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serouscarcinomas(140).
OvarianClearCellCarcinoma
TCGAidentifiedmutationsintheAT-richinteractivedomain 1A(ARID1A) in46–57%of
clear cell carcinomas (141,142). ARID1A encodes a component of the SWItch/sucrose
nonfermentable (SWI/SNF) chromatin remodeling complex, which alters nucleosome
structure, enhances DNA accessibility, and is required for the transcriptional activation of
genes normally repressed by densely packed chromatin. The SWI/SNF complex allows
DNA-bindingproteinstoaccesstheDNA.TheARID1Aproteinhastwodomains.TheARID
domain is a DNA-binding domain specifically binding AT-rich DNA sequences. The Cterminusdomainstimulatestheglucocorticoidreceptor–dependenttranscription.Thereby,the
ARID1A protein may recruit the SWI/SNF complex to specific DNA sequences. ARID1A
mutations may cause abnormalities in DNA transcription, replication and repair in
endometriosis-associatedovariancarcinomas,thatis,clearcellcarcinomaandendometrioid
carcinoma (141). Mutations in ARID1A have been noted in clear cell carcinomas and
adjacentatypicalendometriosis,butnotindistantendometrioticlesions(141).
Furthermore, specific for endometriosis-associated carcinomas are high iron levels that
induceoxidativestress. Hence,stressresponsegenesare oftenhighly expressedinpatients
withclearcellcarcinomawhohadendometriosis,especiallyinthosewithstagesIIIandIV
clearcellcarcinomas(143).
Phosphatidylinositol-4,5-bisphosphate3-kinasecatalyticsubunitα(PIK3CA)mutationshave
beenidentifiedin 33–50%ofclearcellcarcinomas anddeletionofphosphataseand tensin
homolog(PTEN)in20%(144,145).ProteinkinaseB2(AKT2)geneamplificationwasseen
in certain clear cell carcinomas (146). Thereby, the phosphoinositide 3-kinase (PI3K)
pathwayappearsfrequentlyalteredinclearcellcarcinoma.
OvarianEndometrioidCarcinoma
Similarto clear cell carcinomas,mutationsofARID1Ahavebeendetected in 30% of
endometrioidcarcinomas,ofPIK3CAandPTENin20%,andofPPP2R1Ain10%(141).
Unlikeclearcellcarcinoma,cateninbeta-1(CTNNB1),alsoknownasβ-catenin,ismutated
in30%ofendometrioidcancers.β-Cateninisabifunctionalprotein.Itisinvolvedincell
adhesion formation and maintenance and in gene transcription through the
integration1/Wingless(Wnt)signalingpathway.Underphysiologic conditions,CTNNB1is
mainly located at the cell membrane. Most mutations of CTNNB1 are in exon 3, which
encodes the serine–threonine phosphorylation sites. Hypophosphorylated CTNNB1 is not
degraded and accumulates in the cytoplasm and cell nucleus. CTNNB1 degradation is
controlled by the so-called destruction complex, which comprises adenomatous polyposis
coli(APC)andAXIN-1and2(147).Ifthoseproteins are mutated and inactive, CTNNB1
will not be degraded. The accumulated CTNNB1 in the cell nucleus combines with other
transcription factors and activates gene transcription. In the mouse model, inactivation of
bothpathways, theWntand thePI-3K pathway,resultsin endometriosisand endometrioid
cancer(148).
MucinousOvarianCancer
Mucinousovariancancersarerare,comprisingonlyabout3%ofepithelialovariancancers,
andhavethusbeendifficulttostudy.Inupto75%ofmucinousovariancancers,Kirsten
ratsarcoma(KRAS)mutationshavebeenidentified(149).KRASmutationsappeartobe
presentinmucinouscystadenomasandmucinousborderlinetumorsaswell,supporting
thehypothesisthatmucinouscystadenoma,mucinousborderlinetumors,andmucinous
ovariancancersformacontinuumthatallowsprogression(150,151).
