ObstetGynecolClinNAm33(2006)1339

TheGeneticHeterogeneityofUterine
Leiomyomata
MelissaK.Lobel,BS,PriyaSomasundaram,MD,CynthiaC.
Morton,PhDT
DepartmentsofObstetrics,Gynecology,andReproductiveBiologyandPathology,Brighamand
WomensHospitalandHarvardMedicalSchool,77AvenueLouisPasteur,NRB,Room160,
Boston,MA02115,USA

Gotfibroids?Formostwomeninthethirdorfourthdecadeoflife,theanswerto
thisquestionisprobablyyes.Pathologicexaminationoftheuterusshowsthat
approximately77%ofwomenofreproductiveagehaveuterineleiomyomata
(UL);however,only20%to25%ofthesewomenaresymptomatic.ULshow
considerablemorbidity,causingmedicallyandsociallysignificantsymptoms,such
asseveremenorrhagiaandpelvicdiscomfort.Whileatypicalmenstrualperiod
lasts4to5days,womenwithULoftenendureperiodsof7ormoredays.Such
severebleedingcanbedebilitatinginrestrictingwomenfromengagingintheir
dailyactivities,andhasbeenreportedtoleadtoanemiaandevenblood
transfusionsinsomecases.WomenwithsymptomaticULcanalsosufferfrom
urinaryincontinence,orrectaltenesmusandconstipation,iftumorsimpingeon
theurinarybladderorrectum,respectively[1,2].Further,ULareassociatedwith
reproductivedysfunction,oftencontributingtoinfertilityandcomplicationsin
pregnancy.ULareresponsibleforapproximately2%to3%ofallinfertilitycases
[2],andarepresentin1.4%to2%ofallpregnancies[3,4].Ofthesepregnancies,
10%developcomplications[4],suchasspontaneousabortion,prematurelabor,
prematureruptureofthemembranes,antepartumandpostpartum
ThisworkwassupportedbyNationalInstitutesofHealthgrantCA78895(toCCM).T
Correspondingauthor.Emailaddress:cmorton@partners.org(C.C.Morton).
08898545/06/$seefrontmatterD2006ElsevierInc.Allrightsreserved.
doi:10.1016/j.ogc.2005.12.006obgyn.theclinics.com

14lobeletal

hemorrhage,postpartumsepsis,breechpresentation,andplacentalabruption,and
mayrequirecesareansection[38].
Alsoknownasfibroidsormyomas,ULarethemostcommonpelvictumor
inwomen.Arisingfromthemyometriumoftheuterus,ULarebenignneoplasms
thatarehistologicallyseenaswelldifferentiated,whorledbundlesofsmooth
musclecellsformingdistinctnodules.Veryrarely,estimatedatarateofb0.1%,do
malignanciesariseattributedtoULintheformofuterineleiomyosarcomas[2].
TheaverageaffecteduterusexhibitssixtosevenUL,whichcanrangeinsizefrom
10mmtoover20cm[1].Anatomically,ULarefoundinintramural,subserosal,
orsubmucosallocations,andtumorssometimesappearaspedunculatedor
polyploid.AlthoughULaremostcommonlyfoundintramurally,submucosalUL
arereportedtobethemostsymptomatic[9].
ULaresteroidhormonedependenttumors,withestrogenandprogesterone
playinganimportantroleingrowthanddevelopment[10].Estrogeninparticular
isbelievedtobeamajorgrowthstimulusforthesetumors[11],demonstratedby
thefactthatULareonlyseenpostpuberty,growrapidlyduringpregnancy,and
regresspostmenopausally[12,13].RiskfactorsforUL,suchasobesityandearly
ageofmenarche,furthersupportestrogensroleinULdevelopment,asthese
elementsincreaseawomansoveralllifetimeexposuretothehormone.Incon
trast,itwasfoundthatchildbearingatalaterageisinverselyassociatedwiththe
riskofdevelopingUL;thisfindingisintuitivegiventhatparitydecreasesestrogen
exposure[14].DespitethegrowingevidenceforestrogenseffectsonUL,
however,theroleoforalcontraceptivepillsandhormonereplacementtherapyin
ULgrowthanddevelopmentremainscontroversial[15].
Severalrecentlydevelopednonsurgicalmedicaltherapiesarehormonebased,but
thetraditionaltreatmentforULishysterectomy.ULarethemostcommon
indicationforhysterectomyintheUnitedStates,leadingtoover200,000
proceduresperformedannually[16].Byage60,30%ofwomenintheUnited
Stateshavehadahysterectomy,and60%ofthesesurgeriesareduetoUL[17].
BecauseULmostoftenaffectwomenofreproductiveage,andhysterectomyisthe
onlydefinitivetreatmentforthiscondition[16],manywomenmustgrapplewith
theemotionalimplicationsofsurrenderingtheirfertilitypriortochildbearing.
Hysterectomyisalsoamajorinvasiveprocedurewithanestablishedmortalityof
11per10,000surgeries[18].
Anothersurgicaloptionforwomenismyomectomy,whichisamorecon
servativeprocedurethanhysterectomy.MyomectomyservestoremoveULbut
retaintheuterus,thuspreservingfertility,andcanevenbeperformedduring
pregnancy.Upto25%ofwomenhavearecurrenceofULpostmyomectomy,

however,and10%needasecondmajorprocedurewithin1to10years[1921].
Further,myomectomyismorelimitedanatomicallythanhysterectomyinthat
intramuralULaredifficulttoaccessbythisprocedure[22].Uterinearteryem
bolizationontheotherhandisparticularlyusefulinthetreatmentofintramural
UL[23].Althoughuterinearteryembolizationisshowntosignificantlytoim
provemenorrhagiaandpelvicpainby85%andtoreducetumorsizeby50%
[24,25],theimpactonfuturefertilityandpregnancyisunclear[22].
geneticheterogeneityoful15

