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      Cancer epigenetics: Moving forward

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          Abstract

          Defects in chromatin modifiers and remodelers have been described both for hematological and solid malignancies, corroborating and strengthening the role of epigenetic aberrations in the etiology of cancer. Furthermore, epigenetic marks—DNA methylation, histone modifications, chromatin remodeling, and microRNA—can be considered potential markers of cancer development and progression. Here, we review whether altered epigenetic landscapes are merely a consequence of chromatin modifier/remodeler aberrations or a hallmark of cancer etiology. We critically evaluate current knowledge on causal epigenetic aberrations and examine to what extent the prioritization of (epi)genetic deregulations can be assessed in cancer as some type of genetic lesion characterizing solid cancer progression. We also discuss the multiple challenges in developing compounds targeting epigenetic enzymes (named epidrugs) for epigenetic-based therapies. The implementation of acquired knowledge of epigenetic biomarkers for patient stratification, together with the development of next-generation epidrugs and predictive models, will take our understanding and use of cancer epigenetics in diagnosis, prognosis, and treatment of cancer patients to a new level.

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          The blockade of immune checkpoints in cancer immunotherapy.

          Drew M Pardoll (2012)
          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
          Article 0 comments Cited 5128 times – based on 0 reviews     Review now
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            Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199.

            Sylvia Adams, Robert J. Gray, Sandra Demaria … (2014)
            Recent studies suggest that tumor-infiltrating lymphocytes (TILs) are associated with disease-free (DFS) and overall survival (OS) in operable triple-negative breast cancer (TNBC). We seek to validate the prognostic impact of TILs in primary TNBCs in two adjuvant phase III trials conducted by the Eastern Cooperative Oncology Group (ECOG). Full-face hematoxylin and eosin–stained sections of 506 tumors from ECOG trials E2197 and E1199 were evaluated for density of TILs in intraepithelial (iTILs) and stromal compartments (sTILs). Patient cases of TNBC from E2197 and E1199 were randomly selected based on availability of sections. For the primary end point of DFS, association with TIL scores was determined by fitting proportional hazards models stratified on study. Secondary end points were OS and distant recurrence–free interval (DRFI). Reporting recommendations for tumor marker prognostic studies criteria were followed, and all analyses were prespecified. The majority of 481 evaluable cancers had TILs (sTILs, 80%; iTILs, 15%). With a median follow-up of 10.6 years, higher sTIL scores were associated with better prognosis; for every 10% increase in sTILs, a 14% reduction of risk of recurrence or death (P = .02), 18% reduction of risk of distant recurrence (P = .04), and 19% reduction of risk of death (P = .01) were observed. Multivariable analysis confirmed sTILs to be an independent prognostic marker of DFS, DRFI, and OS. In two national randomized clinical trials using contemporary adjuvant chemotherapy, we confirm that stromal lymphocytic infiltration constitutes a robust prognostic factor in TNBCs. Studies assessing outcomes and therapeutic efficacies should consider stratification for this parameter.
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              Cancer genetics and epigenetics: two sides of the same coin?

              Jueng Soo You, Peter A. Jones (2012)
              Epigenetic and genetic alterations have long been thought of as two separate mechanisms participating in carcinogenesis. A recent outcome of whole exome sequencing of thousands of human cancers has been the unexpected discovery of many inactivating mutations in genes that control the epigenome. These mutations have the potential to disrupt DNA methylation patterns, histone modifications, and nucleosome positioning and hence, gene expression. Genetic alteration of the epigenome therefore contributes to cancer just as epigenetic process can cause point mutations and disable DNA repair functions. This crosstalk between the genome and the epigenome offers new possibilities for therapy. Copyright © 2012 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                John M. Greally: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS Genet
                Journal ID (iso-abbrev): PLoS Genet
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosgen
                Title: PLoS Genetics
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Print): 1553-7390
                ISSN (Electronic): 1553-7404
                Publication date (Electronic): 7 June 2018
                Publication date Collection: June 2018
                Volume: 14
                Issue: 6
                Electronic Location Identifier: e1007362
                Affiliations
                [1 ] Dipartimento di Medicina di Precisione, Università degli Studi della Campania “L. Vanvitelli,” Napoli, Italy
                [2 ] Struttura Semplice Dipartimentale Trapianto di Midollo Osseo-Azienda Ospedialiera di Rilievo Nazionale, Santobono-Pausilipon, Napoli, Italy
                Albert Einstein College of Medicine, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0001-5374-3527
                http://orcid.org/0000-0002-7312-5387
                Article
                Publisher ID: PGENETICS-D-17-01240
                DOI: 10.1371/journal.pgen.1007362
                PMC ID: 5991666
                PubMed ID: 29879107
                SO-VID: 0b731514-d457-45a5-9729-e9a857d9ce78
                Copyright © © 2018 Nebbioso et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Page count
                Figures: 2, Tables: 4, Pages: 25
                Funding
                This work was supported by BLUEPRINT (282510), the Italian Flagship Project EPIGEN, Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale PRIN-2015 (no. 20152TE5PK_003), the Italian Association for Cancer Research (AIRC-17217), and Worldwide Cancer Research (formally known as AICR, Grant no. 15-1002). The funders had no role in the preparation of the article.
                Categories
                Subject: Review
                Subject: Biology and life sciences
                Subject: Cell biology
                Subject: Chromosome biology
                Subject: Chromatin
                Subject: Chromatin modification
                Subject: DNA methylation
                Subject: Biology and life sciences
                Subject: Genetics
                Subject: Epigenetics
                Subject: Chromatin
                Subject: Chromatin modification
                Subject: DNA methylation
                Subject: Biology and life sciences
                Subject: Genetics
                Subject: Gene expression
                Subject: Chromatin
                Subject: Chromatin modification
                Subject: DNA methylation
                Subject: Biology and life sciences
                Subject: Genetics
                Subject: DNA
                Subject: DNA modification
                Subject: DNA methylation
                Subject: Biology and life sciences
                Subject: Biochemistry
                Subject: Nucleic acids
                Subject: DNA
                Subject: DNA modification
                Subject: DNA methylation
                Subject: Biology and life sciences
                Subject: Genetics
                Subject: Epigenetics
                Subject: DNA modification
                Subject: DNA methylation
                Subject: Biology and life sciences
                Subject: Genetics
                Subject: Gene expression
                Subject: DNA modification
                Subject: DNA methylation
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Epigenetics
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Chromosome Biology
                Subject: Chromatin
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Epigenetics
                Subject: Chromatin
                Subject: Biology and Life Sciences
                Subject: Genetics
                Subject: Gene Expression
                Subject: Chromatin
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Hematologic Cancers and Related Disorders
                Subject: Lymphomas
                Subject: Medicine and Health Sciences
                Subject: Hematology
                Subject: Hematologic Cancers and Related Disorders
                Subject: Lymphomas
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Blood Cells
                Subject: White Blood Cells
                Subject: T Cells
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: T Cells
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: T Cells
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: T Cells
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancer Treatment
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Breast Tumors
                Subject: Breast Cancer
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Immune Cells
                Subject: Antibody-Producing Cells
                Subject: B Cells
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: Antibody-Producing Cells
                Subject: B Cells
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: Antibody-Producing Cells
                Subject: B Cells
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Blood Cells
                Subject: White Blood Cells
                Subject: B Cells
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: B Cells
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: B Cells
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune Cells
                Subject: White Blood Cells
                Subject: B Cells

                ScienceOpen disciplines: Genetics
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                ScienceOpen disciplines: Genetics

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