SmallCellCarcinomaoftheOvary—HypercalcemicType(SCCOHT)
Thisrareovariancancerofyoungadults(152)hasbeenshowntobeassociatedwithsomatic
andgermlineSMARCA4 mutations (SWI/SNF related, matrix associated, actin dependent
regulatorofchromatin,subfamilya,member4)(153–155).SMARCA4isalsoknownasthe
transcriptionactivatorBRG1.ItispartoftheATP-dependentchromatinremodelingcomplex
SWI/SNF(switch/sucrosenon-fermentable)andthoughttoregulatetranscriptionbyaltering
chromatinstructureandmakinggenesmoreaccessibletothetranscriptionmachinery.BRG1
mutations mostly affect the ATPase sequences of the ATP-binding pocket or the DNAbindingsurfacechangingenhancersandpromotors.ThereisevidencethatBRG1mutations
resultinmodulationofmyelocytomatosis(myc)expression(156).
HereditaryOvarianCancer
Approximately 8–13% of ovarian cancers are hereditary. A significant proportion of
thesearecausedbygermlinemutationsinthebreastcancergenes1and2(BRCA1-2),
but also other components of the homologous recombination pathway and the DNA
mismatch repair system. In the following, we describe different germline mutations
includingthosewiththus-farinconsistentevidence.
BRCA1andBRCA2
Inherited BRCA1 pathogenic variants confer a 20- to 40-fold increased risk of ovarian
cancer, that is, the risk of developing ovarian cancer by age 70 is 39–46% (157–160)
compared to a general population lifetime risk for ovarian cancer of 1–2%. Inherited
BRCA2pathogenicvariantsconfera10-to20-foldincreasedriskofovariancancer,thatis,
theriskforovariancancerbytheage70is10–27%(157–160).BRCA1-2 playacritical
role in maintaining genomic integrity. Under physiologic conditions, DNA double-stand
breaks are repaired by RAD51-dependent homologous recombination (HR; see section on
double-strand break repair above) in which both BRCA1 and BRCA2, are involved.
Homologous recombination implies the use of homologous sequences elsewhere in the
genome, preferably from the sister chromatid, as a template to facilitate DNA repair in S
phase.BeyondtheirroleinHR,BRCA1-2proteinsinthecytoplasmhavebeenfoundtobe
criticalintheregulationofcelldivision.
About 500 different mutations have been identified for BRCA1 and about 300 for
BRCA2.BRCA1-2 mutationsshow a huge diversityin various populationsandmany have
notyetbeenshowntohaveclinicalsignificance.Inthegeneralpopulation,theBRCA1-2
mutation frequency is about 1:300 to 1:800. In certain populations that have been
founded by a small ancestral group, such as the Ashkenazi Jews, French Canadians,
and Icelanders, specific mutations in BRCA1 and BRCA2 are more frequent; these
specific mutations are the so-called founder mutations. In the United States, 1 in 40
AshkenaziJewscarriesoneofthreefoundermutations(161,162):
(i) 5382insC,whichoriginatedfromacommonEuropeanancestor400to500years
ago. This mutation results in a C-terminally truncated BRCA1 protein. It has been
hypothesizedthatthedeletionoftheBRCTtransactivationdomainsmayleadtoloss
intranscriptionalactivationofseveralgenes,whicheventuallymayresultinlossof
apoptoticcelldeathandtherebycontributetocancerdevelopment(163)(Fig.1.5).
(ii) 185delAG,anotherBRCA1foundermutation,showsafrequencyof16.4%inthe
AshkenaziJewishandIndianpopulations.Twonucleotidesaredeletedinexon2of
BRCA1, which results in a functionally null, truncated protein which is 39 amino
acidslong(Fig.1.5).
(iii) C61GisamissenseandfoundermutationinthePolishpopulation.Incontrastto
theaforementionedtwofoundermutations,thismutationdoesnotresultintruncated
BRCA1proteinsbutinsteadinthefulllengthBRCA1proteinwithapointmutation.
This mutation leads to an alteration of the zinc-ligating residues in the really
interestingnewgene(RING)domain(Fig.1.5).
