TranslationalEpigeneticsSeries
TrygveTollefsbol-SeriesEditor
TransgenerationalEpigenetics
EditedbyTrygveO.Tollefsbol,2014
PersonalizedEpigenetics
EditedbyTrygveO.Tollefsbol,2015
EpigeneticTechnologicalApplications
EditedbyY.GeorgeZheng,2015
EpigeneticCancerTherapy
EditedbyStevenG.Gray,2015
DNAMethylationandComplexHumanDisease
ByMichelNeidhart,2015
EpigenomicsinHealthandDisease
EditedbyMarioF.FragaandAgustinF.FFerna´ndez,2015
EpigeneticGeneExpressionandRegulation
EditedbySumingHuang,MichaelLittandC.AnnBlakey,2015
EpigeneticBiomarkersandDiagnostics
EditedbyJoseLuisGarcı´a-Gimenez,2015
DrugDiscoveryinCancerEpigenetics
EditedbyGerdaEggerandPaolaBarbaraArimondo,2015
MedicalEpigenetics
EditedbyTrygveO.Tollefsbol,2016
ChromatinSignalingandDiseases
EditedbyOlivierBindaandMartinFernandez-Zapico,2016
GenomeStability
EditedbyIgorKovalchukandOlgaKovalchuk,2016
ChromatinRegulationandDynamics
EditedbyAnitaGondor,2016
NeuropsychiatricDisordersandEpigenetics
EditedbyDagH.Yasui,JacobPeedicayilandDennisR.Grayson, 2016
PolycombGroupProteins
EditedbyVincenzoPirrotta,2016
EpigeneticsandSystemsBiology
EditedbyLeonieRingrose,2017
CancerandNoncodingRNAs
EditedbyJayprokasChakrabartiandSangaMitra,2017
NuclearArchitectureandDynamics
EditedbyChristopheLavelleandJean-MarcVictor,2017
EpigeneticMechanismsinCancer
EditedbySabitaSaldanha,2017
EpigeneticsofAgingandLongevity
EditedbyAlexeyMoskalevandAlexanderM.Vaiserman,2017
TheEpigeneticsofAutoimmunity
EditedbyRongxinZhang,2018
EpigeneticsinHumanDisease,SecondEdition EditedbyTrygveO.Tollefsbol,2018
EpigeneticsofChronicPain
EditedbyGuangBaiandKeRen,2018
EpigeneticsofCancerPrevention
EditedbyAnupamBishayeeandDeepakBhatia,2018
ComputationalEpigeneticsandDiseases
EditedbyLooKeatWei,2019
Pharmacoepigenetics
EditedbyRamo´nCacabelos,2019
EpigeneticsandRegeneration
EditedbyDanielaPalacios,2019
ChromatinSignalingandNeurologicalDisorders EditedbyOlivierBinda,2019
TransgenerationalEpigenetics,SecondEdition EditedbyTrygveTollefsbol,2019
NutritionalEpigenomics
EditedbyBradleyFerguson,2019
PrognosticEpigenetics
EditedbyShilpySharma,2019
EpigeneticsoftheImmuneSystem EditedbyDieterKabelitz,2020
StemCellEpigenetics
EditedbyEranMeshorerandGiuseppeTesta,2020
EpigeneticsMethods EditedbyTrygveTollefsbol,2020
HistoneModificationsinTherapy
EditedbyPedroCastelo-BrancoandCarmenJeronimo, 2020
EnvironmentalEpigeneticsinToxicologyandPublicHealth EditedbyRebeccaFry,2020
GenomeStability
EditedbyIgorKovalchukandOlgaKovalchuk,2021
TwinandFamilyStudiesofEpigenetics
EditedbyShuaiLiandJohnHopper
EpigeneticsandMetabolomics
EditedbyPabanK.AgrawalaandPoonamRana,2021
MedicalEpigenetics,SecondEdition EditedbyTrygveTollefsbol,2021
SeriesEditor
TrygveTollefsbol
ProfessorofBiology,UniversityofAlabamaatBirmingham,andSeniorScientist, ComprehensiveCancerCenter,ComprehensiveCenterforHealthy,Birmingham, AL,UnitedStates
Aging,ComprehensiveDiabetesCenterandNutritionObesityResearchCenter, Birmingham,AL,UnitedStates Director,CellSenescenceCultureFacility,Birmingham,AL,UnitedStates
Editedby
JoseLuisGarcı´a-Gimenez
CIBEREnfermedadesRaras,CenterforBiomedicalNetworkResearchonRare Diseases,InstitutodeSaludCarlosIII,Valencia,Spain
INCLIVABiomedicalResearchInstitute,Valencia,Spain
DepartmentofPhysiology,SchoolofMedicineandDentistry,Universityof Valencia,Valencia,Spain
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Contributors.......................................................................................................................................xvii Preface..............................................................................................................................................xxiii
CHAPTER1Perspectivesandfuturedirectionsoftranslationalepigenetics inpersonalizedandprecisionmedicine...................................... 1
JoseLuisGarcı´a-Gimenez,Jesu ´ sBeltra ´ n-Garcı ´ a, RebecaOsca-Verdegal,FedericoV.Pallardo ´ ,ToshikazuUshijima,and TrygveO.Tollefsbol
Introduction..............................................................................................................2
Diagnostic,prognostic,andtherapeuticapplicationsofepigenetics inprecisionmedicine...........................................................................................4
Epigenetic-basedtherapies......................................................................................8
Conclusionsandperspective.................................................................................11 References..............................................................................................................13
CHAPTER2Translationalepigeneticsinprecisionmedicineofcolorectal cancer.................................................................................... 19
Jesu ´ sBeltra ´ n-Garcı´a,RebecaOsca-Verdegal,SalvadorMena-Molla ´ , MartaSeco-Cervera,LorenaPeiro ´ -Chova,JoseLuisGarcı´a-Gimenez, PierreLaurent-Puig,andAndresCervantes
Introduction............................................................................................................20
PotentialepigeneticbiomarkersforCRC.............................................................22
EpigeneticbiomarkersforCRCbasedonDNAmethylation..........................22
EpigeneticbiomarkersforCRCbasedonhistoneposttranslational modifications.................................................................................................23
EpigeneticbiomarkersforCRCbasedonmicroRNAs....................................24
Invitrodiagnostictestsbasedonepigeneticbiomarkers.................................25
Epigenetic-basedIVDtestforCRC......................................................................25
TheCologuardstoolDNA-basedtest...............................................................25
TheEpiproColon2.0test.................................................................................28
TheEarlyTectcolorectalcancerassay..............................................................29
miRPredX-31-3p................................................................................................29
Colveracolorectalcancerscreeningtriagetest................................................30
