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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5186_Библиотеки_им_академика_М_И_Перельмана.pdf
(BRIP1). The MRN complex composed of MRE11, RAD50 and NBN, then resects the
damagedDNA site in 5’to3’ direction in ordertoproduceoverhangingendsofsingle-strand
DNA. The sister chromatid is then searched for homologous DNA. BRCA2 is involved in
loading the recombinase RAD51 (B/C/D) onto replication protein A (RPA)-coated DNA.
Partner and localizer of BRCA2 (PALB2)facilitate the interaction between BRCA1, BRCA2,
andRAD51.RAD51nucleoproteinfilamentinvades thehomologousDNA strandandformsa
displacement loop (D-loop). Following D-loop formation, the DNA is synthesized using the
sisterchromatid DNAasatemplate.The Holliday junctions are resolved,mostlywithout any
cross-overeventsandthenewlysynthesizedDNAis ligated (see section on DNArepairand
hereditaryovariancancer).
EpigeneticChanges
EpigeneticsdescribechangesofthechromosomeandnottheDNAnucleotidesequence
itself (51). Epigenetic changes modify gene expression. Central epigenetic changes are
covalentmodificationsof(i)theDNA,forexample,cytosinemethylation(52)andthemore
recently described cytosine hydroxymethylation (53), and (ii) the histones, for example,
lysine,arginineand/orthreonineacetylation,methylation,ubiquitination,andSUMOylation.
DNAMethylation
DNA methylation refers to the addition of methyl groups to cytosines of the DNA,
mostly in so-called CpG sites or CpG islands. In these sites, the nucleotide cytosine is
followedby aguanine linkedby onlyonephosphategroup.In mammals,70–80% ofCpG
cytosines are methylated. Hypermethylated DNA is less transcriptionally active through
mechanisms not completely understood; possibly by modulating access of transcription
factorstopromotorsites(54).AclinicallyimportantexampleofDNAmethylationisMLH1
hypermethylationinendometrialcancer(seesectiononhereditaryendometrialcancer).DNA
methylationcanpersistinthegermlineofoneparentandthenconstitutesthebasisofgenetic
imprinting.
NucleosomeModification
To fitthelong DNAdoublehelixmoleculeinto thecell nucleus,whichis straightened
outabout2metersinlength,theDNAneedstobepackedandcompacted.Tothisend,
the DNA is wrapped around histone proteins and forms so-called nucleosomes. By
stacking nucleosomes, chromatin is formed. During transcription, the DNA is not
completely unwound but instead the packing is only locally unwrapped. Modifications of
histoneproteinsmaychangetheaccessibilityofDNAandtherebyaltergeneexpression.The
most studied covalent histone modification is histone acetylation (55,56). The positively
chargednitrogengroupsofhistonelysinesbindtothenegativelychargedphosphategroups
of the DNAbackbone. Acetylation of lysines replaces those positively charged groups by
neutralgroupsandtherebyloosenstheelectrostaticinteractionsbetweenhistonesandDNA.
TheDNApackagingislesstight,allowsmorefrequentbindingoftranscriptionfactors,and
therebyfacilitatestranscription.
RNAs—microRNA,mRNA
DifferentformsofRNAareknowntomodifyproteinexpression.Differentspliceforms
and methylation of mRNA (messenger RNA) play a role in this context just as so-called
microRNAs(miRNAs). miRNAsare 17–25 nucleotideslong,noncoding RNAsthattarget
and downregulate mRNAs. Each miRNA can neutralize 100 to 200 mRNA copies and
therebypost-translationallyregulateproteinexpression(57).