Similarly, founder mutations have been described in BRCA2. 6174delT is a common
BRCA2mutationintheAshkenaziJewishpopulation.Itisaframeshiftmutation,which
producesatruncated protein with only 2,002 amino acids insteadof3,418.Thistruncated
proteinloses the BRCrepeat domains, DNA binding,C-terminalRAD51bindingdomains,
andthenuclearlocalizationsignal.ThisresultsindefectiveDNArepairmachinerywhichis
unabletoformRAD51fociinthecellnucleus.Reversionmutationof6174delTrestoresthe
openreadingframeofBRCA2andhasbeenshowntobeamechanismofpoly-ADPribosepolymerase (PARP)-inhibitor resistance (164). If a patient is heterozygous for both
BRCA1andBRCA2mutations,theovariancancerphenotypeisgenerallythoughttobe
similarto those with BRCA1 mutation only,although there are some data to suggest
that ovarian cancermay develop at an earlier age and the course of disease may be
moresevere(165,166).
RAD51C/D
HumanRADproteinsarehighlyconservedandshowhighsimilaritytoproteinsinyeastand
bacteria.RAD51C(167)andRAD51D(168)aretwooffiveRAD51 paralogs,which areall
required for efficient DNA double-strand break repair by homologous recombination.
RAD51C and RAD51D form a complex with other proteins, which is critical early in the
processofhomologouspairingbetweensingle-anddouble-strandedDNA(Figs.1.4and1.5).
Theriskofovariancancerisincreasedtwo-tothreefoldifagermlinemutationoccurs.
BRIP1(BRCA1-InteractingProtein1)
BRCA1-interactingprotein1(BRIP1)(169) encodes the Fanconi anemia group J protein, a
helicasethatinteractswithBRCA1viaitsBRCTrepeatsandisimportantinthedouble-strand
breakrepairfunctionofBRCA1(Figs.1.4and1.5).BRIP1germlinemutationincreasesthe
riskforovariancancertwo-tothreefold.
MMRProteins(MismatchRepairProteins)
Germlinemutationsinthemismatchrepairsystem(Lynchsyndrome)increasetherisk
forovarian cancer5-to 10-fold (see section on hereditary endometrial cancer). Elevated
ovariancancerriskisestablishedforMLH1(5–20%),MSH2(10–38%),andMSH6(1–11%),
whileitisnotestablishedforPMS2(100,102,170).
Gene mutations that show inconsistent or only insufficient evidence to support
increasedovariancancerriskareasfollows:
ATM(AtaxiaTelangiectasiaMutated)
Ataxiatelangiectasiamutated(ATM)isaserine/threonineproteinkinaseandinparticulara
DNA damage response kinase, which is recruited by DNA double-strand breaks. It
phosphorylates key DNA damage checkpoint proteins, including BRCA1 and Checkpoint
kinase2(CHEK2),andtherebyinitiatescellcyclearrest.
NBN(Nibrin)
Nibrin (NBN) is involved in double-strand break repair and is a member of the MRN
complex(MRE11/RAD50/NBN) double-strand break repair complex. NBN mutations may
lead to the Nijmegen breakage syndrome characterized by DNAdouble-strand breaks and
chromosomalinstability.Ithasaroleinthemicrohomology-mediatedendjoining(MMEJ)
repairofdouble-strandbreaks,whichisinherentlyinaccurate;thereby,theoverexpressionof
NBNmaygiverisetocancerdevelopment.
PALB2(PartnerandLocalizerofBRCA2)
PartnerandlocalizerofBRCA2(PALB2)permitsstableintranuclearlocalizationofBRCA2.
Itbindssingle-strandedDNAanddirectlyinteractswiththerecombinaseRAD51(171).
TP53(GeneEncodingp53TumorProtein)
TherehasbeenanunresolveddisputewhethergermlineTP53pathogenicvariantspredispose
toovariancancer.Fewcaseshavebeenreported.Theevidencethusfarisinconsistent.
Othergenes,includingCheckpointkinase2(CHEK2),atumorsuppressorgenethatencodes
aDNAdamageresponsekinase,donotappeartoincreasetheriskofovariancancer.
Ovarian cancers with germline or somatic BRCA1-2 mutations respond better to
platinum-based chemotherapy because the tumor cells are not able to repair
intrastrand crosslinks formed by crosslinking platinum agents. They have also been
foundtorespondtotreatmentwithpoly-ADPribose-polymerase(PARP)inhibitors.The
poly(ADP-ribose)polymerasefamilyincludes17knownmembers.PARP1isthefounding
member. Once activated, PARP1 synthesizes poly-ADP-ribose chains that are covalently
bound to chromatin proteins and the PARP proteins themselves. Thereby, DNA repair
proteins are rapidly recruited. PARP proteins contribute to a number of DNA repair
pathways; the base excision repair has been most extensively studied. The base excision
repairisinvolvedinrepairingsingle-strandbreaksor“nicks”intheDNA.
