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      Characterization of cancer genomic heterogeneity by next-generation sequencing advances precision medicine in cancer treatment

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          Abstract

          Cancer is a heterogeneous disease with unique genomic and phenotypic features that differ between individual patients and even among individual tumor regions. In recent years, large-scale genomic studies and new next-generation sequencing technologies have uncovered more scientific details about tumor heterogeneity, with significant implications for the choice of specific molecular biomarkers and clinical decision making. Genomic heterogeneity significantly contributes to the generation of a diverse cell population during tumor development and progression, representing a determining factor for variation in tumor treatment response. It has been considered a prominent contributor to therapeutic failure, and increases the likelihood of resistance to future therapies in most common cancers. The understanding of molecular heterogeneity in cancer is a fundamental component of precision oncology, enabling the identification of genomic alteration of key genes and pathways that can be targeted therapeutically. Here, we review the emerging knowledge of tumor genomics and heterogeneity, as well as potential implications for precision medicine in cancer treatment and new therapeutic discoveries. An analysis and interpretation of the TCGA database was included.

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          Evolution of the cancer stem cell model.

          Genetic analyses have shaped much of our understanding of cancer. However, it is becoming increasingly clear that cancer cells display features of normal tissue organization, where cancer stem cells (CSCs) can drive tumor growth. Although often considered as mutually exclusive models to describe tumor heterogeneity, we propose that the genetic and CSC models of cancer can be harmonized by considering the role of genetic diversity and nongenetic influences in contributing to tumor heterogeneity. We offer an approach to integrating CSCs and cancer genetic data that will guide the field in interpreting past observations and designing future studies. Copyright © 2014 Elsevier Inc. All rights reserved.
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            Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.

            Acute myeloid leukemia (AML) is a heterogeneous disease with respect to presentation and clinical outcome. The prognostic value of recently identified somatic mutations has not been systematically evaluated in a phase 3 trial of treatment for AML. We performed a mutational analysis of 18 genes in 398 patients younger than 60 years of age who had AML and who were randomly assigned to receive induction therapy with high-dose or standard-dose daunorubicin. We validated our prognostic findings in an independent set of 104 patients. We identified at least one somatic alteration in 97.3% of the patients. We found that internal tandem duplication in FLT3 (FLT3-ITD), partial tandem duplication in MLL (MLL-PTD), and mutations in ASXL1 and PHF6 were associated with reduced overall survival (P=0.001 for FLT3-ITD, P=0.009 for MLL-PTD, P=0.05 for ASXL1, and P=0.006 for PHF6); CEBPA and IDH2 mutations were associated with improved overall survival (P=0.05 for CEBPA and P=0.01 for IDH2). The favorable effect of NPM1 mutations was restricted to patients with co-occurring NPM1 and IDH1 or IDH2 mutations. We identified genetic predictors of outcome that improved risk stratification among patients with AML, independently of age, white-cell count, induction dose, and post-remission therapy, and validated the significance of these predictors in an independent cohort. High-dose daunorubicin, as compared with standard-dose daunorubicin, improved the rate of survival among patients with DNMT3A or NPM1 mutations or MLL translocations (P=0.001) but not among patients with wild-type DNMT3A, NPM1, and MLL (P=0.67). We found that DNMT3A and NPM1 mutations and MLL translocations predicted an improved outcome with high-dose induction chemotherapy in patients with AML. These findings suggest that mutational profiling could potentially be used for risk stratification and to inform prognostic and therapeutic decisions regarding patients with AML. (Funded by the National Cancer Institute and others.).
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              Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial

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                Author and article information

                Journal
                Precis Clin Med
                Precis Clin Med
                pcmedi
                Precision Clinical Medicine
                Oxford University Press
                2096-5303
                2516-1571
                June 2018
                14 June 2018
                14 June 2018
                : 1
                : 1
                : 29-48
                Affiliations
                [1 ]Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT USA
                [2 ]University of Tübingen, Tübingen, Germany
                [3 ]Department of Biology, Central Connecticut State University, New Britain, CT, USA
                [4 ]Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
                [5 ]Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southern Medical University
                [6 ]Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Guangzhou, Guangdong Province, China
                Author notes
                Correspondence: Jialing Zhang, Jialing.zhang@ 123456yale.edu ; Xinghua Pan, Panvictor@ 123456smu.edu.cn

                Jialing Zhang and Stephan Stanislaw Späth authors contributed equally to this work.

                Article
                pby007
                10.1093/pcmedi/pby007
                6333046
                30687561
                00e7cb97-076a-45d4-a14c-0294e1c97c91
                © The Author(s) [2018]. Published by Oxford University Press on behalf of West China School of Medicine & West China Hospital of Sichuan University.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@ 123456oup.com

                History
                : 23 March 2018
                : 10 May 2018
                : 21 May 2018
                Page count
                Pages: 20
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81770173
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: R01 DK100858
                Categories
                Review

                genomics,heterogeneity,next-generation sequencing,cancer treatment,precision medicine

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