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ResearchRegardingGeneticMutationsandHighgradeSerousOvarianCarcinoma
BriannaDeFoe
WritingintheSciences,DepartmentofEnglish
NorthDakotaStateUniversity,Fargo,ND58108
July8,2016

Abstract:
Oneofthedeadliest(gynecological)cancerstodateishighgradeserousovariancancer.
Withlittletonooptionsforprescreening,mostwomenfindthattheyarediagnosedinlater
stages,IIIorIV,wheretreatmentoptionsbecomemuchmorelimitedandthecancerouscells
becomemuchhardertotreat.Inthesemoreadvancedstages,manywomenarefacedwith
chancesofcurebeinglessthan40%forthoseinstagesIIIa,IIIb,andIIIc,andlessthan17%for
thoseinthefinalIVstage.Thelifeexpectancyformostofthewomenthathavebeendiagnosed
inthehigherstagesrangesfrom9%34%,basedupontheavailabilityoftreatmentaswellasthe
formofcarcinomapresentwithinthebody.1
Geneticmutationshavebecomeoneofthekeysintheforefrontforunlockingnew
informationaboutthisformofgynecologicalcancers.Newinformationdevelopedfrom
immunohistochemicalstainingofthefimbriatedendsofthefallopiantubeshasshownthatthe
originationforover50%ofthehighgradecasesstemfromthecellscontainedwithinthe
fimbriatedendsofthetubes.1Tobetterunderstandwhatthesehighgradecasesare,firstthis
reviewwillopenadiscussionintothespecificgeneticmutationsitesthathaveshowntoincrease
riskofhighgradeovariancanceroccurringandthenadiscussionofthetwotiersystemof
classificationandhowthepathogenesisofthehighgradeandlowgradetumorsform.
UnderstandingBRCAandTP53Genes:
CurrentresearchisexploringthecausesofthesetypeIItumors(highlyaggressive
highgradeserousovariancarcinomas)stemmingfromthegeneticmutationofBRCA1and2
genes,aswellasTP53.1,2,5
BRCA1and2areDNAdamagerepairgenes.1,2BRCA2workstoregulateRAD51,a
genethatisresponsibleforhomologousrecombinationwhileBRCA1workstorepairDNA
throughsignallingdamagetoDNAaswellasworkingtorepairthroughhomologous

recombination,nucleotideexcisionrepair,andalsoisthoughttoplayaroleinnonhomologous
endjoining.2
TP53isagenethatfunctionsasatumorsuppressorandregulatorinthecellcycle.This
geneactivelyworkstopreventcancerousgrowthswithinthebody.5
MutationsandCancerousPredispositions:
Serousovariancarcinomaisthesubtypethathousesthatlargestamountofovariancancer
malignancies.1Thisgeneralgroupisdividedintoapopular2tiergradingsystem:lowgradeand
highgrade.BothTheJohnsHopkinsHospitalandtheM.D.AndersonCancerCenterhave
conductedresearchintothe2tiergradingsystem,andhavedeterminedthatitistheeasiest
applicablesystemavailable.1,3Thegradingsystemisbrokendownintoindependentpathwaysof
typeIandtypeIItumorformation.
LowgradeSerousCarcinoma:TypeI
Lowgradeserousneoplasmsareoftenpresentinthebodyasclearcell,lowgradeserous,
endometrioid,andmucinousovariancarcinomas.1Recentresearchhassuggestedthatthe
carcinomaformsfromaserouscystadenomaandthencontinuestoprogressslowlytoanatypical
proliferativeseroustumor,andthentoanoninvasivemicropapillaryserousborderlinetumor
andthenontoaninvasivemicropapillaryserousborderlinetumor.3Lowgradeserouscarcinoma
hasbecomeasthetypeItumorformation.TypeItumoranatomicalanalysishasledtothe
hypothesisthatthesetumorstendtodevelopwithinovariansurfaceepithelialcells.Thesecells
arecommonsitesofcysts,aswellaslowgradeprecursorlesions(alsoknownasborderline
tumors).1ThegeneticmutationsthatleadtothistypeIformationincludegenes:KRAS,BRAF,
ERBB2,PTEN,CTNNB1,andPIK3CAthemostcommontumorformationstemsfromKRAS
andBRAF,bothofwhichareregulatorsoftheproteinkinase.1,3,4
HighgradeSerousCarcinoma:TypeII
MuchlessisknownabouttypeIItumorhighgradeserouscarcinomapathogenesis.As
notedabovethecommongeneticmutationsseenintypeIItumorgrowthstemfromthe
mutationsofTP53andBRCA1and2.ThetypeIItumorshavenotbeennotedtobeinginthe
ovariansurfaceepithelialcellsorwithintheprecursorlesions.IthasbeenproposedthattypeII
tumorformationbeginswithinthefallopiantubes,morespecificallywithinthefallopiantube