InOctober2004,FoodandDrugAdministrationapprovalwasreceivedforMRI
guidedfocusedultrasoundsurgery,anoninvasivethermoablativetherapy.This
procedureisinnovativeinitsabilitytotargetspecificUL,andconserveshealth
caredollarsbyallowingforoutpatienttreatmentandshorterrecoveryperiods[26].
Asofyet,however,theprocedureisneitherwidelyavailablenorcoveredby
healthinsurance.
Althoughdesirable,currentlyavailablenonsurgicalmedicaltherapiesareoften
ineffectiveineliminatingULandpreventingrecurrence.Gonadotropinreleasing
hormone(GnRH)analoguetherapyisaFoodandDrugAdministrationapproved
drugforULtreatment,butisseverelylimitedinitsuse.WhileGnRHiseffective
asashorttermpreoperativetreatmentbyreducingtumorsizeandbleeding,itcan
inducemenopausallikesymptoms[22].Inaddition,discontinuationofGnRH
therapyoftenresultsinregrowthofULtotheiroriginalvolume[27].Other
therapies,suchassyntheticprogestinsandoralcontraceptivepills,wereexpected
todecreaseuterinesizeandmenorrhagiabypromotingendometrialatrophy,but
thesetreatmentswereinsteadfoundtostimulateULgrowth[28,29].
BecauseULhavebeenshowntopossesselevatedlevelsofestrogenreceptorsand
progesteronereceptors[30],therapieshavebeendevelopedtargetingthis
characteristic.Anantiprogesterone,RU486,whichremainsunavailableinthe
UnitedStates,hasbeenfoundtoreduceestrogenreceptorsandprogesterone
receptors,suppressULgrowth,andproduceamenorrhea;thelongtermeffectsof
thisdrug,however,remainunknown[31].Morerecentmedicaltherapieshave
beendevelopedintheformofselectiveestrogenreceptormodulatorsandselective
progesteronereceptormodulators.Selectiveestrogenreceptormodulator
treatmentwithraloxifenehasbeenshowntodecreaseULsizeinpostmenopausal
women,butonlyiseffectiveincombinationwithGnRHtreatmentin
premenopausalwomen[32].
DespitethemajorpublichealthimpactofUL,littleisknownabouttheetiology
ofthesetumors.ULcurrentlyaccountforover$1.2billionhealthcaredollars

annually[33],yetresearchremainsgrosslyunderfundedwhencomparedwiththat
ofotherbenigndiseases[22].Nevertheless,epidemiologic,molecular,and
cytogeneticresearchhasbeguntoexplorethepathogenesisandpathobiologyof
UL,uncoveringaclinical,pathologic,andcytogeneticheterogeneityinUL
tumors.ThisresearchsuggestsastronggeneticcomponenttoULdevelopment,
andimpliesthepresenceofmultiplemechanismsoftumorgrowth.
Epidemiologicaspectsofgeneticliability
AnepidemiologicapproachtoULresearchisessential,asitservestoassessthe
geneticbasisoftumordevelopment.Ethnicpredisposition,twin,andfamilial
aggregationstudieshaveallbeenundertakentounderstandthecausesofheri
tability.Inaddition,othergeneticdiseasesassociatedwithULhavebeenex
aminedindepthtoidentifyrelatedpredispositiongenes.
16lobeletalEpidemiologicstudies

EthnicpredispositionstudieshaveshownthatAfricanAmericanwomenhavea
threetoninetimeshigherprevalenceofULincomparisonwithwomenofother
racialandethnicbackgrounds[34].TheNursesHealthStudyconfirmedthisdata,
afteradjustingfordifferencesbetweenracesinsuchfactorsassocioeconomic
statusandaccesstohealthcare,aswellasobesityandparity[35].African
AmericanwomenhavealsobeenshowntohaveanearlierageofULdiagnosis,
higherhysterectomyrateforUL,largerandmoreabundanttumors,andmore
severesymptoms.Differencesbetweenracesinothergynecologicconditions,
however,suchasmenstrualproblemsandadnexalailments,areminimal,
suggestingageneticcomponenttoULpathogenesis[3537].
FamilialaggregationstudieshaveexaminedtheclusteringofULwithinfamily
groups,andfurthersupporttheheritabilityofthesetumors.Astudyperformedin
theUnitedStatesshowedthatfirstdegreerelativesofwomenwithULare2.5
timesmoreatriskofdevelopingtumorswhencomparedwithwomenwithout
affectedrelatives.Thisriskincreasesto5.7forpatientswithanaffectedfirst
degreerelativeoflessthan45yearsold[38],thusconcludingthatULaremore
prevalentinfamilieswithanearlyonsetofthedisease.AsimilarRussianstudy
echoedthisfamilialaggregation,determiningthatULdiagnosisismore
commonlymadewhentwoormorefamilymembershavealreadydeveloped
tumors[39].
TwinstudieshavesuggestedageneticpredispositionforULthroughexami
nationofhysterectomydata,asULarethemostcommonindicationforthe
procedure.Monozygotictwinshavebeenshowntohavetwotimesthecorrelation

forhysterectomythandizygotictwins,concordantwiththedegreeoftheirgenetic
relationship[40].Inaddition,aFinnishtwincohortstudyfoundthatmonozygotic
twins(r=0.31)hadnearlytwicetherateofhospitalizationbecauseofULwhen
comparedwithdizygotictwins(r=0.18)[41],suggestingthatseverityofthe
diseaseisalsoaninheritedfactor.
Heritablediseasesrelatedtouterineleiomyomata
ExaminingheritablediseasesthatincludeULasaphenotypicfeatureofthe
syndromeisinvaluableindeterminingpredispositiongenes,especiallywhen
evaluatingsuchanonsyndromicandheterogeneousdisorderasUL.Inparticular,
syndromesinheritedinaclearMendelianpatternareusefulingeneidentification
byemployinggeneticlinkageanalysis.ULhavebeenassociatedwithReeds
syndrome,BannayanZonanasyndrome,Cowdensyndrome,andhereditaryleio
myomatosisandrenalcellcancer(HLRCC)andshareapathogeneticrelationship
insomeinstances.
Reedssyndrome,alsoknownasfamilialleiomyomatosiscutisanduteri
(MIM150800),isanautosomaldominanttraitwithreducedpenetrance.Females
withReedssyndromesufferfrombothULandcutaneousleiomyomata,thelatter
ofwhichappeartooriginatefromerectorpilimuscles[42].Studiesoffamilies
geneticheterogeneityoful17

withthisdisordersuggestthatpredispositionforULalonemayalsobeinheritedin
anautosomaldominantmanner,ormaypossiblybeanautosomalrecessiveorX
linkeddominanttrait.Noneofthesepatternsofinheritance,however,haveyet
beenclearlydemonstratedinULasasolitaryphenotype[43].
BannayanZonana(MIM153480)andCowden(MIM158350)syndromesareboth
typesofautosomallydominanthamartomatouspolyposisdisordersthatare
characterizedbylipomas,intestinalhamartomatouspolyps,andothernonneo
plasticmanifestations[44].Cowdensyndrome,however,remainsuniqueinits
potentiallymalignantnature,andcarriesahighriskofdevelopingbreastand
thyroidcancers[45].Sincethetwodiseasesinvolvelipomasandhamartomas,
bothofwhicharepathogeneticallyrelatedtoUL,theyareimportanttoolsinthe
identificationofpotentialpredispositiongenes[44].
Severalhereditarycancersyndromeshavebeenobservedthatpredisposepatients
toUL,suchasHLRCC,tuberoussclerosiscomplex,andBirtHoggDube
syndrome.Interestingly,ageneticlinkagehasbeenshownwithallthreeofthese
disordersandrenalcellcarcinoma[46].HLRCC(MIM605839)inparticularhas
beenwidelystudiedinrelationtoUL,andisknowntobeanautosomaldominant

