Table Of ContentThe Handbook
of Biomarkers
Kewal K. Jain
The Handbook of Biomarkers
The Handbook
of Biomarkers
Kewal K. Jain MD, FRACS, FFPM
JainPharmaBiotech,Basel,Switzerland
123
KewalK.Jain
JainPharmaBiotech
Blaesiring7
4057Basel
Switzerland
[email protected]
ISBN978-1-60761-684-9 e-ISBN978-1-60761-685-6
DOI10.1007/978-1-60761-685-6
SpringerNewYorkDordrechtHeidelbergLondon
LibraryofCongressControlNumber:2010920089
©SpringerScience+BusinessMedia,LLC2010
Allrightsreserved.Thisworkmaynotbetranslatedorcopiedinwholeorinpartwithoutthewritten
permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York,
NY10013,USA),exceptforbriefexcerptsinconnectionwithreviewsorscholarlyanalysis.Usein
connectionwithanyformofinformationstorageandretrieval,electronicadaptation,computersoftware,
orbysimilarordissimilarmethodologynowknownorhereafterdevelopedisforbidden.
Theuseinthispublicationoftradenames,trademarks,servicemarks,andsimilarterms,eveniftheyare
notidentifiedassuch,isnottobetakenasanexpressionofopinionastowhetherornottheyaresubject
toproprietaryrights.
Whiletheadviceandinformationinthisbookarebelievedtobetrueandaccurateatthedateofgoing
topress,neithertheauthorsnortheeditorsnorthepublishercanacceptanylegalresponsibilityforany
errorsoromissionsthatmaybemade.Thepublishermakesnowarranty,expressorimplied,withrespect
tothematerialcontainedherein.
Printedonacid-freepaper
HumanaPressispartofSpringerScience+BusinessMedia(www.springer.com)
Preface
This book is an overview of the state of the art of biomarkers. A biomarker is
a characteristic that can be objectively measured and evaluated as an indicator
of a physiological as well as a pathological process or response to a therapeu-
tic intervention. Although there is nothing new about biomarkers such as glucose
for diabetes and blood pressure for hypertension, the current focus is on molecu-
larbiomarkers,whichhavetakenthecenterstageinthedevelopmentofmolecular
medicine.Moleculardiagnostictechnologieshaveenabledthediscoveryofmolecu-
larbiomarkersandarehelpinginthedefinitionoftheirroleinthepathomechanism
ofdisease.Biomarkersformthebasisofdevelopmentofdiagnosticassaysaswell
astargetsfordrugdiscovery.Effectofdrugs,inclinicaltrialsaswellasinpractice,
canbemonitoredbybiomarkerassays.
Thereisatremendousamountofliteratureonbiomarkers,butthereisnocom-
prehensivesourceofinformationonthetopic.Ofthethousandsofbiomarkersthat
arebeingdiscovered,relativelyfewarebeingvalidatedforfurtherapplications,and
itisdifficulttoevaluatethepotentialofabiomarker.Thisbookdescribesdifferent
types of biomarkers and their discovery using various “-omics” technologies such
asproteomicsandmetabolomicsalongwiththebackgroundinformationforevalua-
tionsofbiomarkersaswellastheproceduresfortheirvalidationanduseinclinical
trials.Biomarkersarefirstdescribedaccordingtotechnologiesandthenaccording
to various diseases. An important feature is the correlation between diseases and
classifications of biomarkers, which provides the reader with a guide to sort out
currentandfuturebiomarkers.
This book would be an important source of information on biomarkers for sci-
entistsaswellasphysiciansandthoseinvolvedindrugdiscoveryanddevelopment.
Many of the regulatory issues concerning biomarkers are related to proteomics,
molecular diagnostics, and pharmacogenomics/pharmacogenetics. By facilitating
thecombinationoftherapeuticswithdiagnostics,biomarkerswillplayanimportant
roleinthedevelopmentofpersonalizedmedicine,whichisanimportantemerging
trendinhealthcare.