Figure1.5BRCA1-2protein domains and select founder mutations.A:BRCA1 consists
of1,863aminoacids.Itsmolecularweightisabout220kDa.BRCA1comprisesaRING(really
interestingnew gene) domain, a nuclear localizationsignal(NLS) and nuclear export signal
(NES,notshown),aserineclusterdomain(SCD),andBRCA1C-terminus(BRCT).Important
domainfunctionsareindicatedbyarrows,interactingproteinsmarkedatthesitesofinteraction
with BRCA1. The N-terminally located RING domain exhibits ubiquitin ligase function and is
the BRCA1-associated RING domain protein 1 (BARD1) binding site. Following are
retinoblastoma protein (Rb), RAD50, myelocytomatosis (Myc), and RAD51 binding sites,
NLS, as well as checkpoint kinase 2 (CHEK2) phosphorylation site. The SCD with multiple
phosphorylationsitesistargetedbyataxiatelangiectasiamutated(ATM)checkpointkinases.A
coiled-coil domain is the basis of BRCA1 interaction with partner and localizer of BRCA2
(PALB2), BRCA2. BRCT domains interact and bind various phosphoproteins as well as
BRCA1-interactingprotein1(BRIP1)andp53.ShownhereareimportantexamplesofBRCA1-
2foundermutationsandhowtheyaffectthetranslatedBRCA1-2proteins.Thefollowingthree
mutationsarecommoninBRCA:185ΔAGresultsinatruncatedfunctionlessproteinofonly39
aminoacids;5382insC resultsina C-terminallytruncatedprotein,lackingBRCTdomains;the
C61Gmissensemutationresultsinafull-lengthproteinwithcompromisedfunctionality.BRCA2
consists of 3,418 amino acids. Its molecular weight is about 380 kDa. Important domain
functionsare indicated byarrows, interacting proteins marked at the sites of interaction with
BRCA2.N-terminuscomprisesBRCA1and PALB2(partnerandlocalizer of BRCA2) binding
sites.TheBRCA2proteinharborstwobindingsitesforRAD51(B/C/D),oneintheBRCrepeats
andoneattheC-terminus.Furthermore,DNA-bindingsite,nuclearlocalizationsignal(NLS),
andCHEK2phosphorylationsite have been described. 6174ΔT, a BRCA2 founder mutation,
results in a truncated protein of only 2,002 amino acids (see section on DNA repair and
hereditaryovariancancer).
GeneticChangesinGynecologicMalignancies
EndometrialCancer
SporadicEndometrialCancer
Asidefromthehistologicclassificationforendometrialcancer,differentclassificationshave
been proposed. The most important have been the Bokhman’s classification of estrogendependenttypeIandestrogen-independenttypeIIendometrialcancerandtheclassification
proposedbyTheCancerGenomeAtlas(TCGA)basedoncomprehensivegeneticanalyses.
In the following, these two classifications and associated genetic alterations will be
discussed.
In1983,Bokhman(58)postulatedtwo pathogenetictypesof endometrial cancerdriven
by different metabolic and endocrine signals, the estrogen-dependent type I and the
estrogen-independenttype II. Type I demonstrated low-grade endometrioid histology
with endometrial hyperplasia as a precursor lesion. Endometrioid histology was
associated with early stage at diagnosis and a favorable prognosis. Risk factors for
developing type I endometrial cancer are unopposed estrogen, obesity, and the metabolic
syndrome. The insulin-like growth factor may play a role in carcinogenesis. Estrogen is
consideredtobea“completecarcinogen,”whichmeansitisabletoinitiatemutagenesisand
stimulatecellproliferation(59).DistinctgeneticalterationsintypeIhavebeenreported.