disorderwithsymptomsincludingsmoothmuscletumorsoftheskinanduterus
andpapillarytypeIIrenalcellcarcinoma[4749].
Otherrelatedsyndromes,suchasangioleiomyomataanddisseminatedperitoneal
leiomyomatosis(DPL),havealsobeeninvestigatedinthegenediscoveryquestfor
UL.Alsoknownasangiomyxomasorvascularleiomyomata,
angioleiomyomataarepainfulbutbenignsubcutaneousordeepdermaltumors
mostoftenseenintheextremities[50,51].DPLontheotherhandisararedisease
infemalesthatinvolvesnodularproliferationsthroughouttheomentaland
peritonealsurfaces;histologically,DPLiscomprisedofbenignsmoothmuscle
similartoUL[52].Besidestheirhighdegreeofsymptomaticandhistologic
similarity,thesediseases,inadditiontoReedssyndromeandHLRCC,have
shownoverlapwithULcytogenetically.
Molecularapproachestodecipheringgeneticmechanisms
TheheterogeneityofULgrowthanddevelopmenthasbeenfurtherestablished
throughmolecularresearch.Clonalitystudiesusingglucose6phosphate
dehydrogenase(G6PD)isoenzymeanalysisandthoseusingandrogenreceptor
(AR)geneassayshavebothfoundthatULaremonoclonalindependentlesions,
suchthatmultipletumorsfromthesameuterusariseindependentlyandmayhave
distinctchromosomalabnormalities.Thesestudieshavebeenimportantin
resolvingthatULareclonaldespitetheircytogeneticmosaicisminsomecases.
Clonalitystudies:glucose6phosphatedehydrogenaseanalysis
ULwereoneoftheoriginaltumortypesstudiedbyG6PDisoenzymeanalysisand
provedbythismethodtobeclonaltumors.Oneoftheinitialstudiesusing
18lobeletal

thistechniqueinvolvedusingpolymorphicisoenzymesofXlinkedG6PDin
independenttumorsfromsevenwomenheterozygousforthisenzyme.Itwas
notedthatbothAandBtypeisoenzymescouldbefoundwithinthesamepatient,
thereforeindicatingthatULariseindependentlyandaremonoclonal[5355].
BecausemammalianfemaleshaveessentiallyonlyoneactivatedXchromosome
andonlyoneactiveG6PDalleleineachcell,thisresultwasexpectedforaclonal
tumor,suchasUL[56].Thismethod,however,islimitedinthenumberof
individualswhoqualifyforanalysisbecausewomenmustbeheterozygousforthe
G6PDenzyme;thisisduetothefactthatG6PDisoenzymeanalysisisnota
particularlypolymorphicmarkersystem.Despitetheseconstraints,G6PDiso
enzymestudieswereessentialindisplayingarandompatternofinactivation
amongmultipletumors,provingthatmultipletumorswithinasingleuterusarise

independently,andestablishingthemonoclonalnatureofUL[53,57].
Clonalitystudies:ARgeneanalysis
AssaysbasedontheARgenebothconfirmedandexpandedontheG6PD
clonalitystudies.InevaluatingthehighlypolymorphictrinucleotideCAGrepeat
intheXlinkedARgene,thismethodprovedsuperiortopreviousstudiesin
expandinginformativenessforanalysis.Takingadvantageofthefactthatonlyone
Xchromosomeisactivatedinmammalianfemales,aswellasthemethylation
sensitiverestrictionenzymesiteupstreamoftheCAGrepeatsintheARgene,
oligonucleotideprimerpairsweremadetoflanktheCAGrepeatsforDNAam
plification.TheamplifiedDNAwasthendigestedwithamethylationsensitive
restrictionenzyme,suchasHhaI,inindividualswithvaryingnumbersofCAG
repeats[54].Monoclonalitywasdeterminedinthiswaybyobservingarandom
patternofXchromosomeinactivationamongmultipletumorsfromthesame
patient,suchthatindividualULexpressedonlyoneoftwoalleles[58].Ifthe
tumorswereinsteadpolyclonal,bothmaternalandpaternalXchromosome
productswouldbefound,aseitherXchromosomecouldberandomlyinactivated
[54].ItshouldbenotedthatULgrowingwithincloseproximityandsampledasa
singletumormayappeartobepolyclonal,butareinfacttwoindependent,
monoclonalneoplasms[59].
Evaluatingclonalityin36ULfrom16patientsconfirmedtheseexpectedresults;
onlyoneARallelewasexpressedineachtumorbutbothalleleswererandomly
presentinthetumorpopulation[54].TheARassaynotonlyconfirmedclonality
datafromearlierresearch,butalsoprovidedamethodinwhichtostudyclonality
inchromosomallymosaictumors.ManyabnormalULareinfactmosaic,inthat
theyhaveamixtureofbothchromosomallynormal(46,XX)andabnormalcellsin
thesameculture[54,60].AtBrighamandWomensHospital,approximately30%
of217ULtumorsanalyzedwereshowntohaveabnormalkaryotypescoexisting
withnormal46,XXcells[61].Further,byindependentlyestablishingclonalityand
mosaicisminthesetumorsbytheARassay,itwasproventhatthesetwounique
attributesoccurtogetherinUL.However,examinationofclonalitydatain
conjunctionwiththefactthatmostULarechro
geneticheterogeneityoful19

mosomallynormalsuggeststhatcytogeneticabnormalitiesmaybesecondaryto
establishmentofclonalityintumorigenesisofgeneticallypredisposedcells[15].
RecentresearchexaminedthenumberofCAGrepeatsintheARgenetoascertain
apossiblecorrelationwithsusceptibilitytoUL.In159womenwithULand129
womenwithoutUL,itwasfoundthatthenumberofCAGrepeatsrangedfrom9