TheNu.Qcolorectalcancerscreeningtriagetest.............................................31
A.S.Perry
DNAmethylationinlungcancer....................................................................112
Histoneposttranslationalmodificationsinlungcancer..................................113
NoncodingRNAsinlungcancer....................................................................115
Diagnostic,prognostic,andtherapeuticapplicationsofepigenetics inlungcancer..................................................................................................117
DNAmethylationasbiomarkerforlungcancer............................................118
Histoneposttranslationalmodificationsasbiomarkersfor lungcancer...................................................................................................120
NoncodingRNAsasbiomarkersforlungcancer...........................................121
Drugresponseandtherapeutics..........................................................................123
DNAmethylationastherapeutictargetinlungcancer..................................124
Histoneposttranslationalmodificationsastherapeutictarget inlungcancer..............................................................................................125
NoncodingRNAsastherapeutictargetsinlungcancer.................................130
Conclusionsandperspective...............................................................................131
CHAPTER6Epigeneticsandprecisionmedicineinboneandsofttissue
sarcomas...............................................................................
KanizFatema,SarahLuelling,MatthewKirkham,AdrienePavek, AlexandraL.Heyneman,andJaredBarrott
Introduction..........................................................................................................154
Osteosarcoma.......................................................................................................156
Epigeneticbiomarkersindiagnosisandprognosis ofosteosarcoma...........................................................................................156
Epigenetictherapeuticsinosteosarcoma........................................................159
EpigeneticsinCSCphenotypeandosteoblasticdifferentiation....................162
Ewingsarcoma....................................................................................................163
EpigeneticdiagnosticmethodsinEwingsarcoma.........................................163
EpigeneticprognosticmarkersinEwingsarcoma..........................................163
EpigenetictargetsinthetreatmentofEwingsarcoma...................................164
Undifferentiatedpleomorphicsarcoma...............................................................164
Epigeneticdiagnosticmethodsinundifferentiatedpleomorphic sarcoma........................................................................................................165
Epigeneticprognosticmethodsinundifferentiatedpleomorphic sarcoma........................................................................................................165
Epigenetictargetsinthetreatmentofundifferentiatedpleomorphic sarcoma........................................................................................................165
Synovialsarcoma.................................................................................................166
Epigeneticsasadiagnostictoolinsynovialsarcoma....................................166
Epigeneticsasaprognostictoolinsynovialsarcoma....................................167
Epigeneticsasatherapeutictoolinsynovialsarcoma...................................168
Rhabdomyosarcoma.............................................................................................169
Epigeneticsfordiagnostictestinginrhabdomyosarcoma..............................169
Epigeneticsforprognostictestinginrhabdomyosarcoma..............................170
Epigeneticsasatherapeutictargetforrhabdomyosarcoma...........................170
Leiomyosarcoma..................................................................................................172
Epigeneticsfordiagnostictestinginleiomyosarcoma...................................172
Epigeneticsforprognostictestinginleiomyosarcoma...................................172
Epigeneticsasatherapeutictargetforleiomyosarcoma................................173
Liposarcoma.........................................................................................................173
Epigeneticsfordiagnostictestinginliposarcoma..........................................173
Epigeneticsforprognostictestinginliposarcoma..........................................173
Epigeneticsasatherapeutictargetforliposarcoma.......................................174
Malignantperipheralnervesheathtumor...........................................................174
Epigeneticsasaprognostictoolinmalignantperipheralnerve sheathtumor................................................................................................174
Epigeneticsasadiagnostictoolinmalignantperipheralnerve sheathtumor................................................................................................175
Epigeneticsasatherapeutictoolinmalignantperipheralnerve sheathtumor................................................................................................175
Epigeneticsfordiagnostictestinginfibrosarcoma.........................................176
Epigeneticsforprognostictestinginfibrosarcoma........................................176
Epigeneticsasatherapeutictargetforfibrosarcoma......................................177
CutaneousT-celllymphoma...........................................................................205
CHAPTER8Epigeneticbiomarkeranddrugdevelopmentingynecological
Po-HsuanSu,Lin-YuChen,Rui-LanHuang,Kuo-ChangWen, Phui-LyLiew,andHung-ChengLai
Cervicalcancer....................................................................................................224 PapanicolaousmearandHPVtesting.............................................................225
CHAPTER9Epigeneticsinprecisionmedicineofpancreaticcancer...........
CHAPTER10Epigeneticsandpersonalizedmedicineofbraincancer............
