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      Determining consistent prognostic biomarkers of overall survival and vascular invasion in hepatocellular carcinoma

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          Abstract

          Background: Potential prognostic biomarker candidates for hepatocellular carcinoma (HCC) are abundant, but their generalizability is unexplored. We cross-validated markers of overall survival (OS) and vascular invasion in independent datasets. Methods: The literature search yielded 318 genes related to survival and 52 related to vascular invasion. Validation was performed in three datasets (RNA-seq, n = 371; Affymetrix arrays, n = 91; Illumina gene chips, n = 135) by uni- and multivariate Cox regression and Mann–Whitney U-test, separately for Asian and Caucasian patients. Results: One hundred and eighty biomarkers remained significant in Asian and 128 in Caucasian subjects at p < 0.05. After multiple testing correction BIRC5 ( p = 1.9 × 10 −10), CDC20 ( p = 2.5 × 10 −9) and PLK1 ( p = 3 × 10 −9) endured as best performing genes in Asian patients; however, none remained significant in the Caucasian cohort. In a multivariate analysis, significance was reached by stage ( p = 0.0018) and expression of CENPH ( p = 0.0038) and CDK4 ( p = 0.038). KIF18A was the only gene predicting vascular invasion in the Affymetrix and Illumina cohorts ( p = 0.003 and p = 0.025, respectively). Conclusion: Overall, about half of biomarker candidates failed to retain prognostic value and none were better than stage predicting OS. Impact: Our results help to eliminate biomarkers with limited capability to predict OS and/or vascular invasion.

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          Most cited references 83

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          Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma

            (2017)
          Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole exome sequencing and DNA copy number analyses, and 196 HCC also by DNA methylation, RNA, miRNA, and proteomic expression. DNA sequencing and mutation analysis identified significantly mutated genes including LZTR1 , EEF1A1 , SF3B1 , and SMARCA4 . Significant alterations by mutation or down-regulation by hypermethylation in genes likely to result in HCC metabolic reprogramming ( ALB , APOB , and CPS1 ) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1. Multiplex molecular profiling of human hepatocellular carcinoma patients provides insight into subtype characteristics and points toward key pathways to target therapeutically.
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            Control of apoptosis and mitotic spindle checkpoint by survivin.

            Progression of the cell cycle and control of apoptosis (programmed cell death) are thought to be intimately linked processes, acting to preserve homeostasis and developmental morphogenesis. Although proteins that regulate apoptosis have been implicated in restraining cell-cycle entry and controlling ploidy (chromosome number), the effector molecules at the interface between cell proliferation and cell survival have remained elusive. Here we show that a new inhibitor of apoptosis (IAP) protein, survivin, is expressed in the G2/M phase of the cell cycle in a cycle-regulated manner. At the beginning of mitosis, survivin associates with microtubules of the mitotic spindle in a specific and saturable reaction that is regulated by microtubule dynamics. Disruption of survivin-microtubule interactions results in loss of survivin's anti-apoptosis function and increased caspase-3 activity, a mechanism involved in cell death, during mitosis. These results indicate that survivin may counteract a default induction of apoptosis in G2/M phase. The overexpression of survivin in cancer may overcome this apoptotic checkpoint and favour aberrant progression of transformed cells through mitosis.
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              Centromeres and kinetochores: from epigenetics to mitotic checkpoint signaling.

              The centromere is a chromosomal locus that ensures delivery of one copy of each chromosome to each daughter at cell division. Efforts to understand the nature and specification of the centromere have demonstrated that this central element for ensuring inheritance is itself epigenetically determined. The kinetochore, the protein complex assembled at each centromere, serves as the attachment site for spindle microtubules and the site at which motors generate forces to power chromosome movement. Unattached kinetochores are also the signal generators for the mitotic checkpoint, which arrests mitosis until all kinetochores have correctly attached to spindle microtubules, thereby representing the major cell cycle control mechanism protecting against loss of a chromosome (aneuploidy).
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                Author and article information

                Journal
                R Soc Open Sci
                R Soc Open Sci
                RSOS
                royopensci
                Royal Society Open Science
                The Royal Society
                2054-5703
                December 2018
                5 December 2018
                5 December 2018
                : 5
                : 12
                Affiliations
                [1 ]2nd Department of Pediatrics, Semmelweis University , H-1094 Budapest, Hungary
                [2 ]MTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Hungarian Academy of Sciences , Magyar tudósok körútja 2, H-1117 Budapest, Hungary
                Author notes
                Author for correspondence: Balázs Győrffy e-mail: gyorffy.balazs@ 123456ttk.mta.hu

                Electronic supplementary material is available online at https://dx.doi.org/10.6084/m9.figshare.c.4305461.

                Article
                rsos181006
                10.1098/rsos.181006
                6304123
                © 2018 The Authors.

                Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.

                Product
                Funding
                Funded by: Nemzeti Kutatási, Fejlesztési és Innovációs Hivatal;
                Award ID: FIEK_16-1-2016-0005
                Award ID: KH-129581
                Award ID: NVKP_16-1-2016-0037
                Categories
                1001
                87
                Cellular and Molecular Biology
                Research Article
                Custom metadata
                December, 2018

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