The tumor suppressorgene PTEN is altered in up to 80–90% of type I endometrial
cancers(60,61).MostPTENmutationsresultinatruncatednonfunctionalprotein.In15%,a
pointmutationinthephosphatasedomainhasbeennoted.Inupto20%ofcasesofcomplex
atypicalhyperplasia,PTENmutationshavebeenidentified,andeveninnormalendometrial
glands,PTENmutationshavebeendescribed.Therefore,PTENmutationsareconsidered
earlymutationaleventsinendometrialcancerdevelopment,andfrequentlycoexistwith
other mutations in the phosphatidylinositol 3-kinase (PI-3K) pathway (Fig. 1.2), such as
mutations of the phosphatidylinositol 3-kinase, catalytic subunit α (PIK3CA) and the
phosphatidylinositol 3-kinase regulatory subunit α (PIK3R1) (62–64). Other commonly
mutatedgenesarefibroblastgrowthfactorreceptor2(FGFR2),AT-richinteractivedomain
1A(ARID1A, see section on ovarian clear cell carcinoma),cateninbeta-1(CTNNB1, see
sectiononovarianendometrioidcarcinoma),andKirstenratsarcoma(KRAS,seesectionon
rasabove)(65–67). Microsatellite instability is found in about 30% of type I endometrial
cancers(68).
IncontrasttotypeI,typeIIendometrialcancershavea90%prevalenceofmutations
inthetumorsuppressorgeneTP53,whilePTENisonlyrarelymutated.TP53mutations
occurinonly15%oftypeIcases.MutantTP53overexpressionisseeninmostuterine
serouscancersanditsputativeprecursorlesions(69,70)andthemajority(about75%)of
carcinosarcomas (71) (see section on p53 above). PIK3CA and PPP2R1A (protein
phosphatase 2 regulatory subunit α) are frequently mutated in type II cancers (72,73). In
addition, Her2neu (see section on ErbB above) has been shown to be overexpressed in
uterine serous cancers. The fraction of uterine serous cancers overexpressing Her2neu
remainsuncertain,rangingfrom14–80%indifferentpublications.Theseinconsistentresults
are most likely due to nonstandardized immunostaining protocols for Her2neu receptors
(74–78).
Substantial heterogeneity within, and overlap between, these postulated two types of
endometrial cancerhas been recognized, and this classification neverbecame part of
the formal endometrial cancer staging. Several immunohistochemical and/or mutational
profileshavebeendevelopedtohelpdistinguishendometrialcancer subtypesofprognostic
relevance.Themostcomprehensivemolecularstudytodatehasbeenthatprovidedby
The Cancer Genome Atlas (TCGA) (79). TCGA analyzed tumor samples from 373
patients, primarily endometrioid cancers (82.3%), with fewer of serous (14.2%) or mixed
histology(3.5%).Basedonsomaticmutationfrequency,microsatelliteinstabilityandsomatic
copy-number alterations, endometrial cancers were classified into four groups with
differentprognoses:(1)anultramutatedgroupwith232×10−6mutationsperMb,(2)a
hypermutatedgroup with18×10−6mutationsper Mb, and microsatellite instable (MSI)
cancers, (3) a group with only 2.9 × 10−6 mutations per Mb and microsatellite stable
cancers, and (4) a group with 2.3 × 10−6 mutations per Mb with high copy-number
alterations.
UltramutatedEndometrialCancers
The mutation rate in cancers of this group is 100-fold increased. Mutations in the
catalytic subunit of the DNA polymerase epsilon (POLE) were identified. POLE is
responsibleforreplicationoftheleadingstrandofDNA.Itshowsexonucleaseproofreading
functionandthushigh-fidelityincorporationofbases,whichensuresalowmutationratein
thedaughterstrand.Inendometrialcancers,two hotspot mutations within the exonuclease
domain were identified, that is, P286R in exon 9 and V411L in exon 13. Amino acid
substitutions in these locations have been shown to suppress proofreading (80). Cancers
withPOLEmutationsareassociatedwithhigh-gradefeatures,yetfavorableoutcomes
andlowrecurrencerates.Theseassociationshavebeencorroboratedbyfollow-upstudies
(81–84). On histologic examination, POLE-mutated endometrial cancers show dense
lymphocytic infiltrates. Therefore, POLE-mutated endometrial cancers may respond
favorablytoimmunetherapy(85,86).