to31andwomenwith27CAGrepeatswerereportedtohaveahigherriskofUL
pathogenesis[62].
Cytogeneticanalysisofuterineleiomyomata
Only40%ofULarekaryotypicallyabnormal,exhibitingnonrandomandtumor
specificchromosomalaberrations[63,64].AbnormalUL,whencomparedwith
normalUL,aregenerallymorecellular,haveagreatermitoticindexandlower
DNAcontent,andalsofailtoproduceadecreaseinDNAcontentafterGnRH
agonisttherapy[65,66].Abnormalkaryotypesareoftenobservedin
chromosomallynormalcells,implyingthatneoplastictransformationoccursin
susceptiblecellspriortoanychromosomalchanges[54].Theother60%ofULare
chromosomallynormal[67],suggestingthatgeneticaberrationsmaybesub
microscopicforthesetumors;thisobservationreiteratesthebeliefthatcyto
geneticabnormalitiesmaybesecondarychangesinsusceptiblecells[15,61].
InconcordancewiththeestablishedclinicalandpathologicheterogeneityofUL,
thesetumorsalsodisplayaheterogeneouscytogeneticmakeup.Prompting
researchexaminingthegenotypicandphenotypicpatternspresentinUL,this
cytogeneticdiversityhasbeenobservedintheformofvarioustranslocations,
deletions,andtrisomies.Themostprevalenttypesofchromosomalrearrange
mentsfoundinULincludet(12;14)(q14q15;q23q24),rearrangementof6p21,
anddel(7)(q22q32).Otherlesscommonlyobservedcytogeneticabnormalitiesare
rearrangementsof1p36,10q22,13q2122,andoftheXchromosome,partial
deletionof3q,andtrisomy12.Thevarietyoftheseaberrationsinsinuatesthat
multiplegeneticmechanismsexistinULtumorigenesis,whichisinaccordwith
thefactthatthesetumorsarehighlyprevalent[68].Cytogeneticstudiesstriveto
identifyspecificgenesinvolvedinchromosomalrearrangementofUL,andseekto
understandthediversegeneticpathwaysleadingtoULpathogenesis.
Genotypicandphenotypiccorrelationsofuterineleiomyomata
InexaminingULwithabnormalkaryotypes,certaincorrelationsbetweentumor
genotypeandclinicalphenotypehavebeenobserved.Anatomicallyspeaking,
only12%ofsubmucosalULhavechromosomalrearrangements,followedby
subserosalUL(29%)andthenintramuralUL(35%)[69].However,inspiteof
theirlowfrequencyofkaryotypicrearrangement,submucosalULarehighly
symptomaticandcancauseseveremenorrhagiabecauseoftheiranatomic
proximitytotheendometrium[70].
20lobeletal

Anotherestablishedassociationisthatbetweentumorsizeandtypeofkaryotypic

abnormality.ULwithdel(7)(approximately5cm)tendtobearoundthesamesize
askaryotypicallynormaltumors(approximately5.4cm),butsmallerthanULwith
t(12;14)rearrangements(approximately8.5cm).Thisstudysampleinvolved73
karyotypicallynormaland41karyotypicallyabnormaltumors,butcouldonly
establishatrendratherthanstatisticalsignificance[67];however,aclearerpattern
emergedamongabnormalmosaicandnonmosaictumors.ManymosaicUL,most
withdel(7)rearrangements,aresmallerinsizethantheirchromosomallynormal
counterparts,indicatingthatalossofgeneticmaterialfromchromosome7may
impairULgrowth[60].Itshouldbenoted,however,thatlargerULaremore
likelytobechromosomallyabnormalthansmallerUL[67].
Thusfar,nocorrelationhasbeenestablishedinULbetweentypeofcytogenetic
aberrationandpatientageorparity[71].However,futureanalysisofthe
relationshipbetweengenotypeandphenotypeinthesetumorsseekstoexplore
theseareasfurther,aswellaspossibleassociationswithrace,ethnicity,fibroid
recurrence,ageofonset,andresponsivenesstoGnRHagonisttherapy[56,61].
Thet(12;14)subgroup
TwentypercentofULwithkaryotypicrearrangementspresentast(12;14)(q14
q15;q23q24),makingitthemostcommonchromosomaltranslocationinthese
tumors(Fig.1A)[72].Mostchromosome12translocationsinULinvolve
chromosome14asapartner,atraitalmostuniquetothistypeofmesenchymal
tumor,althoughchromosomes2,4,22,andXhavealsobeenobservedinthese
translocations[73].Althoughthiswasthefirstcytogeneticaberrationfoundtobe
associatedwithUL[72],the12qregionhaslongbeenestablishedasachro
mosomalanomalyinothermesenchymaltumors,suchasangioleiomyomata[74],
breastfibroadenomas[75],endometrialpolyps[76],hemangiopericytomas[77],
lipomas[78],pulmonarychondroidhamartomas[79],salivaryglandadenomas
[80],andlipoleiomyomas[81].Theimplicationofthisregioninsomanymesen
chymaltumorssuggeststhatthisareacontainscriticalgenesintumorigenesis,and
ledtothefocuson12q15inthefirstpositionalcloningprojectsusedtolocate
genesinvolvedinULformation[61].
Inpursuitofpositionalcloningdataforchromosome12attheq15breakpoint,a
highdensityphysicalmapwasdeveloped.Ayeastartificialchromosomewasthen
identifiedbyfluorescenceinsituhybridization(FISH)analysisontumor
metaphasechromosomes.Thisyeastartificialchromosome,981f11,bridgedthe
translocationbreakpointsinUL,pulmonarychondroidhamartomas,andlipomas
andwascrucialinpinpointingthespecificareaonchromosome12likelyto
containgenescriticalinthedevelopmentofthesetumors[81].Ahighmobility
group(HMG)gene,HMGA2(previouslyknownasHMGIC),wasmappedtothe

yeastartificialchromosomecloneandbecameanattractivepotentialcandidate
geneinULpathogenesis[82].Ahomologousgeneinmiceonchromosome10,
Hmga2(previouslyknownasHmgic),waspreviouslyimplicatedincell
geneticheterogeneityoful21

Fig.1.ComparisonofcytogeneticallyabnormalULkaryotypeandleiomyosarcomakaryotype.
(A)At(12;14)(q14q15;q23q24),themostcommontranslocationinUL,hasbeenshownto
resultinelevatedexpressionofHMGA2.(B)Uterineleiomyosarcomasarekaryotypicallymore
complexandmoregeneticallyunstablethanUL.
22lobeletal