KewalK.Jain,MD
Basel,Switzerland
v
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
HistoricalAspectsofBiomarkers . . . . . . . . . . . . . . . . . . . 2
ClassificationofBiomarkers . . . . . . . . . . . . . . . . . . . . . . 3
BiologicalMarkerasResponsetoTherapeuticIntervention . . . . 3
Pharmacokinetic/PharmacodynamicsBiomarkers. . . . . . . . . . 4
PredictiveBiomarkers . . . . . . . . . . . . . . . . . . . . . . . . 4
ValidBiomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . 5
TypesofBiomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . 5
GenesasBiomarkers. . . . . . . . . . . . . . . . . . . . . . . . . 6
ProteinsasBiomarkers . . . . . . . . . . . . . . . . . . . . . . . 6
Proteomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
DNABiomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . 7
MitochondrialDNA . . . . . . . . . . . . . . . . . . . . . . . . . 7
MitochondrialMutations . . . . . . . . . . . . . . . . . . . . . . 8
RNABiomarkers. . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Transcriptomics . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
MicroRNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Metabolomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Glycomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Single-NucleotidePolymorphisms . . . . . . . . . . . . . . . . . 12
Haplotyping . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
CellBiomarkersofDisease . . . . . . . . . . . . . . . . . . . . . 13
StemCellBiomarkers . . . . . . . . . . . . . . . . . . . . . . . . 13
CancerStemCellBiomarkers . . . . . . . . . . . . . . . . . . . . 14
EndoglinasaFunctionalBiomarkerofStemCells . . . . . . . . . 14
p75NTRasaBiomarkertoIsolateAdiposeTissue-Derived
StemCells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
ProteinExpressionProfileasBiomarkerofStemCells . . . . . . . 15
STEMPRO(cid:2)R EZChekTM forAnalysisofBiomarkersofhESCs . . 15
SSEA-4asBiomarkerofMSCs . . . . . . . . . . . . . . . . . . . 16
AutoantibodiesasBiomarkersofAutoimmuneDiseases . . . . . . 16
vii
viii Contents
TheIdealBiomarker . . . . . . . . . . . . . . . . . . . . . . . . . . 17
BiomarkersandSystemsBiology . . . . . . . . . . . . . . . . . . . 18
SystemsBiologyApproachtoBiomarkerIdentification . . . . . . 19
RelationofBiomarkerstoOtherTechnologiesandHealthcare . . . . 20
BiomarkersandTranslationalMedicine . . . . . . . . . . . . . . . 20
LimitationsofUseofBiomarkersinHealthCare . . . . . . . . . . 20
2 TechnologiesforDiscoveryofBiomarkers . . . . . . . . . . . . . 23
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
DetectionofBiomarkersinTissuesandBodyFluids . . . . . . . . . 23
DiseaseBiomarkersinBreath . . . . . . . . . . . . . . . . . . . . . 23
PortableBreathTestforVolatileOrganicCompounds . . . . . . . 24
DetectionofBreathBiomarkersbySensationTechnology . . . . . 24
Detection of Breath Biomarkers Optical Frequency
CombSpectroscopy . . . . . . . . . . . . . . . . . . . . . . . . . 25
GenomicTechnologies . . . . . . . . . . . . . . . . . . . . . . . . . 25
GeneExpression . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
TissueMicroarraysforStudyofBiomarkers . . . . . . . . . . . . 28
EpigenomicTechnologies . . . . . . . . . . . . . . . . . . . . . . . 28
DiscoveryofMethylationBiomarkers. . . . . . . . . . . . . . . . 29
ProteomicTechnologies . . . . . . . . . . . . . . . . . . . . . . . . 30
2DGE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Isotope-CodedAffinityTags . . . . . . . . . . . . . . . . . . . . . 32
MassSpectrometry. . . . . . . . . . . . . . . . . . . . . . . . . . 33
LiquidChromatography–MSCombination . . . . . . . . . . . . . 37
ProteinTomography . . . . . . . . . . . . . . . . . . . . . . . . . 37
ProteinBiochips/MicroarraysandBiomarkers . . . . . . . . . . . 38
Real-TimePCRforQuantificationofProteinBiomarkers . . . . . 39
MagneticBeadsforProteinBiomarkerDiscovery . . . . . . . . . 40
