Cancer Biomarkers in Body Fluids: Biomarkers in Circulation

519 Pages·2017·6.618 MB·English

by  Gabriel D. Dakubo (auth.)

Gabriel D. Dakubo
Cancer
Biomarkers in
Body Fluids
Biomarkers in Circulation
Cancer Biomarkers in Body Fluids
Gabriel D. Dakubo
Cancer Biomarkers in Body
Fluids
Biomarkers in Circulation
GabrielD.Dakubo
MedicalSciencesDivision
NorthernOntarioSchoolofMedicine
WestCampus,LakeheadUniversity
ThunderBay,Ontario
Canada
ISBN978-3-319-48359-7 ISBN978-3-319-48360-3 (eBook)
DOI10.1007/978-3-319-48360-3
LibraryofCongressControlNumber:2016959613
©SpringerInternationalPublishingAG2017
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Theregisteredcompanyaddressis:Gewerbestrasse11,6330Cham,Switzerland
To my best friend and wife, Crescentia, and
our beloved children, Collins, Ethan,
Bernard, and Zaneta.
In memory of George and Nicholas.
Preface
Cancer is a complex disease that continues to burden global healthcare. This
afflictioncanmostlybesafelycurtailedwithenormousinvestmentsintechnology,
coupled with the required regulatory oversight, especially in regard to the bio-
markeranddrugdevelopmentandapprovalprocesses.Effortsattheregulatoryand
other institutional levels are accelerating the pace of the cancer biomarker devel-
opment process. Thus, a new era of cancer care has dawned due to the important
utilization of cancer biomarkers in companion diagnostics and personalized
biotherapies.
The early detection of cancer enables the successful deployment of curative-
intentinterventionsincludingsurgeryandchemoprevention.Detectingallcancers
attheirprecursorstagesisaformidabletask,suchthatcurrentlyonlyafewcancers
are adequately screened for at the population level (e.g., Pap smear). Several
strategies target risk group identification for surveillance, employing approaches
suchasinvasiveendoscopiesandimaging.Althoughthese“screening”procedures
are important to cancer management, they are not suitable for population-wide
screeningprogramsforearlydetectionofcancer,becauseoftheassociatedprohib-
itive costs, radiation exposures, and invasiveness, with their associated possible
complications. Visualization of the molecular alterations that drive cancer initia-
tion, progression, and therapy response are becoming possible with molecular
imaging. However, until the development of modalities or devices that are safe,
effective, affordable, less complicated, and easy to use at the point-of-care or
community level, molecular imaging is unlikely to become a routine screening
tool for cancer early detection in all communities. Especially deprived by such
screeningdeviceswillbetheresource-poorpartsoftheworldwhereunfortunately
most cancers (57% in 2012) are diagnosed, and also where many cancer-related
deaths(65%in2012)occur.
Body fluids obtained by noninvasive or acceptable minimally invasive proce-
duresarearichsourceofbiomarkerinformationthatissuitableforcancerscreen-
ing and monitoring. Technological advancements, such as single-cell analysis, as
wellaschipandmicrofluidictechnologies,arepavingthewayfortheeasycapture
vii
viii Preface
of cancer biomarkers in almost all body fluids. Coupled with nanoscale device
manufacturing, it is now “practically” possible to accurately detect altered cancer
targets using low-cost and easy-to-use portable devices at the point of care. The
future desires such care, and cancer biomarkers in circulation will immensely
contributetowardfulfillingthisvoid.Achievingthisfeatrequiresvalidatedcancer
biomarkers, which are currently limited. “Biomarkers in body fluids” provides a
landscapeofwhathasbeenaccomplishedinthisdirection.
Tomakeitaneasyreadandreferencetext,eachchapterisorganizedinasimilar
defined pattern. The relevant molecular pathology of each cancer is provided,
followedbycirculatingbiomarkers.Thesectionsoncirculatingbiomarkersexplore
their presence in the epigenome, genome, transcriptome (coding and noncoding),
proteome, and metabolome. The biomarker potential and available clinical appli-
cationsofcirculatingtumorcellsandtumor-derivedextracellularvesiclesconclude
eachchapter.
Iamgratefultomyprojectcoordinators,UrsulaGrammandMartinaHimberger,
for seeing this project through to completion, and to my production team, Daniel
IgnatiusJagadisanandR.R.PavanKumar,fortheirdiligentandexpeditedwork.To
myfamily,“finallyitisyourturn...thisoneisforyou,”althoughitcannotrecover
thelostfamilytime.
