revbrashematolhemoter.2016;38(2):95–96
w w w . r b h h . o r g
Revista
Brasileira
de
Hematologia
e
Hemoterapia
Brazilian
Journal
of
Hematology
and
Hemotherapy
Scientific
Comment
Comment
on:
“Validation
of
interphase
fluorescence
in
situ
hybridization
(iFISH)
of
CD138
positive
cells
in
multiple
myeloma”
夽
Ilana
Zalcberg
Renault
∗InstitutoNacionaldeCâncer(INCA),RiodeJaneiro,RJ,Brazil
a
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t
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c
l
e
i
n
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o
Articlehistory:
Availableonline18March2016
Geneticstudies playacentralrole inthestudy ofmultiple
myeloma(MM),astheyareacriticalcomponentinthe
risk-basedclassificationofthedisease.Significantefforthasbeen
madetoidentifyandincludegeneticmarkersintheroutine
clinicalcare.TheworkbyKishimotooninterphase
fluores-cenceinsituhybridization(iFISH)ofpurifiedCD138cellsisan
exampleofsucheffort.
iFISHinpurifiedplasmaticcellsisoneofthemostused
techniquesintheclinicalpracticeduetoitsstraightforward
implementationandsimplicityofdataanalysis.iFISHistoday
thestandardtooltodetectgeneticabnormalitiesandfor
dis-easeprognostication.
Itisworthmentioningthatothergenomic–transcriptomic
techniques used in the risk-based classification of MM
patientssuchascomparativegenomichybridization(aCGH),
nextgenerationsequencing(NGS)andgeneexpression
profil-ing(GEPorRNAseq),alsoneedtobeperformedinpurifiedMM
cellstoensureaccurateresults.ThisfactmakesKishimoto’s
articleoftheutmostimportance.
DOIoforiginalarticle:http://dx.doi.org/10.1016/j.bjhh.2016.01.005.
夽
SeepaperbyKishimotoetal.onpages113–20.
∗ Correspondingauthorat:Lab.BiologiaMolecular,CentrodeTransplantedaMedulaOssea,InstitutoNacionaldeCâncer,Prac¸adaCruz
Vermelha,23,6◦andar,20230-130RiodeJaneiro,RJ,Brazil.
E-mailaddress:ilanazalcberg@yahoo.com.br
Genetic
classification
of
multiple
myeloma
MMisahematologicalmalignancycharacterizedbyan
abnor-mal accumulation of clonal plasma cells (PC) in the bone
marrow(BM).Geneticalterationsareobservedfromtheearly
stagesofthediseaseandarekeyeventsintheestablishmentof
theclonalPCpopulation.Geneticalterationshavebeenused
asabasistoclassifythediseaseandpatientsintodifferent
prognosticgroupsand,moreimportantly,maybeusedinthe
nearfutureaspredictivemarkersoftherapeuticresponse.
TheMayoClinic1proposedasimplifiedgeneticbased
clas-sification (mSMART) which segregates patients into three
prognosticgroups:high,intermediateandstandard
accord-ing togeneticalterations.HighriskMMischaracterizedby
del(17p),t(14;16)andt(14;20);intermediatebyt(4;14),1qgain,
complex karyotype, hypodiploidy or metaphase detected
del13,whilestandardriskMM ischaracterizedbyallother
aberrationsincludingtrisomies(especiallyofchromosomes3,
http://dx.doi.org/10.1016/j.bjhh.2016.03.002
1516-8484/©2016Associac¸ ˜aoBrasileiradeHematologia,HemoterapiaeTerapiaCelular.PublishedbyElsevierEditoraLtda.Thisisan
96
revbrashematolhemoter.2016;38(2):95–965,7,9,11,15,19,and21),t(11;14)andt(6;14).Withthe
excep-tionofthechromosome13deletionwhichshowsprognostic
valueonlyifdetectedbycytogenetics;allotheralterationsare
bestevaluatedbyFISH.2
ItseemsthatFISHwillremainthestandardtechniqueto
detectalterationsandsubsequentstratificationofMMinto
dif-ferentiatedriskgroupsuntilgenomicanalysisbecomeseasyto
interpretandcheaper.ArecentreviewfromtheInternational
Myeloma WorkingGroup (IMWG) pinpointed three specific
aberrations,namelytheIGH/FGFR3fusiongene,1q21gain,and
TP53loss,asmarkerstostratifyhigh-riskMMpatientsat
diag-nosisandrecommendtheiruseintheroutinepractice.3
Two pointsshouldbeemphasized regardingthe genetic
changes that drive risk stratification ofpatients with MM.
Thefirstisthatthe singlemostimportantgenetic
progno-sticfactorinMM,irrespectiveoftreatment,thedel(17p)[TP53
mutation],isnotanearlyeventinMMpathogenesisandis
morecommonlydetectedduringprogression.Theotheristhat
theclonalarchitectureofMMatdiagnosisischaracterizedby
multipleclonesand shiftduringprogressionmainlydueto
therapy.Thismayimplythatprognosticevaluationsneedto
beperformednotonlyatdiagnosisbutalsoduringtreatment.
Finally, it is worth noting that the current genetic
classificationisbased onpatients treatedwith
chemother-apy associated or not to autologous transplantation. New
therapiesbasedonproteasomeinhibitors,
immunomodula-tors(IMiDs) and target-specificdrugs are beingintroduced.
Whetherthissamesetofgeneticalterationswillbesufficient
toindividualizetherapyforMMpatientsinthecontextof
pro-teasomeinhibitorsandIMiDsremainstobedefined.
Alternative
methods
for
detecting
genetic
alterations
in
multiple
myeloma
samples
aCGHisanalternativetechnologytotestcopynumber
varia-tionsthatmaygainaplaceinMMgeneticstratificationinthe
near future. The use of an oligonucleotide 8×60K aCGH
platform complemented with iFISH for
t(4;14)[IGH-FGFR3/MMSET]has recentlybeen described forthe routine
diagnosticsettingofMMpatients.4
Whilethisapproachisvulnerableindetectingsmalland
low numbers of clonalalterations atthe TP53 locus when
comparedtoiFISH,itwasmoreeffectiveindetectingcryptic
losses withintheIGHregion [14q32].Itwassuggestedthat
this approachwas cost neutralwhen comparedwith FISH
screeningandofferstheadvantageofawholegenomescan.
Then again, there are suggestions that the use ofgene
expressionprofiles(GEP)asatechniquetodetect
transloca-tionsinthedetectionofthe17pdeletionmayreplaceiFISH
asatoolforriskstratificationinMM.Finally,nextgeneration
sequencing,ifincludedintheMMevaluation,mayreveal
mod-ificationsinimportantactionabletargetssuchasKRAS,NRAS,
BRAF,FGFR3,CCND1,IDH1,andIDH2.
Nevertheless,untilhigh-resolutiontechniquesarereadyto
entertheclinicalpractice,FISHwillprobablycontinuetobe
thebesttooltoestablishaprognosisforMMpatients.
Conflicts
of
interest
Theauthordeclaresnoconflictsofinterest.
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1.MayoClinic.Availablefrom:www.msmart.org[accessed
03.03.16].
2.BraggioE,KortümKM,StewartKA.SnapShot:multiple myeloma.CancerCell.2015;28(5):678.e1.
3.ChngWJ,DispenzieriA,ChimCS,FonsecaR,GoldschmidtH, LentzschSH,etal.IMWGconsensusonriskstratificationin multiplemyeloma.Leukemia.2014;28(2):269–77.