GeorgeI.Lambrou
Introduction..........................................................................................................282
AshortintroductiontoCNStumorbiology...................................................283
Ontumor“stemness”.......................................................................................286
Onbraintumor“stemness”.............................................................................287
Approachestotheunderstandingoftumorbiology.......................................288
Topersonalize(therapy)ornottopersonalize...............................................289
CHAPTER11Epigeneticsandprecisionmedicineindiabetesandobesity preventionandmanagement....................................................
Post-translationalhistonemodifications(PTMs)............................................332
NoncodingRNAs(ncRNAs)...........................................................................333
Precisionmedicineandepigeneticmarksinmetabolicdisorders......................333
ClinicalrelevanceofepigeneticbiomarkersinobesityandT2D..................334
Epigeneticbiomarkersinnoninvasivesamples..............................................336
CHAPTER12Epigeneticsinprecisionmedicineofcardiovascular disease..................................................................................
Lucı´aPinilla,FerranBarbe,JoseM.Guerra,VicentaLlorente-Cortes, andDaviddeGonzalo-Calvo
Cardiovasculardisease........................................................................................348 Biomarkers...........................................................................................................348
Epigeneticbiomarkers:NoncodingRNAs..........................................................349
MostrelevantnoncodingRNAsubclassesinthefieldofbiomarkers...............350
NoncodingRNAsasdiagnosticbiomarkersofcardiovasculardisease.............352
NoncodingRNAsasprognosticbiomarkersofcardiovasculardisease.............356
NoncodingRNAsinbiomarker-guidedtherapyofcardiovascular disease..............................................................................................................358
Definingclinicalphenotypes:NoncodingRNAsanddecisiontree
CHAPTER13Spermepigenetics:Thefutureofprecisionmedicineinmale
CHAPTER14Epigeneticinprecisionmedicineinautoimmune andinflammatory-mediateddisorders.......................................
JoseSantiagoIba ´ n ¨ ez-Cabellos,Jesu’sCosı´n-Roger,and MartaSeco-Cervera
Introduction..........................................................................................................381
Epigeneticbasesofautoimmuneinflammatory-relateddiseases.......................384
Rheumatoidarthritis........................................................................................384
Rheumatoidarthritis........................................................................................392
Inflammatoryboweldisease............................................................................394
Epigeneticmodifications.................................................................................409
Importanceofepigeneticchangesinallergicdiseases...................................410
Challengesofthetissue-specificityofepigeneticchanges............................413
Whichepigeneticmodificationmightbebestsuitedfortranslation toclinicalsettings?......................................................................................414
Precisionmedicineinallergicdiseases...............................................................415
Diagnosisofallergicdiseases.........................................................................415
Predictingtheonset,remission,and/orseverityofallergicdiseases.............416
Usingepigeneticstodefinesubgroupsofallergicpatients............................419
Epigeneticsforpersonalizedtreatmentdecisionsusingconventional treatmentandbiologics...............................................................................420
Theepigenomeasatargetforpersonalizedtreatment.......................................425
Alteringtheepigeneticphenotypethoughmodulation ofthemicrobiome.......................................................................................425
Epigenetictherapy...........................................................................................427
Epigeneticediting............................................................................................429
TargetingmiRNAsinpatientswithallergicdiseases.....................................430 Conclusions..........................................................................................................431
CHAPTER16Epigeneticsinspinecurvaturedisorders.................................. 449
GissellePerez-Machado,MartaSeco-Cervera, EsterBerenguer-Pascual,SalvadorMena-Molla ´ ,TeresaBasHermida, MoritzC.Deml,andJoseLuisGarcı´aGimenez
Introduction..........................................................................................................450
Epigeneticsinbonemetabolismassociatedtospinedeformity.........................452
DNAmethylation................................................................................................452
NoncodingRNAs.................................................................................................453
RoleofmiRNAsinAIS......................................................................................454
RoleofmiRNAsinDS.......................................................................................457
