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      Cancer Risks in Solid Organ Transplant Recipients: Results from a Comprehensive Analysis of 72 Cohort Studies

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          ABSTRACT

          Understanding the cancer risks in different transplant recipients helps early detection, evaluation, and treatment of post-transplant malignancies. Therefore, we performed a meta-analysis to determine the cancer risks at multiple sites for solid organ transplant recipients and their associations with tumor mutation burden (TMB), which reflects the immunogenicity. A comprehensive search of PubMed, Web of Science, EMBASE, Medline, and Cochrane Library was conducted. Random effects models were used to calculate the standardized incidence ratios (SIRs) versus the general population and determine the risks of different cancers. Linear regression (LR) was used to analyze the association between the SIRs and TMBs. Finally, seventy-two articles met our criteria, involving 2,105,122 solid organ transplant recipients. Compared with the general population, solid organ transplant recipients displayed a 2.68-fold cancer risk (SIR 2.68; 2.48–2.89; P <.001), renal transplant recipients displayed a 2.56-fold cancer risk (SIR 2.56; 2.31–2.84; P <.001), liver transplant recipients displayed a 2.45-fold cancer risk (SIR 2.45; 2.22–2.70; P <.001), heart and/or lung transplant recipients displayed a 3.72-fold cancer risk (SIR 3.72; 3.04–4.54; P <.001). The correlation coefficients between SIRs and TMBs were 0.68, 0.64, 0.59, 0.79 in solid organ recipients, renal recipients, liver recipients, heart and/or lung recipients, respectively. In conclusion, our study demonstrated that solid organ transplant recipients displayed a higher risk of some site-specific cancers, providing individualized guidance for clinicians to early detect, evaluate, and treat cancer among solid organ transplantation recipients. In addition, the increased cancer risk of solid organ transplant recipients is associated with TMB, suggesting that iatrogenic immunosuppression may contribute to the increased cancer risk in transplant recipients. (PROSPERO ID CRD42020160409).

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          Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

          David Moher and colleagues introduce PRISMA, an update of the QUOROM guidelines for reporting systematic reviews and meta-analyses
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            Tumor Mutational Burden and Response Rate to PD-1 Inhibition

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              Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden

              Background High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types. Methods In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome. We then describe the distribution of TMB across a diverse cohort of 100,000 cancer cases and test for association between somatic alterations and TMB in over 100 tumor types. Results We demonstrate that measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly. We find that a subset of patients exhibits high TMB across almost all types of cancer, including many rare tumor types, and characterize the relationship between high TMB and microsatellite instability status. We find that TMB increases significantly with age, showing a 2.4-fold difference between age 10 and age 90 years. Finally, we investigate the molecular basis of TMB and identify genes and mutations associated with TMB level. We identify a cluster of somatic mutations in the promoter of the gene PMS2, which occur in 10% of skin cancers and are highly associated with increased TMB. Conclusions These results show that a CGP assay targeting ~1.1 Mb of coding genome can accurately assess TMB compared with sequencing the whole exome. Using this method, we find that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy. Finally, we identify novel, recurrent promoter mutations in PMS2, which may be another example of regulatory mutations contributing to tumorigenesis. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0424-2) contains supplementary material, which is available to authorized users.
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                Author and article information

                Journal
                Oncoimmunology
                Oncoimmunology
                Oncoimmunology
                Taylor & Francis
                2162-4011
                2162-402X
                29 November 2020
                2020
                29 November 2020
                : 9
                : 1
                : 1848068
                Affiliations
                [a ]Department of Thoracic Surgery and Oncology, China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University; , Guangzhou, China
                [b ]Nanshan School, Guangzhou Medical University; , Guangzhou, China
                [c ]Department of Transplantation, The First Affiliated Hospital of Guangzhou Medical University; , Guangzhou, China
                [d ]First Clinical School, Guangzhou Medical University; , Guangzhou, China
                Author notes
                Wenhua Liang liangwh1987@ 123456163.com Department of Thoracic Surgery and Oncology, the First Affiliated Hospital of Guangzhou Medical University; China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease. No. 151, Yanjiang Rd; , Guangzhou510120, Guangdong Province, China.
                [#]

                Huo ZY, Li CC, Xu X, Ge F are joint first authors.

                [*]

                He JX, Liang WH are joint corresponding authors.

                Author information
                https://orcid.org/0000-0002-9841-5081
                https://orcid.org/0000-0002-6599-8807
                https://orcid.org/0000-0003-1737-8192
                https://orcid.org/0000-0002-1391-8238
                Article
                1848068
                10.1080/2162402X.2020.1848068
                7714465
                db9a4d77-a7fa-475a-bed7-d96867351f24
                © 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                Page count
                Figures: 3, Tables: 1, References: 110, Pages: 1
                Categories
                Research Article
                Original Research

                Immunology
                solid organ transplantation; tumor mutational burden; cancer risk
                Immunology
                solid organ transplantation; tumor mutational burden; cancer risk

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