proliferationanddifferentiationofmesenchymaltissues[83],pointingtothe
possibleroleofHMGA2inhumanmesenchymaltumordevelopment;thisiseven
moresignificantwiththeknowledgethat96%evolutionaryconservationexists
betweenmouseandhumanhomologs[84].Alargegenewithalargetargetfor
rearrangement,HMGA2sinvolvementinchromosome12q15rearrangementshas
sincebeenconfirmedbyFISHstudiesandmolecularexperimentson
mesenchymaltumors[82,85].
HMGA2codesforanarchitecturalfactorthatispartoftheheterogeneousHMG
familyofnonhistoneDNAbindingproteins[84].Studieshaveindicateda
relationshipbetweenelevatedHMGA2expressionandcellularproliferation,with
invitroexperimentssuppressingHMGA2expressionandthenobservinga
reversalofthetumorigenicphenotypeinconjunctionwithinhibitionofcellular
transformation[8688].Structurally,HMGA2encodesthreeDNAbindingmotifs
thatincludesAThooks,regionsthathavebeenidentifiedashavingacrucialrole
ingeneactivity[84].SeveralpossiblemechanismsofHMGA2dysfunctionexist,
andintragenicrearrangementscanleadtodisruptionofregulatorysequences;
however,mostt(12;14)abnormalitiesinULarecausedbyextragenicrearrange
mentsofHMGA2[44,85].
ToassessifdysregulationofHMGA2isafactorintumorgrowthinasubgroup
ofUL,aNorthernblotwasperformedonRNAfromunculturedtissueoffiveUL
witht(12;14)rearrangementsandtheirnormalmatchedmyometrium.Gene
expressionwasobservedinfouroftheULandnoneofthematchedmyometrium.
HMGA2expressionhasalsobeennotedtobeelevatedinULwitht(12;14)
rearrangementswhencomparedwithkaryotypicallynormaltumors[44].
Becausemostt(12;14)rearrangementsoccuroutsideoftheHMGA2coding
region,theentiregeneismovedfromexistingnormalregulatoryregionsto
novelones.FISHanalysisofover24ULshowednearlyallbreakpointsmapping
10to100kilobase(kb)upstreamor5VofHMGA2,withafewULexhibiting
breakpointsmapping3Vofthegene;all,however,leftthecodingregionof
HMGA2intact[44].Theexactmolecularmechanism(s)involvedinHMGA2
dysregulationinULremainunclear,althoughformationoffusionmRNA
transcripts,proteintruncation,anddisruptionofHMGA2regulatorysequences
haveallbeenobservedinchromosome12translocationstudiesinULandother

benignmesenchymaltumors[61].Inonesuchcasestudy,an8yearoldboywith
multiplelipomaspresentedwithapericentricinversionofchromosome12,
inv(12)(p11.2;q14.3),implicatingHMGA2andexhibitingthefirstknown
constitutionalrearrangementofthisgene.Furtherclinicalandgeneticanalysisof
thisuniquecasemayprovideclarityastotheroleandmechanismsofHMGA2in
humangrowthanddevelopment,aswellasinbenignmesenchymaltumori
genesis[89].
Althoughregion12q15andHMGA2havebeenthoroughlystudied,thegeneson
chromosome14implicatedint(12;14)rearrangementsremainmoreelusive.Since
thebreakpointregiononchromosome14wasinitiallyidentified,mapped,and
clonedtoq24[90,91],severalgeneshavebeenproposedtobeinvolvedinthis
translocationincludingtheestrogenreceptorbgene(ESR2)andRAD51L1
geneticheterogeneityoful23

(alsoknownasRAD51B,hREC2,andR51H2).Locatedonthelongarmof
chromosome14(14q23q24)approximately2megabase(Mb)fromthet(12;14)
breakpoint,ESR2wasconsideredasapotentialcandidategenebecauseofthe
responsivenessofULgrowthtoestrogen.However,expressionanalysisfailedto
indicateanydifferenceinESR2transcriptionlevelsbetweenULwithandwithout
t(12;14)rearrangements,makingtheESR2geneunlikelytohaveadirectrolein
ULpathogenesis[9294].
RAD51L1,ontheotherhand,hasbeenfoundtoberearrangedinsomet(12;14)
ULcases,albeitinfrequently[44].Also,mappingtochromosomebands14q23
q24,RAD51L1isinvolvedinDNArecombinationrepair,cellproliferation,cell
cycleprogression,andapoptosis[95,96],allpointingtowardapossiblerolein
tumorigenesis.AlthoughfusiontranscriptsarerarelyfoundinULwitht(12;14)
rearrangementsduetotheextragenicnatureofthebreakpoint,fusiontranscriptsof
RAD51L1andHMGA2havebeenobservedinsomet(12;14)UL.FISHanalysis
andreversetranscriptasepolymerasechainreactionhavebothbeenusedintrying
todeterminetheexpressionofHMGA2RAD51L1andRAD51L1HMGA2
fusiontranscriptsinULcells,butthepathobiologicsignificanceofthisfusionis
yettobeelucidated[97].PartnergenesforHMGA2otherthanRAD51L1have
beenshowninfourUL,butnotwithintheestablished14q23q24breakpoint.
TheseincludeCOX6Cat8q22q23[98],ALDH2at12q24.1[99],HEI10at14q11
[100],andthe3VRTVLHgeneonchromosome12[101].Althoughtheirexact
roleisunknown,itispossiblethatthesegenesarepartofalternativetranslocations
involvingchromosome12orarepartofmorecomplextranslocationsinvolving
bothchromosomes12and14[71];regardless,thegenesonchromosome14
involvedint(12;14)translocationsmeritfurtherinvestigation.

The6p21rearrangementsubgroup
Rearrangementsofchromosome6atbandp21occurinlessthan10%of
karyotypicallyabnormalUL.Typically,theserearrangementsinvolvetrans
locationswithchromosomes1,2,4,10,and14,andspecificallyhavebeenob
servedast(1;6)(q23;p21),t(6;14)(p21;q24),andt(6;10)(q21;q22)[64,102106].It
shouldbenotedthatrearrangementsarerarelyseeninULbetweenband6p21and
thesameregionofchromosome14implicatedint(12;14)translocations.Other
benignmesenchymaltumors,suchaslipomas,pulmonarychondroidhamartomas,
andendometrialpolyps,alsoexhibit6p21rearrangements,andatamuchhigher
frequencythanUL;inparticular,theseaberrationsmostoftenappearast(6;14)
translocationswithband14q23q24involvedasinULt(12;14)rearrangements
(Fig.2A)[106112].
AnotherHMGgene,HMGA1(previouslyknownasHMGIY),hasbeenidentified
asresidinginband6p21.PartofthesamefamilyasHMGA2,HMGA1isalsoan
architecturalfactorgenecodingforanHMGprotein.AfterHMGA2was
identifiedashavinganassociationwitht(12;14)UL,alteredexpressionof
HMGA1wasrecognizedashavingaroleinULwith6p21rearrangements.This
rolewasconfirmedthroughFISHanalysis,inwhichmetaphasesfroma46,XX,
24lobeletal

Fig.2.KaryotypicrepresentationofspecificchromosomalaberrationsinUL.(A)t(6;14)
(p21;q24)hasbeenobservedinULandothermesenchymaltumors,andimplicatesHMGA1at
band6p21.(B)Tumorswithdel(7)(q22q32)abnormalitiesarelesscommonandgenerallysmaller
insizethantumorswitht(12;14)translocations.(C)AminorcytogeneticsubgroupofUL,
t(10;17)(q22~q24;q21~q22),hasbeenobservedinasubsetoftumorsandinvolvestheMORF
geneatthe10q22breakpoint.