HypermutatedEndometrialCancers
Thiscategorycomprisedone-thirdofallexaminedendometrialcancersinTCGA,andwere
mostly Bokhman’s type I. This group is defined by defects in the post-replicative DNA
mismatch repair system and shows microsatellite instability (MSI; see section on MMR
proteins above). The detected mutation rate is 10-fold higher than in microsatellite stable
endometrialcancers.InTCGA,microsatelliteinstabilitywasdeterminedby apaneloffour
mononucleotide repeat loci (polyadenine tracts BAT25, BAT26, BAT40, and transforming
growth factor receptor type II) and three dinucleotide repeat loci (CArepeats in D2S123,
D5S346, and D17S250) in addition to the recommended markers by the National Cancer
Institute(87). Cancers were defined (i) microsatellite-stable(MSS) if none of the markers
showedalterations,(ii)low-levelMSI(MSI-L)ifonetotwomarkerswerealtered(lessthan
40%),and(iii)high-levelMSI(MSI-H)ifthreeormoremarkerswerealtered(greaterthan
40%).
Mismatch repair deficiencies can result from (i) the inherited Lynch syndrome (see
section on hereditary endometrial cancer), (ii) acquired, somatic mutations, or (iii)
epigenetic events, for example, methylation of one of the genes involved in mismatch
DNA repair, most commonly MLH1. Additional frequent mutations in this group of
endometrialcancerswerenotedintheKirstenratsarcoma(KRAS)gene.
MicrosatelliteStableEndometrialCancers
Thisgroup showsa lowmutational rate,ismicrosatellitestable,andhaslow copy-number
alterations,but frequentmutationsin thecatenin beta-1(CTNNB1; see sectionon ovarian
endometrioid carcinoma) pathway, which is involved in cell–cell adhesion and WNT
(integration1/Wingless)signaling.
HighCopy-NumberAlterationEndometrialCancers
Copy-number variations are structural alterations in which sections of the genome are
increased or decreased in number by either multiplication or deletion. Fluorescent in situ
hybridization (FISH) and comparative genomic hybridization (CGH) have been used for
detectingstructuralvariationsinthegenome.Thedrawbackofthesetechniqueshasbeenthe
lowresolutionandonlylargerepeatscouldbedetected.Nextgenerationsequencingallowed
for single nucleotide resolution and the detection of single nucleotide substitution, which
result in so-called single-nucleotide polymorphisms (SNPs). TCGA used an Affymetrix
platform to detect those SNPs from frozen tissue. Hierarchical clustering identified
significantlyreoccurringregionsofamplificationsordeletionsanddefineda“copynumber
(CN) high” subgroup. This group exhibited frequent TP53 mutations and comprised
uterineserousandgrade-3endometrioidendometrialcancers.
Ithasbeenhypothesizedthathighlymutatedcancers,thatis,POLE-mutatedand,toa
lesser extent, MSI-H tumors, have a higher neoantigen load, are thus more
immunogenicandshowanimmunecell-richtumormicroenvironment.Therefore,these
tumors, despite their pathologically aggressive nature, may have a favorable prognosis.
Following the TCGA data, different groups have collaborated to distinguish parameters
suggested by TCGA, that is, POLE, MSI-H, TP53 and have implemented different more
affordabletestingtools(83,88).Furthermore,theendometrialcancerclassificationsuggested
byTCGAwasimplementedinclinicaltrialstoassessifthisclassificationcouldhelpguide
therapeuticdecisions.Themostprominentexampleis the ongoing postoperative radiation
therapyinendometrialcancer(PORTEC)-4study,whichisthefirstrandomizedclinicaltrial
to assess the use of a molecular profile to assign adjuvant treatment for women with
endometrialcancer(NCT03469674)(89).
