2019.09.003","article-title":"Redefining malignant pleural mesothelioma types as a continuum uncovers immune-vascular interactions","volume":"48","author":"Alcala","year":"2019","journal-title":"eBioMedicine"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"102101","DOI":"10.1016\/j.ctrv.2020.102101","article-title":"Is DNA repair a potential target for effective therapies against malignant mesothelioma?","volume":"90","author":"Roca","year":"2020","journal-title":"Cancer Treat. Rev."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/17\/4309\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:41:22Z","timestamp":1760128882000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/15\/17\/4309"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,29]]},"references-count":39,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["cancers15174309"],"URL":"https:\/\/doi.org\/10.3390\/cancers15174309","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,29]]}}}