inv(6)(p21q15)ULshowedhybridizationsignalsat6p21and6q15correspond
ingtoasplitintheclonecontainingHMGA1[113,114].Electrophoreticmobility
shiftassaywasalsousedinanalysisofHMGA1expressioninULwith6p21
rearrangements,andelevatedbindingactivitywasdetectedin9of16ULexam
ined.Incontrast,noHMGA1activitywasdetectedinanymatchedmyometrial
tissue[15].Otherresearch,however,hasindicatedsomelevelofHMGA1ex
pressioninkaryotypicallynormalUL,inkaryotypicallyabnormalULwithre
arrangementsotherthan6p21,andinmatchedmyometrium,suggestingwider
expressionofHMGA1thanHMGA2[68].
ComparisonofHMGA2andHMGA1
AlthoughHMGA2andHMGA1aresimilarstructurallyandmechanistically,both
contributingtothedevelopmentofULwhendisruptedordysregulated,theydiffer
intheirexpressionpatterns,function,andmeansofregulation.Inastudyof17
UL,noneshowedbothHMGA2andHMGA1expression,andexpressionof
neithergenewasobservedinsomeUL;thisindicatesnotonlythattheHMG
proteinsplayasimilarroleinULpathobiology,butalsothatanotherrelatedgene
geneticheterogeneityoful25

mayexistthatservesaparallelfunction[15].Thehighestlevelofbothgenesis
seenintumorcellsandinnormallydevelopingembryonictissue,although
HMGA2hasbeendetectedatlowlevelsinadultkidneyandlungtissuesandthe
lessrestrictedexpressionpatternofHMGA1showslowlevelsofthegeneinmany
normalnonproliferatingadulttissues[115,116].Thismaysuggestamore
diversifiedroleforproteinHMGA1beyondservingsolelyasaproliferationfactor
[56].
TheHMGproteins,andspecificallytheHMGIproteinsHMGA2andHMGA1
encodedbyHMGA2andHMGA1,respectively,arechromatinarchitecturaland
DNAbindingfactorsthatarehypothesizedtoplayaroleingenomicstability
[117].BybindingtotheminorgrooveofATrichDNAthroughtheAThook,
theseproteinsaffectgeneactivitythroughvariousproteinproteinandprotein
DNAinteractions[118,119].Specifically,DNAconformationismodulatedand
accesstotranscriptionfactorstotargetgenesisregulated,althoughtheproteins

themselvesappeartohavenotranscriptionalactivity.Ingeneral,HMGA2and
HMGA1serveasproliferationfactorsinnormalgrowingtissues,particularly
thoseofmesenchymalorigin,andalsoinfluenceavarietyofothercellular
processes,suchasdifferentiation,growth,andapoptosis[120,121].Althoughit
hasbeenfirmlyestablishedthattheHMGproteinsHMGA2andHMGA1playa
roleinULpathogenesis,theirexactfunctionisyettobedetermined;itremains
unclearifbindingoftheHMGfamilytranscriptionfactorsservestoinducegene
expressionorifbindingpreventsactivationoftumorsuppressorgenes[122].
Thedel(7q)subgroup
Occurringinapproximately17%ofkaryotypicallyabnormalUL,del(7)(q22q32)
isaninterstitialdeletionofchromosome7thatusuallyoccursinmosaicULwith
46,XXnormalcells(Fig.2B)[60,123125].Althoughdel(7)(q22q32)and
translocationsinvolving7q22q32havebeenobservedinothermesenchymal
tumors,suchaslipomasandendometrialpolyps,theseaberrationsaremost
commonlyfoundinUL[76,124,126,127].Translocationsinvolving7q22are
infrequentlywitnessedinULrelativetodeletions,althoughtheirexistencenot
onlyfurtherimplicatesthisregionasbeinginvolvedinULpathogenesisbutalso
servesasavaluableinvestigativetoolinexploringpredispositiongeneson
chromosome7[124].Thedel(7q)abnormalitieshavealsobeenseeninpatients
withprimaryacutenonlymphocyticleukemia(7.6%),myelodysplasticsyndrome
(19%),secondaryacutemyelocyticleukemia(26.8%),andsecondarymyelodys
plasticsyndrome(41%),andareoftenconsideredapoorprognosticfactorasso
ciatedwithlimitedremissionandresistancetotherapy[128].ULandotherbenign
mesenchymaltumorswiththesameaberration,however,donotexhibitsevere
clinicalfeatures,possiblyindicatingthatthedeletionbreakpointistissuespecific
ormolecularlyheterogeneous[61].
OfnoteisthefactthatULassociatedwithdel(7)(q22q32)abnormalitiesare
smallerwhencomparedwitht(12;14)translocations,whichmaybecausedbya
26lobeletal

tumorsuppressorgenepresentat7q22involvedinregulatingcellgrowth.Further,
tumorswiththisdeletionoftensufferalossofchromosomallyaberrantcellsin
culture,suggestingtumorinstabilityandagainpointingtothepossiblepresenceof
atumorsuppressorgene[60,67,117].Thedel(7)(q22q32)abnormalitiescanbe
presentaloneorinconjunctionwitht(12;14)rearrangementsand,asopposedto
tumorswithonlydel(7)(q22q32),ULwithbothaberrationsarestableinculture
andexhibitHMGA2expression.Thissuggeststhatthegenesinvolvedat7q22q32
maynotbeessentialinULpathogenesisandthatdel(7)(q22q32)maybeanearly

geneticeventinULevolution[60,122,129,130].
Mappingprojectsofthedel(7q)regionhavebeensuccessfulinnarrowingdown
thebreakpointfromq11.23q36toq22q32,anareaoflessthan500kb,although
itremainsdifficulttoisolateULspecificgenesbecausetheregionoffocusstill
hasahighdensityofgenes[123125,131134].FISHanalysishasdelimiteda
critical2to3Mbareaonbandq22,andrecentmolecularanalysishasfurther
identifieda10cM(centimorgan)criticalregionon7q22[135138].Although
furtherresearchstrivestonarrowthecriticalregiononchromosome7toa4cM
area[139],7q22canpresentlybesaidtobeinvolvedingrowthanddevelopment
forasubsetofUL.
Specificgenediscoveryremainselusiveinthischromosomalband,however,and
nogeneshaveasyetbeenidentifiedasbeinginvolvedinULdevelopmentfor
thosetumorswithdel(7q)aberrations[61].Geneslocatedin7q22thatare
potentiallyinvolvedinULtumorigenesisincludeCUTL1(transcriptionalre
pression),ORC5L(DNAreplication),PAI1(hemostasisandsmoothmusclecell
andadipocytemigration),PMS218(DNAmismatchrepair),COL1A2and
PCOLCE(collagenmetabolism),andDLX5andDLX6(developmentalpro
cesses)[123,140143].DOCK4,atumorsuppressorgenemappingto7q22q31,
hasalsobeenidentifiedasapotentialcandidategeneandmayprovidealarge
targetfordeletionormutationsimilartoHMGA2[144].AlthoughULwith
chromosome7deletionshaveshownlossofheterozygosityorreducedgeneex
pressionofCUTL1,ORC5L,PAI1,andPCOLCE,noconsistentgenedeletions
havebeenobserved[145147].
Chromosome1rearrangementsandfumaratehydratase
Rearrangementsofchromosome1ofteninvolveringchromosomeformation,such
asr(1)(p34q32),althoughtranslocationst(1;6)(q23;p21)andt(1;2)(p36;p24)have
alsobeenobserved.Ringchromosomesareusuallyonlyfoundincombination
withothercytogeneticaberrations,althoughassuchmaybeconsideredtobe
secondarychangesinkaryotypicallyabnormaltumors[148152].Interestingly,a
memberoftheHMGgenefamilylocatedonchromosome1atp35,HMGI7,was
foundtobedeletedinaULwitharingchromosome;however,adeletionimplies
thatelevatedexpressionofHMGI7doesnotplayaroleinULdevelopmentbut
insteadpossiblycontributestotumorformationthroughalternativemechanisms
[153].OtherULhaveshownnonrandomrearrangementsat1p36[154]ora
deletionofmuchoftheshortarmofchromosome1along
geneticheterogeneityoful27