TCGAanalyzed57uterinecarcinosarcomas(90)andfoundevidencethatmostuterine
carcinosarcomasde-differentiatefromuterineserousprecursors,whilefewarederived
fromanendometrioidlineage.TCGAdatasuggestacarcinomaoriginandthepreservation
of certain ancestral genetic alterations in uterine carcinosarcomas. More than 75% of the
casesshowedalterationsinF-box/WDrepeat-containingprotein7(FBXW7),aproteinthat
likelybindscyclinEandmediatesitsubiquitin-mediateddegradation,G1/Sspecificcyclin-
E1(CCNE1),orretinoblastoma(RB),allofwhichindicatedysregulationsinthecellcycle.
About50%ofcaseshadamutationinphosphatidylinositide3-kinase(PI-3K)(seeFig.1.2).
ManytumorsshowedalterationsinAT-richinteractivedomain1A(ARID1A;seesectionon
ovarianclearcellcarcinoma).
HereditaryEndometrialCancer
Three to 5% of endometrial cancers develop because of Lynch syndrome. Lynch
syndrome was previously known as hereditary nonpolyposis colorectal cancer (HNPCC).
Lynch syndrome is an autosomal dominant inherited condition and is caused by
mutations in one of the following proteins involved in DNA mismatch repair: mutL
homolog1(MLH1),mutShomolog2(MSH2),mutShomolog6(MSH6),pms1homolog2
(PMS2),andepithelialcelladhesionmolecule(EPCAM).
In1913,AldredScottWarthin5(92)publishedthefirstreportonafamilywithanincreased
incidenceofuterineandgastrointestinalcancers.In1971(93)and2005(94), HenryLynch
expandedthisreportonthecancerfamilyG:in2005,thecancerhistoryoffamilyGincluded
929 descendants over seven generations. Aside from family G, Henry Lynch examined
severalotherfamiliessince1966(95).In1985,HenryLynchhimselfnamedtheunderlying
syndrome HNPCC, while others have called it Lynch syndrome since 1984. Individuals
affected by Lynch syndrome have a lifetime risk of developing endometrial cancer
throughtheageof70of16–61%(96,97)comparedtoabaselinelifetimeriskof2.7%.
ThelifetimeriskinferredbyLynchsyndromevariesdependingupontheaffectedMMR
protein:MLH143–57%,MSH221–57%,MSH617–46%,andPMS20–15%(98–103).
ThelifetimeriskforendometrialcancerinferredbyEpCammutationscanbesimilarto
thatofMSH2(104,105).Thelifetimeriskforcolorectal cancer is in the range of 18–
61%,similartotheinferredriskforendometrialcancerwithLynchsyndrome(97).By
comparison,thelifetimeriskofcoloncancerinthegeneralpopulationisabout4.5%.
Endometrial canceris the most common sentinel cancerof Lynchsyndrome. Ovarian
cancer risk is increased to 5–12% in Lynch syndrome, compared to 1–2% in the general
population.Averageageatdiagnosisofendometrialcanceris46,andofovariancanceritis
42. Lynch syndrome–associated endometrial cancers are mostly well-differentiated
endometrioidcancersandearly-stage(106,107).Theriskofdevelopingcancersoftheupper
gastrointestinal tract (including gastric, duodenal, hepatobiliary, pancreatic), urinary tract,
prostate,andbrainismildlytomoderatelyincreased.
Defectsin themismatch repairsystemresultingenomic instability.Diagnostic testsof
the cancer specimen may examine either the expression of MMR proteins by
immunohistochemistryormicrosatelliteinstabilityusingDNAprimers(seesectiononMMR
proteins). Concordance between microsatellite testing and immunohistochemistry has been
reportedas93.3–97.5%(108,109).Bothmicrosatelliteinstabilityandloss ofMMR protein
expression can be caused by epigenetic gene silencing through hypermethylation.
NoninheritedmethylationoftheMLH1promoterisseenin20–30%ofendometrialcancers
and must be excluded. Therefore, loss of MLH1 protein expression on
immunohistochemistry should be followed by hypermethylation testing. Inherited
deletion of the 3′ end of the EpCAM gene, which encodes a transmembrane glycoprotein,
causeshypermethylationofthepromotorregionofMSH2andtherebyepigeneticinactivation
of MSH2. Germline testing is needed to confirm definitively the diagnosis of Lynch
syndrome.