About 104 single-strand breaks (SSBs) occur every day. In the absence of PARP
proteins, these SSBs persist. If gaps in a single strand are encountered by the DNA
replication fork, it may degenerate into double-strand breaks (DSBs). In the absence of
BRCA1,these DSBs cannot be repaired, the replication forks cannot be restarted and they
collapse(172,173).
PARP inhibition is the first example of targeting a nonessential DNA repair protein
aloneto treatcancer. It has been described with the concept of synthetic lethality,which
wasoriginallyusedinthemodelorganismDrosophilabyCalvinBridgesin1922(174). In
1946,Dobzhansky(175)coinedtheterm“syntheticlethality.”Syntheticlethalitydescribes
therequirementfortwoindependentandcomplementarygenetichitsthataretolerated
individuallybutresultincelldeathifoccurringtogether.
More recently, possible mechanisms of PARP-inhibitor resistance have been described.
SomaticreversionmutationsinBRCA1-2appearcriticalandwerefirstreportedin2008,in
pancreaticcancerandovariancancercelllines(164,176).Secondarymutationswerefoundto
restore the BRCA1-2 open reading frame. These secondary mutations were more
frequently detected in ovarian cancers, which had been exposed to multiple
chemotherapies,especiallyplatinum-resistantepithelialovariancancers.Mostsecondary
BRCA1-2mutationstakeplaceafterplatinumchemotherapy;thusfar,thereareonlylimited
reports of secondary mutations after PARP inhibitor treatment. In autopsy studies, many
distinct reversion events in the same patient have been identified, contributing to the
intrapatientheterogeneityofovariancancer(177).
OvarianSexCordStromalTumors
STK11(Serine/ThreonineKinase11)LKB1(LiverKinaseB1)
Serine/threonine kinase 11 (STK11), or also called liver kinase B1 (LKB1), is directly
upstreamoftheadenosinemonophosphate–activatedproteinkinase(AMPK)andtherebya
keyelementinthe regulation of cell metabolism. When nutrients are scarce, STK11/LKB1
suppressesgrowthandproliferation.Furthermore,itisinvolvedinmaintainingcellpolarity.
With both functions, it acts as a tumor suppressor. Germline mutations have been
associatedwithPeutz6–Jeghers7syndrome(PJS)(179,180).PJSisanautosomaldominant
syndrome of variable penetrance that is characterized by intestinal polyps and
mucocutaneous pigmentations as well as other neoplasms. PJS carriers have a two- to
threefoldincreasedriskfordeveloping sex cord stromaltumors with annulartubules
(SCTAT). The tumors are usually bilateral, benign tumors, and 50% are associated with
hyperestrogenism. In fact, one-third of patients with SCTATs have Peutz–Jeghers
syndrome.However,largerunilateralSCTATtumorsaremorelikelysporadic.
FOXL-2(ForkheadBoxProteinL2)
ForkheadboxproteinL2(FOXL-2)isatranscriptionfactorinvolvedinsexdetermination,
ovarian development and function, and suppression of development of the testes. It is
requiredforgranulosacelldifferentiation.Itsdefiningmotifistheforkheadbox, 80to100
aminoacids,thatbindsDNA.Thismotifappearslikeabutterflyinstructureandistherefore
called the winged helix. Amissense mutation in the FOXL2 gene (C134W) is found in
mostofthegranulosacelltumorsoftheadulttype,someofthethecomasandrarelyin
juvenile-typegranulosacelltumors(180).
DICER1
DICER1 mutations in the RNase IIIb domain have been described in about 30%
nonepithelial ovarian cancers, especially sex cord stromal tumors. They have been
describedinupto60%ofSertoli–Leydigcelltumors(181).ThereportedDICER1mutations
havebeenfoundtochangethetumor’smicroRNAprocessingabilitieswithoutcausingitto
lose them entirely. It was hypothesized that these mutations may shift miRNAs to an
oncogenicpattern.