withmonosomy19or22[155].Inaddition,arecentlydiscoveredsubsetofUL
wasshowntocontainchromosome1deletionsexhibitingtranscriptionalprofiles
paralleltothoseofleiomyosarcomas[156];thissuggeststhatleiomyosarcomas
mayarisefromaspecificsubsetofUL[22],althoughfurtherinvestigationand
comparisonofthemoleculareventsleadingtoULandleiomyosarcoma
developmentisnecessary.Karyotypesofthetwotumors,however,aredistinctly
different,withleiomyosarcomasexhibitingmuchmorecomplexchromosomal
abnormalitiesthanthoseofcytogeneticallyaberrantUL(Fig.1A,B).
Moreattentionhasrecentlybeenputonrearrangementsofchromosome1atbands
q42q44inULbecauseoftheidentificationoftheFHgeneinthatregionasa
pathogeneticfactorinbothHLRCCandReedssyndrome[49,157,158].MCUL1
hasalsobeenidentifiedasapredisposinggeneforReedssyndromeinthesame
bandsat1q42.3q43,althoughtheregionasawholehasseldombeenobservedto
beinvolvedinnonsyndromicULcytogeneticabnormalities[47,159,160].FISH
analysishasshownlossoffunctionofFHinsomeULwith1q42rearrangements,
however,indicatingthatmutationsofthisgene,includingproteintruncating
deletions,largegermlinedeletions,missensemutations,andinframedeletions,
maybeimportantinthedevelopmentofasubsetofUL[71,158].Ahousekeeping
genecodingforanenzymeinthecitricacidcycle,FHisimportantinenergy
metabolismandalsoappearstoactasatumorsuppressor[48,159].Aberrationsof
FHhavethusfarrarelybeenseeninpatientswithnonsyndromicUL,asshownby
ananalysisof797karyotypedULsinwhichonlysix1q42q44rearrangements
(approximately0.008%)wereobserved;further,FHmutationswereonly
observedinULofwhitewomen[158,160].
Otherresearchexamined123familieswithatleastoneaffectedsisterpair,and
performedlinkageanalysisonpatientDNAtoevaluatetheroleofFHmutationsin
predispositionofUL.ThisanalysisconfirmedtheinvolvementofFHinasubset
ofnonsyndromicUL,andalsofoundevidencesuggestingearlierageofonsetof
ULiscorrelatedwithFHgenemutations.Becauseofthelimitedstatisticalpower
ofthisstudy,however,evaluationofalargersampleanduseofsecondstage
markersclosertoorwithinFHcouldmoredefinitivelydetermineifthisgene
servesasapredispositionfactorforUL[158].Anotherrecentstudyuseddirect
DNAsequencinganalysistoscreenforFHgermlinemutationsin21patientswith
HLRCCandtheirfamilies,whilealsoevaluatingtheclinicalpresenceofrenal
tumors,cutaneousleiomyomata,andUL.FHgermlinemutationsweredetected
in100%(21of21)ofthefamilies,with62%(13/21)exhibitingrenalcancerand
76%(16/21)displayingcutaneousleiomyomavaryinginseverity;ULwere
observedin100%(22of22)offemaleFHmutationcarriersin16families[161].

Cytogeneticcharacteristicsofheritablediseasesrelatedtouterineleiomyomata
BecauseoftheprovenbenefitsofcomparingULwithrelatedMendeliandisorders,
examinationofsomecytogeneticcharacteristicsofdiseases,suchas
28lobeletal

Reedssyndrome,angioleiomyomas,andDPL,mayservetoprovidecluesinUL
genediscovery.Apossiblelocusofinteresthasbeenidentifiedontheshortarmof
chromosome18inaReedspatient,withthespecificchromosomalaberration
observedbetweenchromosomes9and18,resultinginpartialtrisomy9pand
partialmonosomy18p[162].Angioleiomyomashavedemonstratedapossible
cytogeneticrelationshiptoULinthepresenceoftumorswithabnormalities,such
asdel(6p)[163]oraberrationsoftheXchromosome[164,165].Ofparticular
interestwasoneangioleiomyomaexhibitingt(8;12)(p12;q15),becauseakinto
manyUL,theregion12q15wasimplicatedandHMGA2expressionwasaltered
[166].XinactivationstudiesofDPLhaveshownthepathogenesisofthedisease
tobeparalleltothatofUL[52];onetumorshowedt(7;18)(q22;p11.3),important
becauseoftheobservationofsimilar7q22aberrationsinUL,whereasanother
showedanadditiontothelongarmofchromosome12,potentiallyaffecting
HMGA2expression[162].
Minorcytogeneticsubgroupsinuterineleiomyomata
LesscommonkaryotypicabnormalitiesfoundinULincludethoseofchro
mosomesX,3,10,13,andtrisomy12[148,154,167171].Althoughthelongand
shortarmsofchromosomeXcanbothberearranged,theregionXp11p22appears
tobepreferentiallyinvolved[153].Thisregionhas,infact,beenshowntocontain
anHMGA1likesequence,HMGIYL1,butfurtherassessmentisneededof
potentialaberrantexpressionofthisgeneinUL[172].Specificaberrationsthat
havebeenobservedincludedel(X)(p11.2),t(X;12)(p22.3;q15),X,der(5)t(X;5)
(p11;p15),del(X)(q12),del(X)t(X;3)(p22.3;q11.2),andinv(X)(p22q13)
[133,167,173176].
Asforchromosome3,rearrangementscanoccuraloneorwithrearrangementson
otherchromosomes.Insertions,longandshortarmdeletions,andtranslocations
withchromosome7haveallbeenfoundinUL,andspecificallyappearedas
ins(2;3)(q31;p12p25),del(3)(p14),del(3)(q24),andt(3;7)(p11;p11)[176178].
Chromosome10aberrationsoccurinapproximately5%ofkaryotypically
abnormalUL,withmostrearrangementsappearingastranslocationsbetween
10q22andchromosomes4,6,or12.Deletions,suchasdel(10)(q22q24),however,
havealsobeenobservedinULashasmonosomy10.Nospecificcandidategene

