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      Prediction and prognostic significance of BCAR3 expression in patients with multiple myeloma

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          Abstract

          Background

          Multiple myeloma (MM) is the plasma cell tumor, which is characterized by clonal proliferation of tumor cells, with high risk of progression to renal impairment, bone damage and amyloidosis. Although the survival rate of patients with MM has improved in the past decade, most people inevitably relapse. The treatment and prognosis of MM are still urgent problems. Breast Cancer Antiestrogen Resistance 3 (BCAR3) is a protein-coding gene that is associated with many tumors. However, there have been few studies on the relationship of BCAR3 and MM.

          Methods

          We analyzed 1878 MM patients (1930 samples) from 7 independent datasets. First, we compared the BCAR3 expression level of MM patients in different stages and MM patients with different amplification of 1q21. Second, we analyzed BCAR3 expression levels in MM patients with different molecular subtypes. Finally, we explored the event-free survival rate (EFS) and overall survival rate (OS) of MM patients with high or low BCAR3 expression, including patients before and after relapse, and their therapeutic responses to bortezomib and dexamethasone.

          Results

          The expression of BCAR3 showed a decreasing trend in stages I, II and III (P = 0.00068). With the increase of 1q21 amplification level, the expression of BCAR3 decreased (P = 0.022). Patients with high BCAR3 expression had higher EFS and OS (EFS: P < 0.0001, OS: P < 0.0001). The expression of BCAR3 gene before relapse was higher than that after relapse (P = 0.0045). BCAR3 is an independent factor affecting prognosis (EFS: P = 5.17E−03; OS: P = 3.33E−04).

          Conclusion

          We found that high expression level of BCAR3 predicted better prognosis of MM patients. Low expression of BCAR3 at diagnosis can predict early relapse. BCAR3 is an independent prognostic factor for MM. BCAR3 can be used as a potential biomarker.

          Electronic supplementary material

          The online version of this article (10.1186/s12967-018-1728-8) contains supplementary material, which is available to authorized users.

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          Most cited references31

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          Reduced mortality after allogeneic hematopoietic-cell transplantation.

          Over the past decade, advances have been made in the care of patients undergoing transplantation. We conducted a study to determine whether these advances have improved the outcomes of transplantation. We analyzed overall mortality, mortality not preceded by relapse, recurrent malignant conditions, and the frequency and severity of major complications of transplantation, including graft-versus-host disease (GVHD) and hepatic, renal, pulmonary, and infectious complications, among 1418 patients who received their first allogeneic transplants at our center in Seattle in the period from 1993 through 1997 and among 1148 patients who received their first allogeneic transplants in the period from 2003 through 2007. Components of the Pretransplant Assessment of Mortality (PAM) score were used in regression models to adjust for the severity of illness at the time of transplantation. In the 2003-2007 period, as compared with the 1993-1997 period, we observed significant decreases in mortality not preceded by relapse, both at day 200 (by 60%) and overall (by 52%), the rate of relapse or progression of a malignant condition (by 21%), and overall mortality (by 41%), after adjustment for components of the PAM score. The results were similar when the analyses were limited to patients who received myeloablative conditioning therapy. We also found significant decreases in the risk of severe GVHD; disease caused by viral, bacterial, and fungal infections; and damage to the liver, kidneys, and lungs. We found a substantial reduction in the hazard of death related to allogeneic hematopoietic-cell transplantation, as well as increased long-term survival, over the past decade. Improved outcomes appear to be related to reductions in organ damage, infection, and severe acute GVHD. (Funded by the National Institutes of Health.).
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            The molecular classification of multiple myeloma.