Epigeneticbiomarkersinscoliosisprecisionmedicine......................................460
DNAmethylationbiomarkersinAISprecisionmedicine.................................460
miRNAsbiomarkersinAISprecisionmedicine................................................461
Conclusionsandfutureprospects........................................................................462
Acknowledgmentsandfunding...........................................................................463 References............................................................................................................463
CHAPTER17MethylatedcirculatingtumorDNAbiomarkersforthe blood-baseddetectionofcancersignals.................................. 471 MeganP.Hitchins
Introduction..........................................................................................................472
Thepublichealthburdenofcancerandtheneedforminimallyinvasive testsforcancerdetection.................................................................................473
CirculatingtumorDNAasabiomarkerforthedetection ofcancersignals..............................................................................................474
ChoiceofsomaticsequencemutationorDNAmethylationasctDNA biomarkers.......................................................................................................476
CharacteristicsandcompositionofcfDNAandctDNA....................................477
ctDNAdetectiontechnologies.............................................................................480
Bestpreanalyticalpracticesforobtaininghigh-qualitycfDNAtemplates........480
Bloodcollectionandpreanalyticalvariables......................................................480
Cell-freeDNAisolationandqualitycontrol......................................................481
SodiumbisulfiteconversionofcfDNAforDNAmethylationanalyses............481
Cell-freeDNAassaytypes..................................................................................482
Real-timePCR-basedassaysfortargetedloci....................................................482
Next-generationsequencing(NGS)-basedassays..............................................483
“Real-world”applicationsofcfDNAtechnologytothedetectionofcancer signals..............................................................................................................485
Earlydetectionofcancerviapopulation-basedscreening.................................485
Population-basedscreeningforthedetectionofcolorectalcancer usingthemethylated SEPTIN9, “mSEPT9”blood-basedctDNAtest.......487
DevelopmentofmulticancerscreeningtestbasedonmethylatedctDNA profiles.............................................................................................................490
TheGalleritestbyGRAILInc...........................................................................491
ApplicationofctDNAtechnologyinoncologyfortheclinical managementofcancerpatients.......................................................................494
UtilityofctDNAtestingformonitoringtumorburdenincancerpatients........494
Benefitsofthedetectionofmolecularresidualdisease,recurrence,and tumorburdeninthesettingofcolorectalcancer............................................495
PersonalizedNGS-basedassayforthedetectionofminimalresidual diseaseandcancerrecurrence.........................................................................496
MethylatedctDNAtestforthedetectionofminimalresidualdisease andrecurrenceofCRC....................................................................................497
Liquidbiopsy.......................................................................................................500
Liquidbiopsyforthepredictionofresponsetotreatment.................................501 Conclusionsandfuturedirections.......................................................................503 References............................................................................................................505
CHAPTER18DietaryregulationofmiRNAinprecisionmedicine
PriyaMondalandSyedMusthapaMeeran
Introduction..........................................................................................................514
BiogenesisofmiRNA..........................................................................................514
RoleofmiRNAinlungcancerprogression.......................................................516
Cellproliferationandapoptosis......................................................................517
Modulationofstemnessproperties.................................................................517
Alteringtheexpressionoftumorsuppressorgenesoroncogenes.................517
Alteringthemetabolicpathways.....................................................................518
Regulatingtheexpressionofimmunity-associatedgenes..............................518
RoleofmiRNAinlungcancerchemoresistance...........................................519
RoleofmiRNAsinlungcancertherapeutics.....................................................519
miRNAsasdiagnostictools............................................................................519 miRNAsasprognostictools............................................................................524 miRNAsaspredictivetools............................................................................525
DietaryregulationofmiRNAinlungcancer.....................................................526