onchromosome10hasyetbeenfoundtocontributetoULpathogenesis,buttwo
tumorsuppressorgenes,PTEN/MMAC1at10q23.3andDMBT1at10q25.326.1,
bothmaptothelongarmofthischromosome[169,177,178].Inaddition,10q22
breakpointswererecentlyfoundwithingeneMORFinfourUL,withthreeofthe
tumorsexhibitingat(10;17)(q22~q24;q21~q22)translocation(Fig.2C)[179].
Aberrationsofthelongarmofchromosome13havebeenobservedinasubgroup
ofULandinlipomas,whetheraloneorinconjunctionwithotherrearrangements
[61,155];itisthoughtthatdeletionsof13qasthesoleabnormalitymayplaya
primaryroleintheformationofsomeUL[63,170,180].Whiledeletionssuchas
thisgenerallyresultinalossofgeneexpression,
geneticheterogeneityoful29

trisomies,suchastrisomy12,usuallyincreasegeneexpressionbecauseofan
elevatedgenedosage[61].Forthisreason,thepresenceofanextracopyof
chromosome12mayincreasethelevelofHMGA2andincreasethegeneproduct
thatisinvolvedinULdevelopment[64,68].
Futuredirectionofuterineleiomyomataresearch
ThefuturepathofULresearchseekstocontinueexploringtheepidemiologic,
molecular,andcytogeneticaspectsofthediseaseaswellasemploynewtech
nologytoexpandknowledgeaboutthegeneticpathwaysandmechanismsofUL.
EpidemiologicresearchstrivestostudywomenwithULandtheirsimilarly
affectedfirstdegreerelativestomoreefficientlylocatethegeneticlociinvolvedin
tumorigenesis[117].InastudyunderwayattheCenterforUterineFibroidsin
Boston,Massachusetts(www.fibroids.net),affectedsisterpairsarecurrentlybeing
analyzedforidentificationofpredispositiongenes;theapproachisagenomewide
screenexaminingknownpolymorphicmarkersinthegenome.Inaddition,further
studyofpatientswithdiseasesrelatedtoUL,suchasBannayanZonanasyndrome
andCowdensyndrome,isalsodesirable,asthesepathogeneticallyrelated
disordersmaygiveinsightintothemolecularmechanismsofULdevelopment
[61].Anothermolecularpathwaythatmeritsexaminationisthatof
leiomyosarcomas,followedbyananalysisofwhatdifferentiatesthismalignant
tumorfromitsbenigncounterpart[15].
ManydifferentanglesexistinapproachingfuturecytogeneticresearchofUL,
includingexaminationoftheexactroleofHMGA2andHMGA1inUL
pathobiology,evaluationofthesignificanceoft(12;14)anddel(7q)appearingboth
togetherandindependently,identificationofcandidategenesonchromosomes
X,3,10,and13,andperformanceoflinkageanalysisonthecandidateregionof

chromosome1importantinHLRCCandReedssyndromeinnonsyndromicUL
[56,61,68].Noveltechnologicapproacheswillnodoubtbeavailableforusein
pursuitoftheseresearchendeavors,andanumberofstudiesusingtranscriptional
profilinghavebeenperformed[68].Thismultigeneapproachtogene
identificationhasonlybeenmadepossiblewiththeuseofdatafromtheHuman
GenomeProject,andULareexcellentcandidatesforthistypeofanalysisbecause
oftheabilitytocontrolforenvironmentalandhormonalinfluencesbyobtaining
multipletumorsfromthesamepatient[61,68].Proteinanalysisisanother
potentialdirectionforresearchthroughproteomics,anexpandingfieldusedto
relategeneexpressiontoproteinfunction,andspecificallymass
spectophotometry.Byformingproteinarraysandmakingprofilesoftheproteins
presentindiseasedandhealthytissues,massspectophotometryallowsforanalysis
ofproteinexpressionandfunctioninUL[181,182].Animalmodels,suchasmice,
guineapigs,andEkerrats,havebeenwidelyusedinpastULstudies,but
problems,suchasinefficientproductionoftumorsortheproductionoftumors
histologicallydifferentfromhumanUL,havelimitedthisvenueforresearch
[183185].
30lobeletalSummary

ResearchinvestigatingthegeneticsofULhasalreadybeensuccessfulingathering
epidemiologicevidenceforheritability,establishingtheclonalandmosaicnature
ofthesetumors,correlatinggenotypicandphenotypiccharacteristics,defining
cytogeneticsubgroups,andidentifyingspecificgenesinvolvedintumorigenesis.
AlthoughULareknowntobebenigntumors,theimpacttheyhaveonthelivesof
somanywomencanonlybedescribedasmalignant.Forthisreason,
continuingthequesttoascertainthegenes,functions,andmechanismsintegralto
ULdevelopmentisabsolutelyimperative.Genetictests
PatientwithUL

FamilyHistoryofUL?

ifyes
ifno

Historyof:

TypeIIPapillaryRenalCellCancer?
CutaneousLeiomyomata?

UterineLeiomyosarcoma?
Possibletreatmentoptions:MyomectomyUAEMRgFUS

Medicaltherapy

ifnegativeforFHandforpredispositiongenes

PositiveHistory
DiscussionofscreeningforFHmutation,withpossiblereflextootherULsusceptibilitygenes
NegativeHistory
DiscussionofscreeningforULsusceptibilitygenes,excludingFH
ifpositiveforFH
ifpositiveforpredispositiongenes

DiscusshysterectomyasapossibletherapyforsymptomaticULtoreducetheriskofrecurrentdisease

DiscusshysterectomyasapossibletherapyforsymptomaticULtoreducetheriskofdevelopinguterine
leiomyosarcoma,andperformrenalcancerscreening(e.g.MRI)

Fig.3.ProposedschemaformanagementofpatientswithUL,incorporatingvarioustreatment
optionsbasedonfamilyhistoryofthediseaseandsubsequentgenetictesting.MRgFUS,MRI

guidedfocusedultrasoundsurgery;UAE,uterinearteryembolization;UL,uterineleiomyomata.
geneticheterogeneityoful31

forpersonalizedmedicalmanagementofwomenwithfibroidsisatthethreshold
forprovidingthemostappropriatetreatments(Fig.3),andcombinedwithdevel
opinglessinvasivetherapiesportendsabrighterfutureforamajorhealthprob
lemforwomen.
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