Martínez-Escardó, L.

Universitat Autònoma de Barcelona. Facultat de Biociències

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Epigenetics of CancerA New Way to Manage Oncology PatientsMartínez-Escardó L1BiomarkersIV. ResultsTherapies 1Degree in Biomedical Sciences, Facultat de Biociencies, Universitat Autònoma de Barcelona, Barcelona, Spain.The punctuation marks in the genomeA partnership of genetic abnormalities in malignant Figure 1. Epigenetic modifications control gene expression leading to gene activationor gene silencing. Tail domains that protrude from the core histones are subject tocovalent modification that include lysine (K) acetylation by HAT and methylation by HMT.DNMTs methylate DNA by convertint SAM to SAH, a mechanism that can be inhibited byDNMTi. MBPs recognise methylated DNA and recruit HDACs, which deacetylate lysines inthe histone tails, leading to a repressive state.HMT, histone methyltransferase; HAT, histone acetyltransferase; DNMT, DNA methyltransferase; DNMTi,DNMT inhibitor; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; MBP, methyl-binding domain;HDAC, histone deacetylase;HDACi, HDAC inhibitors.Epigenetic Biomarkers in Cancer Detection Cancer:     Prostate CancerSample:    Urine / Blood plasma / Ejaculate Target:      GSTP1Cancer:     Lung CancerSample:    Bronchial aspirate / Blood plasmaTarget:      SHOX2Cancer:     Colorectal CancerSample:    Blood plasma / FecesTarget:      SEPT9SHOX2 is hypermethylated in 96% of lung cancer tumors. A Blood-based test for SHOX2 methylation resulted in an overall sensitivity of62% and in a specificity of 90%. Current tests such as computedtomography show early stage cancers but X-rays used may cause lungdamage. SHOX2 methylation analysis could be useful simple, quick,and not harmful tool in patients suspected of having lung cancer.GSTP1 has been found hypermethylated in at least 80% of prostatecancer tissues. The noninvasive analysis of this epigenetic mark incirculating DNA could be considerate as an alternative to the widelyused prostate specific antigen (PSA) associated to prostate cancer, butalso to prostatitis or benign prostatic hyperplasia providing falsepositive results in prostate cancer screening.SEPT9 blood-based methylation detection test with a specificity of90% could be a good choice for the screening of individuals at risk ofTargets and Stages of Epigenetic Drug DevelopmentCBP/EP300; DOT1L1; EZH2; KDM1ADNMT; HDAC; JAK2; Aurora; PARP; BET (BRD2/3/4)DNMT (Azacitidine and Decitabine); HDAC (Vorinostat and Romidepsin); JAK2 (Ruxolitinib)Chromatin readersPreclinicalIn development Clinical trials FDA approvedGene Activation Gene SilencingIn order to understand the role and advantages that epigenetics could have on the clinic as a biomarker it is necessary to consider the early onsetof epigenetic modifications in tumor development and the gradual manner of acquisition. The reversal property of epimutations will be necessaryto comprehend the mechanism that most of epigenetic therapies are using or trying to use.I. IntroductionEpigenetics in cancerEpigeneticsIn the 1940s, Conrad Waddington introduced the term epigenetics,literally ‘over’ genetics. The field remains the object of ambiguity andcontention, however is broadly accepted as the mitotically and/ormeiotically heritable changes in gene expression that occur withoutchanges in DNA sequence. DNMT inhibitorsFigure 4. Kaplan-Meier survival curves for azacitidine and conventional care groupsin a randomised, open-label, phase III study. Azacitidine treatment was associated witha significant improvement in overall survival comparing it with best supportive care.Azacitidine has been licensed by the FDA for use in all subtypes of inthe treatment of myelodysplastic syndrome (MDS). Demarcate the start and end of genes. Provide structure to the chromosome. Leads to gens being expressed (Active)or not expressed (Silent, inactive). Chemically Stable. Heritable and Reversible. Modulated by environ-mental factors.AzacitidineConventional care BET inhibitorsFootnote: L.M.