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      Biological Predictors of De Novo Tumors in Solid Organ Transplanted Patients During Oncological Surveillance: Potential Role of Circulating TERT mRNA

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          Abstract

          Background

          De novo tumors are a major cause of morbidity and mortality after long-term solid organ transplantation. Chronic immunosuppression strongly affects solid organ transplanted (SOT) patients’ immune system by promoting immune evasion strategies and reactivations of viruses with oncogenic potential, ultimately leading to cancer onset. In this scenario, an oncological Surveillance Protocol integrated with biobanking of peripheral blood samples and evaluation of immunovirological and molecular parameters was activated for SOT patients at CRO-IRCCS Aviano, with the aim of identifying suitable biomarkers of cancer development.

          Methods

          An exploratory longitudinal study was designed based on two serial peripheral blood samples collected at least three months apart. Forty nine SOT patients were selected and stratified by tumor onset during follow-up. Spontaneous T-cell responses to EBV, CMV and tumor associated antigens, EBV-DNA and CMV-DNA loads, and circulating TERT mRNA levels were investigated.

          Results

          Significantly higher levels of circulating TERT mRNA were observed 3.5-23.5 months before and close to the diagnosis of cancer as compared to tumor-free patients. Plasmatic TERT mRNA levels >97.73 copies/mL at baseline were significantly associated with the risk of developing de novo tumors (HR=4.0, 95%C.I. = 1.4-11.5, p=0.01). In particular, the risk significantly increased by 4% with every ten-unit increment in TERT mRNA (HR=1.04, 95%C.I. = 1.01-1.07, p=0.01).

          Conclusions

          Although obtained in an exploratory study, our data support the importance of identifying early biomarkers of tumor onset in SOT patients useful to modulate the pace of surveillance visits.

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          Most cited references63

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          The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                21 October 2021
                2021
                : 11
                : 772348
                Affiliations
                [1] 1 Department of Biomedical Sciences, University of Sassari , Sassari, Italy
                [2] 2 Immunopathology and Cancer Biomarkers, CRO Aviano, National Cancer Institute, IRCCS , Aviano, Italy
                [3] 3 Department of Surgery, Oncology and Gastroenterology, Section of Oncology and Immunology, University of Padova , Padova, Italy
                [4] 4 Cancer Epidemiology Unit, CRO Aviano, National Cancer Institute, IRCCS , Aviano, Italy
                [5] 5 Immunology and Diagnostic Molecular Oncology Unit, Veneto Institute of Oncology (IOV) – IRCCS , Padova, Italy
                [6] 6 Microbiology and Virology Unit, “S. Maria degli Angeli” Hospital , Pordenone, Italy
                [7] 7 Clinical Pathology, “S. Maria degli Angeli” Hospital , Pordenone, Italy
                [8] 8 Division of Medical Oncology A, Centro di Riferimento Oncologico (CRO) Aviano, National Cancer Institute, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) , Aviano, Italy
                [9] 9 Centre for Cancer Immunotherapy, Peter MacCallum Cancer Centre , Melbourne, VIC, Australia
                [10] 10 Sir Peter MacCallum Department of Oncology, The University of Melbourne , Melbourne, VIC, Australia
                [11] 11 Department of Microbiology and Immunology, The University of Melbourne , Melbourne, VIC, Australia
                [12] 12 Faculty of Medicine, The University of Queensland Diamantina Institute , Brisbane, QLD, Australia
                Author notes

                Edited by: Walter J. Storkus, University of Pittsburgh, United States

                Reviewed by: Diana Metes, University of Pittsburgh, United States; Gilda Alves Brown, Rio de Janeiro State University, Brazil

                *Correspondence: Riccardo Dolcetti, Riccardo.Dolcetti@ 123456petermac.org

                This article was submitted to Genitourinary Oncology, a section of the journal Frontiers in Oncology

                †These authors have contributed equally to this work and share first authorship

                ‡These authors have contributed equally to this work and share senior authorship

                Article
                10.3389/fonc.2021.772348
                8567137
                47948511-06e8-4890-8582-ead17c075827
                Copyright © 2021 Cangemi, Zanussi, Rampazzo, Bidoli, Giunco, Tedeschi, Pratesi, Martorelli, Casarotto, Martellotta, Schioppa, Serraino, Steffan, De Rossi, Dolcetti and Vaccher

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 09 September 2021
                : 30 September 2021
                Page count
                Figures: 2, Tables: 4, Equations: 0, References: 63, Pages: 12, Words: 7099
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                transplant,immunosuppression,oncological surveillance,cancer,circulating tert mrna,t cells

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