Curcumin.........................................................................................................526
Teacatechins...................................................................................................529
Genistein..........................................................................................................530
Quercetin..........................................................................................................531
Resveratrol.......................................................................................................532
Sulforaphane....................................................................................................532
Glossary...............................................................................................................542
CHAPTER19Epigeneticbiomarkersinmaleinfertilityanditspotential useinassistedreproductivetechnology...................................
JoseLuisGarcı´a-Gimenez,ValterLuizMaciel, MinervaFerrer-Buitrago,SalvadorMena-Molla ´ ,andMiguelRuiz-Jorro
Introduction..........................................................................................................544
Epigeneticsinspermatogenesisandmaleinfertility..........................................546 DNAmethylationandmaleinfertility............................................................546
Histonesandhistonevariantsandtheirroleinmaleinfertility.....................551
Thepotentialofepigeneticstoimproveclinicalmanagementofmale
Conclusionsandfutureprospects........................................................................562
Contributors
FerranBarbe
TranslationalResearchinRespiratoryMedicine,UniversityHospitalArnaudeVilanovaandSanta Maria,IRBLleida,Lleida;CIBERofRespiratoryDiseases(CIBERES),InstituteofHealthCarlosIII, Madrid,Spain
RyanC.Barney
DepartmentofPhysiologyandDevelopmentalBiology,BrighamYoungUniversity,Provo,UT, UnitedStates
JaredBarrott
DepartmentofBiomedicalandPharmaceuticalSciences,IdahoStateUniversity,Pocatello,ID, UnitedStates
Jesu ´ sBeltra ´ n-Garcı ´ a
DepartmentofPhysiology,SchoolofMedicineandDentistry,UniversityofValencia;CIBER EnfermedadesRaras,CenterforBiomedicalNetworkResearchonRareDiseases(CIBERER), InstituteofHealthCarlosIII;INCLIVABiomedicalResearchInstitute,Valencia,Spain
EsterBerenguer-Pascual
DepartmentofPhysiology,CenterforBiomedicalNetworkResearch,InstitutodeSaludCarlosIII, EpiDiseaseS.L.ParcCientı´ficdelaUniversitatdeVale ` nciaBiomedicalResearchInstituteINCLIVA, MedicineandDentistrySchool,UniversityofValencia,Valencia,Spain
AlejandroCardona-Monzonı ´ s
DepartmentofPhysiology,SchoolofMedicineandDentistry,UniversityofValencia,Valencia, Spain
JulianCarretero
DepartmentofPhysiology,FacultyofPharmacy,UniversityofValencia,Valencia,Spain
AndresCervantes
INCLIVABiomedicalResearchInstitute;MedicalOncologyDepartment,HospitalClı´nico UniversitariodeValencia;CenterforBiomedicalNetworkResearchonOncology(CIBERONC), InstituteofHealthCarlosIII;DepartmentofMedicine,SchoolofMedicineandDentistry,University ofValencia,Valencia,Spain
Lin-YuChen
DepartmentofObstetricsandGynecology,ShuangHoHospital,TaipeiMedicalUniversity, NewTaipeiCity,Taiwan
Jesu ´ sCosı´n-Roger
DrPesetHospital-FISABIO,Valencia,Spain
AnaB.Crujeiras
EpigenomicsinEndocrinologyandNutritionGroup,InstitutodeInvestigacionSanitaria(IDIS), ComplejoHospitalarioUniversitariodeSantiago(CHUS/SERGAS),SantiagodeCompostela;CIBER FisiopatologiadelaObesidadyNutricion(CIBERobn),Madrid,Spain
DaviddeGonzalo-Calvo
TranslationalResearchinRespiratoryMedicine,UniversityHospitalArnaudeVilanovaandSanta Maria,IRBLleida,Lleida;CIBERofRespiratoryDiseases(CIBERES),InstituteofHealthCarlosIII, Madrid,Spain
MoritzC.Deml
DepartmentofOrthopaedicSurgeryandTraumatologyInselspital,UniversityHospitalBern, UniversityBern,Bern,Switzerland
KanizFatema
DepartmentofBiomedicalandPharmaceuticalSciences,IdahoStateUniversity,Pocatello,ID, UnitedStates
MinervaFerrer-Buitrago
CREA,CenterforReproductiveMedicineS.L.,Valencia,Spain
MatthewH.Friedland
UniversityofMichiganMedicalSchool,AnnArbor,MI,UnitedStates
WilliamM.Gallagher
CancerBiologyandTherapeuticsLaboratory,UCDConwayInstitute;UCDSchoolofBiomolecular andBiomedicalScience;UCDSchoolofBiologyandEnvironmentalScience,UniversityCollege Dublin,Dublin,Ireland
JoseLuisGarcı´a-Gimenez
DepartmentofPhysiology,SchoolofMedicineandDentistry,UniversityofValencia,Valencia; CIBEREnfermedadesRaras,CenterforBiomedicalNetworkResearchonRareDiseases (CIBERER),InstituteofHealthCarlosIII,Valencia;INCLIVABiomedicalResearchInstitute, Valencia;EpiDiseaseS.L.ParcCientı´ficdelaUniversitatdeVale ` nciaSpin-OffofCIBERER(ISCIII), Patern,Spain
JoseM.Guerra
DepartmentofCardiology,HospitaldelaSantaCreuiSantPau,BiomedicalResearchInstituteSant Pau(IIBSantPau),AutonomousUniversityofBarcelona,Barcelona;CIBERofCardiovascular Diseases(CIBERCV),InstituteofHealthCarlosIII,Madrid,Spain
TeresaBasHermida
HospitalUniversitariiPolite ` cnicLaFe,InstitutodeInvestigacio ´ nSanitariaLaFe,Valencia,Spain
AlexandraL.Heyneman
DepartmentofBiomedicalandPharmaceuticalSciences,IdahoStateUniversity,Pocatello,ID, UnitedStates
MeganP.Hitchins
DepartmentofBiomedicalSciences,Cedars-SinaiMedicalCenter,LosAngeles,CA,UnitedStates
Rui-LanHuang
DepartmentofObstetricsandGynecology,ShuangHoHospital,TaipeiMedicalUniversity,New TaipeiCity;DepartmentofObstetricsandGynecology,SchoolofMedicine,CollegeofMedicine, TaipeiMedicalUniversity,Taipei,Taiwan
JoseSantiagoIba ´ n ˜ ez-Cabellos