ToidentifypatientsatriskforLynchsyndromebasedonfamilyhistory,differentscreening
criteria have been developed. The initial AmsterdamCriteria from 1990 did not include
extracolonicmalignancies(110)andwerereplacedbytheBethesdaGuidelines from1997
and its revised version from 2004 (87,111). Although the Bethesda criteria are more
sensitivethan theAmsterdam criteria,upto 50%ofLynchsyndromepatientsdonot
meettherevisedBethesdaGuidelines.
UterineMesenchymalTumors
SporadicUterineMesenchymalTumors
EndometrialStromalSarcoma
JAZF1/SUZ12(JuxtaposedwithAnotherZincFingerProtein1/Suppressorof
Zeste-12)
In1991,thefirst reportonthechromosomal translocationt(7;17)inlow-grade endometrial
stromal sarcoma was published (112). This translocation results in the fusion of two zinc
finger, DNA-binding proteins JAZF1/SUZ12 (previously, JAZF1/JJAZ1) (113). This gene
fusionhasbeenfoundin75%ofendometrialstromalnodules,50%oflow-gradeendometrial
stromalsarcomas,andonly15%ofhigh-gradeendometrialstromalsarcomas(114).Despite
its use for diagnostic purposes, especially in combination with YWHAE (see section on
YWHAEbelow), the functionof the genefusion remains unclear.Ithas beenhypothesized
thatJAZF1mayfunctionasatumorsuppressorgeneandmaylosethisfunctioninthegene
fusion product (115). Other gene fusions have been described in low-grade endometrial
stromalsarcomaincludingJAZF1/PHF1,EPC1/PHF1,andMEAF6/PHF1(116).
YWHAE/NUTM2A/B(Tyrosine(Y)3-Mono-oxygenase/Tryptophan(W)5-MonooxygenaseActivationProteinEpsilon/NuclearProteininTestisFamilyMember
2A/B)
High-grade endometrial stromal sarcomas show the chromosomal translocation t(10;17),
which results in the YWHAE-NUTM2A/B (previously, YWHAE-FAM22A/B) fusion protein.
YWHAE encodes the 14-3-3ε protein. 14-3-3 proteins bind to proteins that contain
phosphoserineorphosphothreoninemotifsandareknowntointeractwithover200proteins.
Thereby,theyareinvolvedinamultitudeofcellularfunctionsincludingsignaltransduction,
cellcycling,apoptosis,andneuronaldevelopment.NUTM2AandBproteinfunctionispoorly
describedaswell.Thefusionproteinof14-3-3εandNUTM2A/Bretainsthefunctionofthe
14-3-3ε, but results in aberrant nuclear localization of the 14-3-3ε (117). The
pathomechanism of this fusion protein has not been elucidated. KIT and platelet-derived
growth factor receptor alpha (PDGFR-α) mutations have been described in YWHAE-
NUTM2A/Brearrangedhigh-gradeendometrialstromalsarcomas(118).
Leiomyosarcoma
Thusfar,nomolecularmarkerhasbeenfoundtobeconsistentlyassociatedwithuterine
leiomyosarcomas. However, low-molecular mass protein 2 (LMP2) deficiency has been
showntoresultinthedevelopmentofleiomyosarcomasinalmost40%ofmice(119).LMP2
seemstobeabsentinuterineleiomyosarcomas,butpresentinleiomyomata.LMP2ispartof
theimmunoproteasome,inducedbyinterferon-γandassuchpotentiallyinvolvedintheMHC
I-mediatedtumorrejection(120).
HereditaryUterineMesenchymalTumors
Leiomyoma
In 1973, Reed et al. (121) reported families with successive generations of patients with
cutaneous and uterine leiomyomas and/or leiomyosarcomas. Later, the association of
cutaneous and uterine leiomyomatosis with renal cell cancer was described (122).