OvarianGermCellTumors
Theexactmolecularmechanismofthemostcommonbenignovariangermcelltumor,
the mature teratoma or dermoid, is not known. The most accepted theory on its
developmentinvolvesparthenogenetic,thatis,asexualwithoutmalegamete,activation
ofoocytes.Thekaryotypeis46,XXinalmostallmatureteratomas,andtheyarediploidwith
maternal chromosomes alone. This is, as it were, a maternal phenomenon similar to the
complete paternal karyotype which results in a complete mole (see section on Gestational
TrophoblasticDiseasebelow).
There are little data available on genetic alterations and molecular mechanisms of the
tumorigenesisofmalignantgermcelltumors.Dysgerminomasareknowntodevelopfrom
dysgeneticgonads,howevertheexactmechanismisunknown.Therehavebeenreportson
miRNAoverexpression(182),DICERmutations,andKITamplification(183,184),aswellas
raregeneticalterationsinTP53andKRAS.
CervicalCancer
SporadicCervicalCancer
Cervicalcancerisaclassicexampleofvirus-inducedcarcinogenesis.Inthe1970s,human
papillomavirus(HPV)wassuspectedtoplayaroleincervicalcancer.Thefirstexperiments
tosearchforpapillomavirusincervical cancer were performed by Harald zur Hausen and
colleaguesin1974(185),andthefirststudytodemonstratearoleforHPVinfectioninmild
dysplasia was published in 1976 (186). In 1983, HPV16 was the first human
papillomavirustypetobedirectlyisolatedfromcervicalcancerbiopsies(187). Shortly
thereafter,HPV18 was isolated(188). The mechanism of the virus-induced carcinogenesis
wasdefinedinsubsequentstudiesincludingthedescriptionofE6/E7incervicalcancercells
and specific HPV deletions after integration into the host-cell DNA(189). The first large
epidemiologicstudyofHPVinfectionwaspublishedin1987(190).
HPVisbelievedtoinducecarcinogenesisbyintegrationofitsgenomeintothehostcell
genome.Thetwo primaryoncoproteinsofhigh-riskHPVaretheproteinsE6andE7,
earlygene6and 7, indicating that these two proteins are expressed early in the HPV life
cycle. E6 (early gene 6) interacts with a 100-kDa cellular protein, E6AP (E6-associated
protein), which functions as a ubiquitin ligase. The E6/E6AP complex binds the tumor
suppressorTP53leadingtoitsrapidubiquitinationanddegradationthroughproteasomes.E7
bindstothehypophosphorylatedformofpRb(retinoblastoma)leadingtoitsdegradationvia
the ubiquitin-proteasome pathway and thereby promoting progression of the cell into S
phase. The E7/Rb interaction mimics the CDK-mediated phosphorylation, and renders the
cellindependentofanycellcyclecontrol,resultingindisinhibitedcellproliferation.
HereditaryCervicalCancer
Minimaldeviationadenocarcinomaoradenomamalignumisarareentityaccountingfor1–
3% of all cervical adenocarcinomas. Its development is not related to HPV but appears
associatedwithsporadicSTK11(serine/threoninekinase11)mutations;itcanbeassociated
withPeutz–Jegherssyndrome(seesectiononSTK11above).
VulvarCancer
Sporadic
HPV-relatedvulvarcancersarepresumedtofollowasimilarpathogenesistoallotherHPVrelated carcinomas of the lower anogenital tract as outlined for cervical cancer. HPV-
independentvulvarcancersfollowadifferentcarcinogenesis,butlittleisknownabout
themolecularmechanisms.Inearlierstudies,allelicimbalancesandlossofheterozygosity
were frequently described in HPV-independent carcinomas (191). Furthermore, HPVindependentprecursorlesions,thatis,differentiatedvulvarintraepithelialneoplasia(dVIN),
aswell as vulvarsquamouscell carcinomas arisingfrom dVIN, showahigh rate ofTP53
mutations.TP53mutationshavebeenfoundinupto70%ofcasesofLichensclerosus,60%
ofdVIN,and80%ofvulvarcancers(192,193).