ConsortiumCenterforBiomedicalNetworkResearch-InstitutodeSaludCarlosIII(CIBER-ISCIII); BiomedicalResearchInstituteINCLIVADept.Physiology,MedicineandDentistrySchool, UniversityofValencia,Valencia;EpiDiseaseS.L.Spin-OfffromtheCIBER-ISCIII,ParcCientı´ficdela UniversitatdeVale ` ncia,Paterna,Spain
AndreaG.Izquierdo
EpigenomicsinEndocrinologyandNutritionGroup,InstitutodeInvestigacionSanitaria(IDIS), ComplejoHospitalarioUniversitariodeSantiago(CHUS/SERGAS),SantiagodeCompostela;CIBER FisiopatologiadelaObesidadyNutricion(CIBERobn),Madrid,Spain
TimothyG.Jenkins
DepartmentofPhysiologyandDevelopmentalBiology,BrighamYoungUniversity,Provo,UT, UnitedStates
AsiaC.Jordan
CancerBiologyandTherapeuticsLaboratory,UCDConwayInstitute;UCDSchoolofBiologyand EnvironmentalScience,UniversityCollegeDublin,Dublin,Ireland
HongSunKim
DepartmentofPathology,RogelCancerCenterandCenterforRNABiomedicine,Universityof Michigan,AnnArbor,MI,UnitedStates
MatthewKirkham
DepartmentofBiomedicalandPharmaceuticalSciences,IdahoStateUniversity,Pocatello,ID, UnitedStates
Hung-ChengLai
DepartmentofObstetricsandGynecology,ShuangHoHospital,TaipeiMedicalUniversity,New TaipeiCity;DepartmentofObstetricsandGynecology,SchoolofMedicine,CollegeofMedicine, TaipeiMedicalUniversity,Taipei,Taiwan
GeorgeI.Lambrou
NationalandKapodistrianUniversityofAthens,MedicalSchool,FirstDepartmentofPediatrics, ChoremeioResearchLaboratory,Athens,Greece
PierreLaurent-Puig
CordeliersResearchCenter,INSERM,CNRSSNC5096,SorbonneUniversity,UniversityofParis; InstituteofCancerParisCARPEM,APHP,DepartmentofBiology,EuropeanHospitalGeorges Pompidou,Paris,France
Phui-LyLiew
DepartmentofPathology,ShuangHoHospital,TaipeiMedicalUniversity,NewTaipeiCity; DepartmentofPathology,SchoolofMedicine,CollegeofMedicine,TaipeiMedicalUniversity, Taipei,Taiwan
VicentaLlorente-Cortes
CIBERofCardiovascularDiseases(CIBERCV),InstituteofHealthCarlosIII,Madrid;Instituteof BiomedicalResearchofBarcelona(IIBB),SpanishNationalResearchCouncil(CSIC),Barcelona; GroupofLipidsandCardiovascularPathology,BiomedicalResearchInstituteSantPau(IIBSant Pau),SantaCreuiSantPauHospital,Barcelona,Spain
PaulaM.Lorenzo
EpigenomicsinEndocrinologyandNutritionGroup,InstitutodeInvestigacionSanitaria(IDIS), ComplejoHospitalarioUniversitariodeSantiago(CHUS/SERGAS),SantiagodeCompostela;CIBER FisiopatologiadelaObesidadyNutricion(CIBERobn),Madrid,Spain
SarahLuelling
DepartmentofBiomedicalandPharmaceuticalSciences,IdahoStateUniversity,Pocatello,ID, UnitedStates
ValterLuizMaciel
DepartmentofSurgery,DivisionofUrology,HumanReproductionSection,UniversidadeFederal deSaoPaulo,SaoPaulo,Brazil
JeanS.McGee
DepartmentofDermatology,BethIsraelDeaconessMedicalCenter;HarvardMedicalSchool, Boston,MA,UnitedStates
SyedMusthapaMeeran
LaboratoryofCancerEpigenetics,DepartmentofBiochemistry,CSIR-CentralFoodTechnological ResearchInstitute(CSIR-CFTRI),Mysore;AcademyofScientificandInnovativeResearch(AcSIR), Ghaziabad,India
SalvadorMena-Molla ´
DepartmentofPhysiology,FacultyofPharmacy,UniversityofValencia;EpiDiseaseS.L.Parc Cientı´ficdelaUniversitatdeVale ` nciaBiomedicalResearchInstituteINCLIVA,Spin-OffofCIBERER (ISCIII),Valencia,Spain
PriyaMondal
LaboratoryofCancerEpigenetics,DepartmentofBiochemistry,CSIR-CentralFoodTechnological ResearchInstitute(CSIR-CFTRI),Mysore;AcademyofScientificandInnovativeResearch(AcSIR), Ghaziabad,India
JagadishNatesh
LaboratoryofCancerEpigenetics,DepartmentofBiochemistry,CSIR-CentralFoodTechnological ResearchInstitute(CSIR-CFTRI),Mysore;AcademyofScientificandInnovativeResearch(AcSIR), Ghaziabad,India
A ´ ngelL.Ortega
DepartmentofPhysiology,FacultyofPharmacy,UniversityofValencia,Valencia,Spain
RebecaOsca-Verdegal
DepartmentofPhysiology,SchoolofMedicineandDentistry,UniversityofValencia;CIBER EnfermedadesRaras,CenterforBiomedicalNetworkResearchonRareDiseases(CIBERER), InstituteofHealthCarlosIII;INCLIVABiomedicalResearchInstitute,Valencia,Spain
FedericoV.Pallardo ´
DepartmentofPhysiology,SchoolofMedicineandDentistry,UniversityofValencia;CIBER EnfermedadesRaras,CenterforBiomedicalNetworkResearchonRareDiseases(CIBERER), InstituteofHealthCarlosIII;INCLIVABiomedicalResearchInstitute,Valencia,Spain
AdrienePavek
DepartmentofBiomedicalandPharmaceuticalSciences,IdahoStateUniversity,Pocatello,ID, UnitedStates
LorenaPeiro ´ -Chova
INCLIVABiomedicalResearchInstitute;EpiDiseaseS.L.ParcCientı´ficdelaUniversitatdeVale ` ncia BiomedicalResearchInstituteINCLIVA,Spin-OffofCIBERER(ISCIII),Valencia,Spain
DhanamjaiPenta
LaboratoryofCancerEpigenetics,DepartmentofBiochemistry,CSIR-CentralFoodTechnological ResearchInstitute(CSIR-CFTRI),Mysore;AcademyofScientificandInnovativeResearch(AcSIR), Ghaziabad,India
GissellePerez-Machado
DepartmentofPhysiology,CenterforBiomedicalNetworkResearch,InstitutodeSaludCarlosIII, EpiDiseaseS.L.ParcCientı´ficdelaUniversitatdeVale ` nciaBiomedicalResearchInstituteINCLIVA, MedicineandDentistrySchool,UniversityofValenciaHospital,UniversitariIPolite ` cnicLaFe, Valencia,Spain
A.S.Perry
CancerBiologyandTherapeuticsLaboratory,UCDConwayInstitute;UCDSchoolofBiologyand EnvironmentalScience,UniversityCollegeDublin,Dublin,Ireland
Lucı´aPinilla
TranslationalResearchinRespiratoryMedicine,UniversityHospitalArnaudeVilanovaandSanta Maria,IRBLleida,Lleida;CIBERofRespiratoryDiseases(CIBERES),InstituteofHealthCarlosIII, Madrid,Spain
M.Prencipe
CancerBiologyandTherapeuticsLaboratory,UCDConwayInstitute;UCDSchoolofBiomolecular andBiomedicalScience,UniversityCollegeDublin,Dublin,Ireland
MiguelRuiz-Jorro
CREA,CenterforReproductiveMedicineS.L.,Valencia,Spain
MartaSeco-Cervera