secretoryepithelialcellscontainedwithinthefimbriatedendofthetubes(thefiberyendofthe
fallopiantubesystem),whichattachtotheovaries.
Thishypothesiswasproposedafterastudiesshowedapositivetrendlinebetweenwomen
withinheritedBRCA1/2mutationsandtheformationofhighgradeserouscarcinoma.1These
women,whoinheritedthemutationsofthegeneBRCA1or2werethenplacedintoahighrisk
category,asithasbeenshowninstudiesthatinheritanceoftheBRCA1genecanleadtoa50%
increaseinriskofcancerdevelopment,similarlytheriskforBRCA2genecanleadtoacancer
riskincreaseof20%beyondthatofthegeneralpopulation.4Inthestudiesexperiencedbilateral
salpingooophorectomies(asurgerythatisconductedtoremovebothsetsofthefallopiantubes
andtheovaries),boththetubesandtheovariesofeachofthesewomenwerestudied.Ineachof
thesewomen,thefimbriatedendsofthefallopiantubeswerefoundtohavewhataretermedas
p53signatures.Thesesignaturesareputativeserouscarcinomaprecursorlesions(essentiallythe
cellsthatarepresentinthefimbriatedendsofthetubeshavebeguntochangetheirshapepriorto
anycancerousgrowth)thatappearonthefallopiantubesecretoryepithelialcells,whichare
themselvesbenign,howeverwhenstainedandanalyzedshowedhighp53immunostaining.1,3The
highimmunostainingisevidencedasanadditionalmutationofnotonlyeitherBRCA1/2
mutations,butalsoamutationoftheTP53gene.6ThehypothesizedtypeIIpathogenesisbegins
withtherapiddevelopmentoftheintraepithelialcarcinomaswithinthefimbriatedportionofthe
tubes,thisleadstothep53mutationsfollowedshortlybyahighlevelofchromosomal
irregularitiesinstability.1,3ThepathenogenesisisalsomarkedbyBRCA1/2inheritedmutations
aswellasalackofmutationofKRAS,BRAF,orERBB2,whicharecommonintypeI
mutations.3
PotentialFormationofTypeIIfromTypeI
Whileithasgenerallybeenperceivedthatthetwotiersofthe2tiersystemareseparate
entities,recentstudieshaveshownthatthismaynotalwaysbethecase.TheJohnHopkins
Hospitalhasfoundthatapproximately3%oftheserouscarcinomas,analyzedbothwithinthe
hospitalaswellasotheroutsideconsultations,haveindicativemarkersofbothlowgrade
carcinomaandhighgradecarcinoma.3IneachofthesecasesitwasnotedthattypeIIdeveloped
fromtypeI,neverviceversa.

AsnotedabovetypeIandtypeIIarenotedtohavedifferingmorphologicalpathways,
howeverwithinthelimitednumberofevolutionarycases,asthetumorswereanalyzed,the
highgradeserouscarcinomaswerenotedtohavenorealdefiningmarkersseparatingthemfrom
thehighgradeserouscarcinomasthatdevelopedpurelyfromtheTypeIIpathway.Withsuch
limitedliteratureavailableonthisoddity,itisunclearastowhethertraditionaltreatment
methodshaveadifferingclinicaloutcomesandresponses.3
RelevanceofGeneticMarkersinFutureResearch
Thestudyoftumorpathogenesis,aswellastheoriginsitesandthespecificgenetic
mutationsthatoccurwithinthecellsthatleadtotheformationofmalignantcancerousgrowths
willcontinuetobeimperativeinfuturestudies.Theabilitytofindandtargetthemalignantcells
helpstocreatenewandbetterscreeningoptionsaswellastobetterenhancethetherapy
treatmentoptionsavailabletothosewhosebodiesarecurrentlyfightingmalignantgrowths.Until
thelastfewyearshighgradeserousovariancarcinoma(typeIItumorformation)hada
pathogenesisthathasbeendifficulttoidentify,whichhasdelayedthefindingofthesite(s)or
originaswellas.Duetothenumerousbilateralsalpingooophorectomiesfromhighriskwomen
andtheimmunohistochemicalstainingofthefimbriatedendsofthefallopiantubes,theresulting
statisticsareindicativethatover50%ofthehighgradecasesthatdevelopstemfromthese
originationsinthefimbriatedendsofthefallopiantubes.1
Withthisknowledgegleanedfromthestudiesintothecellsofthefimbriatedendsofthe
fallopiantubesaswellasthosewithintheovarieshavelaunchednumerousotherstudiesintothe
effectsofaprophylacticsalpingooophorectomyinwomenwhohavehadgenetictestingand
haveinheritedeitherBRCA1orBRCA2,orevenbothofthemutatedgenes.Thesesurgeries
haveconcludedthatthepreventativeremovalofthefallopiantubesandtheovariesafterthe
childbearingyearshavebeencompletedhaveapositivecorrelationinthereducedriskof
gynecologicalcancersinthesehighriskcandidates.DoctorKarenH.LuofTheUniversityof
TexasM.D.AndersonCancerCentercitesthatthestudiesconductedinBRCApositivewomen
whohaveoptedtohavetheprophylacticsalpingooophorectomyhasreducedcancerriskupto
96%.7

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