            To better define the molecular basis of multiple myeloma (MM), we performed unsupervised hierarchic clustering of mRNA expression profiles in CD138-enriched plasma cells from 414 newly diagnosed patients who went on to receive high-dose therapy and tandem stem cell transplants. Seven disease subtypes were validated that were strongly influenced by known genetic lesions, such as c-MAF- and MAFB-, CCND1- and CCND3-, and MMSET-activating translocations and hyperdiploidy. Indicative of the deregulation of common pathways by gene orthologs, common gene signatures were observed in cases with c-MAF and MAFB activation and CCND1 and CCND3 activation, the latter consisting of 2 subgroups, one characterized by expression of the early B-cell markers CD20 and PAX5. A low incidence of focal bone disease distinguished one and increased expression of proliferation-associated genes of another novel subgroup. Comprising varying fractions of each of the other 6 subgroups, the proliferation subgroup dominated at relapse, suggesting that this signature is linked to disease progression. Proliferation and MMSET-spike groups were characterized by significant overexpression of genes mapping to chromosome 1q, and both exhibited a poor prognosis relative to the other groups. A subset of cases with a predominating myeloid gene expression signature, excluded from the profiling analyses, had more favorable baseline characteristics and superior prognosis to those lacking this signature.
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              NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers.

              Using sequential gene expression profiling (GEP) samples, we defined a major functional group related to drug resistance that contains chromosomal instability (CIN) genes. One CIN gene in particular, NEK2, was highly correlated with drug resistance, rapid relapse, and poor outcome in multiple cancers. Overexpressing NEK2 in cancer cells resulted in enhanced CIN, cell proliferation and drug resistance, while targeting NEK2 by NEK2 shRNA overcame cancer cell drug resistance and induced apoptosis in vitro and in a xenograft myeloma mouse model. High expression of NEK2 induced drug resistance mainly through activation of the efflux pumps. Thus, NEK2 represents a strong predictor for drug resistance and poor prognosis in cancer and could be an important target for cancer therapy. Copyright © 2013 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                zhangwl2012@126.com
                1175312943@qq.com
                xiaoniliu1203@163.com
                hexue8@163.com
                zhangye816zy@163.com
                fwmark516@126.com
                bgiyangzuozhen@gmail.com
                yangping198302@163.com
                crystal_bmu@163.com
                xiaohu7079@sina.com
                zhangxiuru999@163.com
                gzweiyou@163.com
                yxlyyxs@126.com
                drjinghm@163.com
                Journal
                J Transl Med
                J Transl Med
                Journal of Translational Medicine
                BioMed Central (London )
                1479-5876
                18 December 2018
                18 December 2018
                2018
                : 16
                : 363
                Affiliations
                [1 ]ISNI 0000 0004 0605 3760, GRID grid.411642.4, Department of Hematology, Lymphoma Research Center, , Peking University Third Hospital, ; No. 49 North Garden Road, Haidian District, Beijing, 100191 People’s Republic of China
                [2 ]GRID grid.440714.2, Gannan Medical University, ; Ganzhou, 341000 China
                [3 ]GRID grid.452437.3, Department of Respiratory Medicine, , The First Affiliated Hospital of Gannan Medical University, ; No. 23 Qingnian Road, Zhanggong District, Ganzhou, 341000 People’s Republic of China
                [4 ]ISNI 0000 0004 0642 1244, GRID grid.411617.4, Department of Pathology, , Beijing Tiantan Hospital Affiliated With Capital Medical University, ; No. 6 Tiantan Xili, Beijing, 100050 China
                [5 ]ISNI 0000 0001 2179 088X, GRID grid.1008.9, Melbourne School of Population and Global Health, , The University of Melbourne, ; Melbourne, VIC 3010 Australia
                [6 ]ISNI 0000 0004 0605 3760, GRID grid.411642.4, Peking University Third Hospital, ; Beijing, 100191 China
                Article
                1728
                10.1186/s12967-018-1728-8
                6299524
                30563570
                14abde6f-e45c-4287-9861-44e50ad489b1
                © The Author(s) 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 1 October 2018
                : 5 December 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100004826, Natural Science Foundation of Beijing Municipality;
                Award ID: 7132183
                Award ID: CHPF-zlkysx-001
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100009399, Peking University Third Hospital;
                Award ID: BMU2018MB004
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2018

                Medicine
                bcar3,multiple myeloma,prognosis,gene expression profile
                Medicine
                bcar3, multiple myeloma, prognosis, gene expression profile

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