CIBEREnfermedadesRaras,CenterforBiomedicalNetworkResearchonRareDiseases (CIBERER),InstituteofHealthCarlosIII;INCLIVABiomedicalResearchInstitute;Consortium CenterforBiomedicalNetworkResearch-InstitutodeSaludCarlosIII(CIBER-ISCIII),Biomedical ResearchInstituteINCLIVADept.Physiology,MedicineandDentistrySchool,Universityof Valencia;DepartmentofPhysiology,CenterforBiomedicalNetworkResearch,InstitutodeSalud CarlosIII,EpiDiseaseS.L.ParcCientı´ficdelaUniversitatdeVae ` nciaBiomedicalResearchInstitute INCLIVA,MedicineandDentistrySchool,UniversityofValenciaHospital,UniversitariiPolite ` cnicLa Fe,Valencia,Spain
JiaqiShi
DepartmentofPathology,RogelCancerCenterandCenterforRNABiomedicine,Universityof Michigan,AnnArbor,MI,UnitedStates
RominaSilva
CancerBiologyandTherapeuticsLaboratory,UCDConwayInstitute;UCDSchoolofBiologyand EnvironmentalScience;UCDSchoolofMedicine,UniversityCollegeDublin,Dublin,Ireland
Po-HsuanSu
DepartmentofObstetricsandGynecology,ShuangHoHospital,TaipeiMedicalUniversity,New TaipeiCity;DepartmentofObstetricsandGynecology,SchoolofMedicine,CollegeofMedicine, TaipeiMedicalUniversity,Taipei,Taiwan
TrygveO.Tollefsbol
ComprehensiveCancerCenter;CenterforAging;ComprehensiveDiabetesCenter;Nutrition ObesityResearchCenter;CellSenescenceCultureFacility,UniversityofAlabamaatBirmingham, Birmingham,AL,UnitedStates
JorgTost
LaboratoryforEpigeneticsandEnvironment,NationalCenterforResearchonHumanGenomics, CEA–InstituteforBiologyFrancoisJacob,UniversityofParis-Saclay,Evry,France
ToshikazuUshijima
DivisionofEpigenomics,NationalCancerCenterResearchInstitute,Tokyo,Japan
Kuo-ChangWen
DepartmentofObstetricsandGynecology,ShuangHoHospital,TaipeiMedicalUniversity,New TaipeiCity;DepartmentofObstetricsandGynecology,SchoolofMedicine,CollegeofMedicine, TaipeiMedicalUniversity,Taipei,Taiwan
JulieZ.Yi
DepartmentofDermatology,BethIsraelDeaconessMedicalCenter,Boston,MA;EasternVirginia MedicalSchool,Norfolk,VA,UnitedStates
Preface
AlthoughtheHumanGenomeProjectwascompletedin2003andlarge-scalegeneticassociationanalyseshavebeenperformedinmanydiseasesinordertoelucidatethemechanismofdisease,theuseof geneticmarkersaloneisnotsufficienttoexplaincompletelythediseaseonsetandprogression.Progressinthefieldofhumanepigeneticshasbeenaccelerated,thankstorecenttechnologicaladvances andthecomprehensionofepigeneticdysregulationoccurringinhumandiseases.
SincetheNIHRoadmapEpigenomicsProject,epigeneticshasbecomeahottopicinbiomedicine. Epigeneticscontrolsmyriadphysiologicalandpathologicalstates,towardmechanismsinvolvingcell identityandgeneexpressioninbothhealthanddisease.Foragivenpathogenicphenotypeinacomplex disease,therearemultiplepotentialgenesthatcouldbegeneticallyaltered(i.e.,mutations,copynumbervariations,andtripletexpansion)andepigeneticallycontrolled[i.e.,DNAmethylation,posttranslationalmodifications(PTMs)ofhistonesandmiRNAsandlncRNAs,etc.].Therefore,the investigationofepigeneticmechanismsimprovesourunderstandingofthediseasemechanismscontributingtothenaturalhistoryofadisease.Moreover,epigeneticsisdemonstratingepigeneticmarks andepigeneticmechanismsareusefulasbiomarkerstoguideclinicaldecisionsandimprovepersonalizedmanagementofhumandiseasesincludingthedetection,diagnosis,deepphenotyping,riskstratification,andprognosis.Moreover,epigeneticsmaycontributetomoreaccuratepredictionofpatients whowillbenefitfromaspecifictreatmentorpreventionstrategyforaparticulardisease,whichhas crucialimplicationsforthehealthofthepatientandtheefficientuseofhealthcaresystemresources. Inthisregard,therearealreadysomeinvivodiagnostic(IVD)testsbasedonepigeneticbiomarkersthat arecurrentlybeingcommercializedandaredescribedinthisnewvolume EpigeneticsinPrecision Medicine. Importantly,itisexpectedthatthenumberofepigenetic-basedIVDtestswillincreasesubstantiallyinthecomingyears,afterdemonstratingthepotentialofepigeneticbiomarkerstoimprove clinicalsettings.
Manymethods,includingnext-generationsequencing-basedtechnologies,arecurrentlyavailable tocliniciansandresearcherstoanalyzeepigeneticbiomarkersisolatedfromseveralbiologicalsources. However,despitethespectacularprogressofepigeneticresearchinhumandiseases,therearestillsome challengestobesolvedsuchastheinterpretationofexistingandfuturedatageneratedmainlybynextgenerationsequencingapproachesinlargecohortsofpatients,theeffectproducedbyepigeneticdrugs orlifestyleanddietaryinterventionsintheepigenome,andthesignificanceofepigeneticchangesoccurringinpatientsparticipatinginclinicaltrials,justtomentionafew.Itisnoteworthythatmoststudiesaddressingpersonalizedmedicineusingepigeneticbiomarkersanddrugshavebeenperformedin smallexploratorycohortsandthereforehadlowstatisticalsignificance.So,thesystematicinclusionof theanalysisofepigeneticmodifications(includingDNAmethylation,longnoncodingRNAs,and microRNAs)inlarge-scaleclinicaltrials,withwell-selectedpatients,wouldgreatlyimproveourcapacitytodefinecompaniondiagnosticbiomarkerscorrelatingwithtreatmentresponseorevenpredict responsebeforethestartofthetherapy.
Importantly,theintegrationofclinicalinformationwithdatasetsgeneratedbyhigh-throughput technologieswillhelpdecipherthecomplexinterplayofthedifferentepigeneticmechanismsandgene regulatorynetworks,therebycontributingtotheidentificationoftherapeutictargets,anddemonstrate thepharmacologicalpotentialofnewepigeneticdrugs.Importantly,technicalprogressand
bioinformaticmethodswillenableustoincreaseourcapacitytoanalyzelargecohortsofpatientswith high-dimensionalmultiomicdatasets.So,itisconceivablyanimprovementofprecisionmedicine, thankstotheincorporationofartificialintelligenceandbioinformatics.