(cid:2)
CellCartaR ProteomicsPlatform . . . . . . . . . . . . . . . . . . 40
MASStermindTM . . . . . . . . . . . . . . . . . . . . . . . . . . 41
SearchforBiomarkersinBodyFluids. . . . . . . . . . . . . . . . 41
Challenges and Strategies for Discovery of Protein
BiomarkersinPlasma . . . . . . . . . . . . . . . . . . . . . . . . 41
BiomarkersintheUrinaryProteome . . . . . . . . . . . . . . . . 47
PeptidesinBodyFluidsandTissuesasBiomarkersofDisease . . . 47
VerificationforInterlaboratoryReproducibilityofProtein
Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
SignificanceofSimilarProteinBiomarkersinDifferentTissues . . 50
GlycomicTechnologies . . . . . . . . . . . . . . . . . . . . . . . . 51
MetabolomicTechnologies . . . . . . . . . . . . . . . . . . . . . . . 51
MassSpectrometry-BasedKitsforDiscoveryofMetabolic
BiomarkersinPlasma . . . . . . . . . . . . . . . . . . . . . . . . 52
UrinaryProfilingbyCapillaryElectrophoresis . . . . . . . . . . . 52
LipidProfiling . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Contents ix
Role of Metabolomics in Biomarker Identification
andPatternRecognition . . . . . . . . . . . . . . . . . . . . . . . 53
Validation of Biomarkers in Large-Scale Human
MetabolomicsStudies . . . . . . . . . . . . . . . . . . . . . . . . 54
Lipidomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54
FluorescentIndicatorsforBiomarkers . . . . . . . . . . . . . . . . . 55
MolecularImagingTechnologies . . . . . . . . . . . . . . . . . . . 56
ComputerTomography . . . . . . . . . . . . . . . . . . . . . . . 56
MagneticResonanceImaging . . . . . . . . . . . . . . . . . . . . 57
PositronEmissionTomography . . . . . . . . . . . . . . . . . . . 57
AdvantagesofImagingBiomarkers . . . . . . . . . . . . . . . . . 58
MonitoringInVivoGeneExpressionbyMolecularImaging . . . . 58
MolecularImagingInVivoasaBiomarker . . . . . . . . . . . . . 59
ChallengesandFutureProspectsofMolecularImaging . . . . . . 59
MolecularImaginginClinicalPractice . . . . . . . . . . . . . . . 60
NuclearMagneticResonance . . . . . . . . . . . . . . . . . . . . . 61
ChemicalDerivatizationtoEnhanceBiomarkerDetection
byNMR . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
FluxomicsbyUsingNMR . . . . . . . . . . . . . . . . . . . . . . 62
Nanobiotechnology . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
NanomaterialsforBiolabeling . . . . . . . . . . . . . . . . . . . . 63
NanoproteomicsandBiomarkers . . . . . . . . . . . . . . . . . . 65
NanoparticlesforMolecularImaging . . . . . . . . . . . . . . . . 66
NanoparticlesforDiscoveringBiomarkers . . . . . . . . . . . . . 67
NucleoproteinNanodevicesforDetectionofCancerBiomarkers. . 67
FutureProspectsofApplicationofNanobiotechnology
forBiomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
Bioinformatics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
BiomarkerWorkflowGuide . . . . . . . . . . . . . . . . . . . . . 68
AnalysisofMicroarrayDataforSelectingUsefulBiomarkers . . . 68
RoleofBioinformaticsinDiscoveryofProteomicBiomarkers . . . 69
RoleofBioinformaticsinDetectionofCancerBiomarkers. . . . . 70
BiomarkerDatabases . . . . . . . . . . . . . . . . . . . . . . . . 70
GeneNetworksasBiomarkers. . . . . . . . . . . . . . . . . . . . 71
PitfallsintheDiscoveryandDevelopmentofBiomarkers . . . . . . . 71
3 BiomarkersandMolecularDiagnostics . . . . . . . . . . . . . . . 73
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
MolecularDiagnosticTechnologies . . . . . . . . . . . . . . . . . . 73
PolymeraseChainReaction . . . . . . . . . . . . . . . . . . . . . 73
CombinedPCR–ELISA . . . . . . . . . . . . . . . . . . . . . . . 75
Non-PCRMethods . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Transcription-MediatedAmplification . . . . . . . . . . . . . . . 77
RapidAnalysisofGeneExpression . . . . . . . . . . . . . . . . . 77
WAVENucleicAcidFragmentAnalysisSystem . . . . . . . . . . 77