Cyclin-dependentkinaseinhibitor2A(CDKN2A) hasbeenreportedtobemutatedin upto
60%ofvulvarcancers(194),butnotinLichensclerosusordVIN(195).Otherstudieshave
reported epigenetic changes including CDKN2A silencing by hypermethylation (196,197).
The CDKN2A gene encodes for two proteins, p16INK4 (inhibitors of CDK4) and p14arf
(alternatereadingframe),bothofwhicharetumorsuppressorgenes.p16inhibitsthecyclindependentkinases4and 6(CDK4and6),therebyactivatingpRb(retinoblastomaprotein),
whichinturnblocksG1/Stransition.p14arfactivatesp53.
Other mutations including phosphatidylinositol 3-kinase, catalytic subunit α (PIK3CA),
FBXW7, Harvey rat sarcoma (HRAS), fibroblast growth factor receptor 3 (FGFR3),
serine/threonine kinase 11 (STK11), AKT1, SMAD4 (named after their homologs in C.
elegans, sma = small body size, and in Drosophila, Mad = mothers against dpp), and
phosphataseandtensinhomolog(PTEN)have beenidentified inlowfrequencies and may
leadto the activation ofthephosphatidylinositide 3-kinase (PI-3K) pathway (see Fig. 1.2)
(194).
Hereditary
Nohereditaryformsofvulvarcancerareknown.
GestationalTrophoblasticDisease
SporadicGestationalTrophoblasticDisease
Complete hydatidiform moles are usually diploid and androgenetic in origin. Eighty
percentresultfromtheduplicationofthehaploidgenomeofasinglesperm,andabout
20%fromdispermicfertilization.EitherwaythenuclearDNAispaternal,whileonlythe
mitochondrialDNA is of maternal origin. In contrast to complete moles, partialmolesare
almostalwaystriploid.Twospermfertilizeanormaloocyte,or,veryrarelyadiploidsperm
fertilizesanormaloocyte.
No immunohistochemical or genetic markers are known that can help predict which
gestational trophoblastic disease will persist. Thus, every patient with gestational
trophoblastic disease needs clinical surveillance and monitoring of human chorionic
gonadotropin(hCG)levels.Sincepostmolargestationaltrophoblasticneoplasiaisdiagnosed
clinically and not pathologically,tissue is rarely available for genetic analysis, and where
available,itreflectsthecausativepregnancy.
HereditaryGestationalTrophoblasticDisease
Recurrentmolesaccountfor2%ofallhydatidiformmoles.Someofthesemaybedueto
a familial syndrome, the autosomal recessive familial recurrent hydatidiform mole
syndrome (FRHM). These moles are biparental in genetic origin (diploid biparental
complete hydatidiform moles [BiCHM]) in contrast to the usual androgenetic complete
hydatidiformmoles(AnCHM).FRHMsyndromepredisposestopregnancylossandusually
resultsinacompletemole.About55%ofthecasesarecausedbyamutationinNLRfamily
pyrindomaincontaining7(NLRP7)(198–201)andabout5%byaKHDC3Lmutation(KH
domaincontaining3like,subcorticalmaternalcomplexmember)(202,203).
NLRP7 is a cytoplasmic protein that consists of an N-terminal pyrin domain (PYD), a
NACHTdomain,aNACHT-associateddomain,andaC-terminalleucine-richrepeat(LRR)
region.TheNACHTdomainisa highlyconserveddomainandfound inapoptotic proteins
andproteinsregulatingmajorhistocompatibilitycomplexII(MHCII)transcription.Assuch,
NLRP7isinvolvedinactivationofproinflammatorycaspasesandtheformationofso-called
inflammasomes. The mechanism by which mutation in NLRP7 leads to a complete mole
remains unknown. NLRP7 has no ortholog in mice, which makes studying its function
difficult.ExpressionstudiesinhumansshowthatNLRP7ispresentinoocytesandallstages
ofthepreimplantationembryo(204,205).KHDC3Lisspecificallyexpressedinoocytesand
recentstudies suggestthat itmay functionas aregulatorofgenomicimprinting inoocytes
(206).Whilethemajorityofwomenwithrecurrentandrogeneticcompletehydatidiform
moles(AnCHMs)benefitfrominvitrofertilization(IVF),womenwithFRHMwillhave
anormalpregnancyonlythrougheggdonation.
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