Finally,epigeneticdrugsregulatingepigeneticmechanismsaregainingparticularinterestforthe treatmentofseveraldiseases.Inthelastdecade,boththeFoodandDrugAdministration(FDA)andthe EuropeanMedicineAgency(EMA)haveapprovedvariousepigeneticdrugsusedtotreatawidevariety ofdiseasessuchasdifferentcancers,hypertension,andeveninfectionscausedbyviruses,among others.Inparticular,someepigeneticdrugssuchasDNAmethyltransferaseinhibitors,histoneacetyltransferasemodulators,histonedeacetylaseinhibitors,histonemethyltransferaseinhibitors,histone demethylaseinhibitors,bromodomaininhibitors,andnoncodingRNAsorantago-miRNAsareacquiringspecialrelevanceinthepharmaceuticalindustry.
Interestingly,lifestyleanddietaryregimescanalsotargetepigeneticmechanisms,therebyimpactingdirectlyonthehealthstatus.Inrecentyears,thereisagrowinginterestintheexplorationofthe effectofdietaryregimesontheepigeneticreprogramming.Therefore,inthecomingyearswewill assisttoanexplosionofnewtherapeuticapproachesbasedonchangesinlifestyleandnutritionin ordertointerveneinspecificepigeneticmechanismsaffectinghealthanddiseasestatus.
Thisbookisfocusedoncomplexepigeneticmechanismsinseveralpathologiesandexploreshow epigeneticscanfuelprecisionmedicinenotonlyimprovingIVDandprognostictoolsbutalsoprovidingnewefficientepigenetic-basedtherapeuticapproachestohumandiseases.Thebookfocuseson recentprogressinseveralareasofclinicalepigeneticsanddiscussestheadvancesinepigenomic technologies,includingtoolsandapplicationsbasedonnext-generationsequencingtodiscovernew epigeneticbiomarkersthatcanhelpimplementepigeneticsintopersonalizedmedicine.
Furthermore,thisnewvolumefor“TranslationalEpigeneticSeries”expandsfromtheutilityofepigeneticbiomarkersfordiagnosisandprognosisofseveraldiseasestotheuseofepigeneticdrugsforthe treatmentofsomehumandiseases.Thenewvolumefocussesonthepotentialofepigeneticstoimprove theprecisionmedicineincancer(i.e.,lungcancer,colorectalcancer,prostatecancer,gynecological cancers,bonecancer,pancreaticcancer,andbraincancer),cardiovascularandmetabolicdiseases, diabetesandobesity,inflammatoryandautoimmunedisorders,skindiseases,infertility,bone-related diseases,andneurodegenerativediseases,amongothers.
Thebookwaswritteninadescriptiveandcomprehensivemannerbyoutstandingexpertsintheir correspondingfieldsforabroadtargetaudiencewhoareinterestedinthisexcitingfieldwiththe vocationofimprovingprecisionmedicine.
Perspectivesandfuturedirections oftranslationalepigenetics inpersonalizedandprecision medicine
JoseLuisGarcı´a-Gimeneza,b,c,Jesu ´ sBeltra ´ n-Garcı ´aa,b,c,RebecaOsca-Verdegala,b,c,
FedericoV.Pallardo ´ a,b,c,ToshikazuUshijimad,andTrygveO.Tollefsbole,f,g,h,i DepartmentofPhysiology,SchoolofMedicineandDentistry,UniversityofValencia,Valencia,Spaina CIBER
EnfermedadesRaras,CenterforBiomedicalNetworkResearchonRareDiseases(CIBERER),InstituteofHealthCarlos III,Valencia,Spainb INCLIVABiomedicalResearchInstitute,Valencia,Spainc DivisionofEpigenomics,National CancerCenterResearchInstitute,Tokyo,Japand ComprehensiveCancerCenter,UniversityofAlabamaatBirmingham, Birmingham,AL,UnitedStatese CenterforAging,UniversityofAlabamaatBirmingham,Birmingham,AL,United Statesf ComprehensiveDiabetesCenter,UniversityofAlabamaatBirmingham,Birmingham,AL,UnitedStatesg NutritionObesityResearchCenter,UniversityofAlabamaatBirmingham,Birmingham,AL,UnitedStatesh Cell SenescenceCultureFacility,UniversityofAlabamaatBirmingham,Birmingham,AL,UnitedStatesi
Abbreviations
AIartificialintelligence
ccfDNAcell-freecirculatingDNA
ChIP-SeqChromatinImmunoprecipitationSequencing
CRCcolorectalcancer
DNMTDNAmethyltransferase
DNMTiDNMTinhibitor
EGFRepidermalgrowthfactorreceptor
ENCODEENCyclopediaofDNAelements
FDAFoodandDrugAdministration
FFEPformalin-fixedparaffin-embeddedsamples
HDAChistonedeacetylase
HDACihistonedeacetylaseinhibitor
HEPHumanEpigenomeProject
IHECInternationalHumanEpigenomeConsortium
IVDinvitrodiagnostic
slncRNAlongnon-codingRNAs
mAbmonoclonalantibody
MSmassspectrometry
NGSnextgenerationsequencing
PTMspost-translationalmodifications
EpigeneticsinPrecisionMedicine. https://doi.org/10.1016/B978-0-12-823008-4.00014-7
Copyright # 2022ElsevierInc.Allrightsreserved.