ThunderBay,Ontario,Canada GabrielD.Dakubo
August2016
Contents
1 MelanomaBiomarkersinCirculation. . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.2 ScreeningRecommendationsforMelanoma. . . . . . . . . . . . . . . 3
1.3 MolecularPathologyofMelanoma. . . . . . . . . . . . . . . . . . . . . 3
1.3.1 BRAFMutationsinMelanoma. . . . . . . . . . . . . . . . . . 3
1.3.2 RASMutationsinMelanoma. . . . . . . . . . . . . . . . . . . 4
1.3.3 AlterationsinCellCycleControlGenes
inMelanoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3.4 TP53MutationsinMelanoma. . . . . . . . . . . . . . . . . . . 5
1.3.5 KITMutationsinMelanoma. . . . . . . . . . . . . . . . . . . . 5
1.3.6 MITFMutationsinMelanoma. . . . . . . . . . . . . . . . . . 6
1.3.7 PI3KPathwayAlterationsinMelanoma. . . . . . . . . . . 6
1.3.8 MolecularSubtypesofMelanoma. . . . . . . . . . . . . . . . 6
1.3.9 MolecularProgressionModelofMelanoma. . . . . . . . 7
1.4 CirculatingMelanomaBiomarkers. . . . . . . . . . . . . . . . . . . . . 8
1.4.1 CirculatingMelanomaCell-FreeNucleicAcid
Biomarkers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
1.4.2 CirculatingMelanomaEpigeneticBiomarkers. . . . . . . 9
1.4.3 CirculatingMelanomaGeneticBiomarkers. . . . . . . . . 10
1.4.4 CirculatingMelanomaCodingRNABiomarkers. . . . . 13
1.4.5 CirculatingMelanomaNoncodingRNABiomarkers. . . 13
1.4.6 CirculatingMelanomaProteinBiomarkers. . . . . . . . . 16
1.4.7 CirculatingMelanomaCells. . . . . . . . . . . . . . . . . . . . 27
1.4.8 MelanomaExtracellularVesicles. . . . . . . . . . . . . . . . 32
1.4.9 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
2 HeadandNeckCancerBiomarkersinCirculation. . . . . . . . . . . . . 41
2.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
2.2 ScreeningRecommendationsforHNC. . . . . . . . . . . . . . . . . . . 43
ix
x Contents
2.3 TheNeedforNoninvasiveScreeningTestsforHNC. . . . . . . . 43
2.4 MolecularPathologyofHNC. . . . . . . . . . . . . . . . . . . . . . . . . 45
2.4.1 MolecularClassificationofHNC. . . . . . . . . . . . . . . . 45
2.4.2 MolecularPathologyofHPV-PositiveHNC. . . . . . . . 47
2.4.3 SpecificGeneticAlterationsinHNC. . . . . . . . . . . . . . 47
2.5 CirculatingHNCBiomarkers. . . . . . . . . . . . . . . . . . . . . . . . . 50
2.5.1 CirculatingCell-FreeNucleicAcidsasHNC
Biomarkers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
2.5.2 CirculatingHNCEpigeneticBiomarkers. . . . . . . . . . . 51
2.5.3 CirculatingHNCNoncodingRNABiomarkers. . . . . . 52
2.5.4 CirculatingHNCSerumProteinBiomarkers. . . . . . . . 53
2.5.5 CirculatingHNCCells. . . . . . . . . . . . . . . . . . . . . . . . 54
2.5.6 CirculatingHPV-PositiveHNCBiomarkers. . . . . . . . 57
2.5.7 HNCExtracellularVesicles. . . . . . . . . . . . . . . . . . . . 58
2.6 NasopharyngealCarcinoma. . . . . . . . . . . . . . . . . . . . . . . . . . . 58
2.6.1 CirculatingEBVDNAinNPCPatients. . . . . . . . . . . . 59
2.6.2 CirculatingNPCExosomes. . . . . . . . . . . . . . . . . . . . 61
2.6.3 EBV-EncodedmiRNAsinNPC. . . . . . . . . . . . . . . . . 63
2.6.4 ClinicalPotentialofCirculatingEBVTargets
inNPCs. . . .. . . . . .. . . . . .. . . . . .. . . . . .. . . . . .. 65
2.6.5 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
3 LungCancerBiomarkersinCirculation. . . . . . . . . . . . . . . . . . . . . 71
3.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
3.2 ScreeningRecommendationsforLnCa. . . . . . . . . . . . . . . . . . 73
3.3 MolecularPathologyofLnCa. . . . . . . . . . . . . . . . . . . . . . . . . 75
3.3.1 GeneticAlterationsinLnCa. . . . . . . . . . . . . . . . . . . . 76
3.3.2 MolecularClassificationofLnCaandPersonalized
Medicine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
3.3.3 MultistepCarcinogenesisandFieldCancerization