-E. performed this work under the “Bachelor’s Degree Final Project" program from Universitat Autònoma de Barcelona, as undergraduate student of Biomedical Sciences.cellular transformation Highlight the role that the changes of epigenetic landscape couldhave on the genesis of cancer. Detect potential epigenetic targets in cancer cells which cancontribute to the management of cancer patients in different areas. Analyze the real applicability of those potential epigenetic targetsand its benefit to oncology patients.Epigenetic Biomarkers in Cancer Prognosis Epigenetic Biomarkers in Treatment ResponseCancer:     Breast CancerSample:    Blood plasmaTarget:      BRCA1Cancer:     Glioblastoma CancerSample:    Blood plasma Target:      MGMTdeveloping colorectal cancer. This test could also be an alternative tothe routinely intrusive and discomfort test used in the clinic whichinclude occult blood test, colonoscopy and sigmoidoscopy.BRCA1 is critical for double-stranded DNA breaks repair. Defects in theDNA repair machinery due to methylation in BRCA1 accelerate thedevelopment of breast cancer and therefore is associated with pooroutcome. BRCA1 methylation could be a predictive marker in theclinical management of patients.MGMT promoter hypermethylation has been used to predict cancerpatients’s treatment response to Temozolomide. Those human primarytumors undergoing hypermetilation of this gene which encodes a DNArepair protein that removes alkyl groups, will be more sensitive tochemotherapeutic drug such as Temozolomide used as an alkylatingagent in glioblastomas.Altered histone modification patternCpG-island methylation5mCNormal Tissue Hyperplasia Neoplasia InvasionFigure 2. Epigenetic alteration can lead to tumor progression. There is a progressiveloss of total DNA methylation content, an increased frequency of hypermethylated CpGislands, and an increased histone-modification imbalance in cancer development.“Epigenetic Control of Gene Expression“ courseCourse of 6 weeks         Offered by The University of Melbourne6 Sessions        23 Speakers        50 Posters“Barcelona Conference on Epigenetics and Cancer”“Challenges, Opportunities and perspectives”November, 21 and 22, 201330 out of 50 recent papers and reviews selected accordingto their quality and data of publication.Keywords (alone or in combination): epigenetics, cancer,DNA methylation, biomarker, detection, prognosis,treatment response, epigenetic therapy.Figure 3. Three main sources of information governed the performance of thisproject. Literature research on PubMed and ScienceDirect for paper published prior theend of may 2014; six weeks course offered by the education platform Coursera; andcongress assistance. Doctoral thesis consulting from TESEO database and Google Booksservice were also used in this bibliographic work.II. ObjectivesIII. MethodologyV. Conclusions• What clearly comes out from this work is that disruption of epigenetic landscape is a central contributor tohuman cancer, traditionally seen as a “genetic disease”.• For its heritability, stability, detection at early stages and quantification in human cells by genome-wide andgene- specific methods, DNA methylation is perfect as a biomarker .• The possibility to analyze the reliable biomarker in surrogate tissues such as blood or other body fluids obtainedthrough minimally invasive procedures justify its implementation as routine analytic procedure in oncology.• The reversal property of epimutations has enabled the development of small-molecule inhibitors againstchromatin regulators with the aim to repair the epigenetic landscape in cancer cells.• It is essential a good quality basic research to detect what goes wrong in cancer epigenetics, but is becomingincreasingly necessary going one step further and contribute directly in patients' benefit. HDAC inhibitorsHDACs reverse lysine acetylation and its expression levels appear to bealtered in numerous malignancies. HDAC inhibitors such asVorinostat and Romidepsin have recently been granted FDAapproval for clinical use in patients with cutaneous T celllymphoma.Fenaux, P. et al. Lancet Oncol. 10, 223–32 (2009).BCL2CDK6C-MYCBCL2CDK6C-MYCFigure 5. Schematic model proposing the mode of action for I-BET in MLL-fusionleukaemia. MLL target genes (BCL2, CDK6, MYC) are down regulated by I-BET due to thedisplacement of BRD3/4, PAFc and SEC components from chromatin.MLL, mixed lineage leukaemia; BET, bromodomain and extra terminal family of proteins; I-BET, BET inhibitors;SEC, super elongation complex; PAFc, polymerase-associated factor complex.BET inhibition is an effective treatment for MLL-fusionleukaemia.Data presented in this poster comes from: 

Epigenetics of cancer : a new way to manage oncology patients

http://ddd.uab.cat/pub/tfg/2014/126440/TFG_LMartinezEscardo.pdf

Epigenetics of cancer : a new way to manage oncology patients

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