inLnCa. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
3.4 CirculatingLnCaBiomarkers. . . . . . . . . . . . . . . . . . . . . . . . . 82
3.4.1 CirculatingCell-FreeNucleicAcidContentasLnCa
Biomarkers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
3.4.2 CirculatingLnCaEpigeneticBiomarkers. . . . . . . . . . . 84
3.4.3 CirculatingLnCaGeneticBiomarkers. . . . . . . . . . . . . 87
3.4.4 CirculatingLnCaCodingRNABiomarkers. . . . . . . . . 89
3.4.5 CirculatingLnCaNoncodingRNABiomarkers. . . . . . 90
3.4.6 CirculatingLnCaSerumProteinBiomarkers. . . . . . . . 92
3.4.7 CirculatingLnCaProteomicBiomarkers. . . . . . . . . . . 96
3.4.8 CirculatingLnCaCells. . . . . . . . . . . . . . . . . . . . . . . . 98
3.5 LnCaExtracellularVesicles. . . . . . . . . . . . . . . . . . . . . . . . . . 101
3.6 CommercialCirculatingLnCaBiomarkerProducts. . . . . . . . .. 102
Contents xi
3.7 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103
4 BreastCancerBiomarkersinCirculation. . . . . . . . . . . . . . . . . . . . 109
4.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
4.2 ScreeningRecommendationsforBrCa. . . . . . . . . . . . . . . . . . . 111
4.3 MolecularPathologyofBrCa. . . . . . . . . . . . . . . . . . . . . . . . . 111
4.3.1 HistopathologicClassificationofBrCa. . . . . . . . . . . . 111
4.3.2 MolecularClassificationofBrCa. . . . . . . . . . . . . . . . 113
4.3.3 ClinicallyRelevantBrCaTranscriptomic
Biomarkers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
4.3.4 MolecularModelofBrCaProgression. . . . . . . . . . . . 116
4.4 CirculatingBrCaBiomarkers. . . . . . . . . . . . . . . . . . . . . . . . . 116
4.4.1 CirculatingCell-FreeNucleicAcidContentasBrCa
Biomarkers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
4.4.2 CirculatingBrCaEpigeneticBiomarkers. . . . . . . . . . . 118
4.4.3 CirculatingBrCaGeneticBiomarkers. . . . . . . . . . . . . 121
4.4.4 CirculatingBrCaCodingRNABiomarkers. . . . . . . . . 123
4.4.5 CirculatingBrCaNoncodingRNABiomarkers. . . . . . 124
4.4.6 CirculatingBrCaProteinBiomarkers. . . . . . . . . . . . . 126
4.4.7 CirculatingBrCaMetabolomicBiomarkers. . . . . . . . . 131
4.4.8 CirculatingBrCaCells. . . . . . . . . . . . . . . . . . . . . . . . 132
4.4.9 CirculatingBrCaStemCells. . . . . . . . . . . . . . . . . . . . 137
4.5 BrCaExtracellularVesicles. . . . . . . . . .. . . . . . . . . . . . . . . .. 138
4.6 Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
5 EsophagealCancerBiomarkersinCirculation. . . . . . . . . . . . . . . . 147
5.1 Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
5.2 RiskFactorsofEsCa. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
5.3 ScreeningRecommendationsforEsCa. . . . . . . . . . . . . . . . . . . 149
5.4 APlaceforEarlyDetectionBiomarkersforEsCa. . . . . . . . . . . 151
5.5 MolecularPathologyofEsCa. . . . . . . . . . . . . . . . . . . . . . . . . 152
5.5.1 Barrett’sEsophagus. . . . . . . . . . . . . . . . . . . . . . . . . . 152
5.5.2 EsophagealCancer. . . . . . . . . . . . . . . . . . . . . . . . . . . 153
5.5.3 EpigeneticChangesinEsCa. . . . . . . . . . . . . . . . . . . . 154
5.5.4 GeneticChangesinEsCa. . . . . . . . . . . . . . . . . . . . . . 155
5.5.5 MultistepEsophagealCarcinogenesis. . . . . . . . . . . . . 159
5.6 CirculatingEsCaBiomarkers. . . . . . . . . . . . . . . . . . . . . . . . . 159
5.6.1 CirculatingCell-FreeNucleicAcidContentasEsCa
Biomarkers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160
5.6.2 CirculatingEsCaEpigeneticBiomarkers. . . . . . . . . . . 160
5.6.3 CirculatingEsCaGeneticBiomarkers. . . . . . . . . . . . . 161
5.6.4 CirculatingEsCaCodingRNABiomarkers. . . . . . . . . 162
5.6.5 CirculatingEsCaNoncodingRNABiomarkers. . . . . . 163
5.6.6 CirculatingEsCaProteinBiomarkers. . . . . . . . . . . . . 166