Hereditaryleiomyomatosisand renalcell cancer (HLRCC), or Reed syndrome, is an
autosomaldominantconditioncharacterizedby(i)cutaneouspiloleiomyomas,(ii)earlyonset uterine leiomyomas and (iii) early-onset, that is, before the age of 40, type II
papillaryrenalcellcancer.Theunderlyingheterozygousgermlinemutationwasidentified
in 2002 in mutations of the fumarate hydratase (FH) gene (123). Germline FH mutations
havebeendetectedinabout75–100%offamilieswithsuggestiveclinicalfeatures(124,125).
Fumarase or fumarate hydratase has two isoenzymes; the mitochondrial isoenzyme is
involved in the Krebs cycle (citric acid cycle or tricarboxylic acid cycle [TCA]) and the
cytosolicisoenzyme partakesin the metabolismof aminoacidsand fumarate.In the TCA,
FH catalyzes the reversible hydration of fumarate to malate and thereby facilitates a
transition step in cellular NADH production. The pathologic mechanism of this enzyme
defectinHLRCCisnotclear.Ithasbeenhypothesizedthatpseudohypoxiaduetodefectsin
TCAmaydrivetumorigenesis(126)orthatFHmayactasatumorsuppressorgene(127).
OvarianCancer
SporadicOvarianCancer
Epithelial ovarian cancers are a rather heterogeneous group with respect to behavior and
histology. Various classifications have been attempted but have not been as successful in
clinical use as the aforementioned endometrial cancer classifications. Kurman and Shih
(128)suggestedgroupingepithelialovariancancersintotwotypeswithdifferentclinical
behavioranddifferentmolecularcharacteristics. TypeI includedborderlineandinvasive
but low-grade cancers of serous, mucinous, endometrioid and clear cell histology,
comprisingabout25%ofepithelialovariancancers. Thesecancers arein generalslow-
growing,confinedtotheovaryatthetimeofdiagnosisanddevelopfromprecursorlesions.
They are genetically stable and show mutations in Kirsten rat sarcoma (KRAS), rapidly
activated fibrosarcoma (BRAF), phosphatase and tensin homolog (PTEN), and catenin
beta-1(CTNNB1).TypeIIincludesabout75%ofepithelialovariancancers,includinghigh-
grade serous ovarian cancers, carcinosarcomas, and undifferentiated ovarian cancers. This
typeisrapidlygrowing,hasnowell-definedprecursorlesionsandis characterizedby high
geneticinstabilityandfrequentTP53mutations.
High-GradeSerousCarcinoma
TheCancer GenomeAtlaspublished a genomic analysisof489 patients with high-grade
serousovariancancer(129).TP53andBRCA1wereconfirmedtobethemostfrequently
mutatedgenesinhigh-gradeserousovariancancer(130,131).In96%ofcases,thetumor
suppressorgeneTP53wasfoundtobemutated.TP53mutationshavebeenfoundinserous
tubal in situ carcinomas (STICs) and are known to be early events in ovarian cancer
development(132).Two-thirdsofhigh-gradeserouscancershavemissensemutationsinthe
DNA-binding domains, that is, in exons 5 to 8. These missense mutations are dominant
negative mutations and mediate greater protein stability resulting in p53 overexpression.
Other mutations in TP53 lead to a truncated nonfunctional protein, which is usually
accompaniedbyalossoftheotherTP53allele(130,133).
IntheTCGAdata,abouthalfoftheanalyzedhigh-gradeovariancancershaddefectsin
thedouble-strandDNAhomologousrecombination(HR)pathway.BRCA1and BRCA2
germline mutations were present in 9% and 8%, respectively and an additional 3% had
somaticBRCA1orBRCA2(BRCA1-2)mutations.EpigeneticsilencingofBRCA1inducedby
promotorhypermethylationwasfoundin11%,consistentwithpriordata(134).Thissuggests
thatapproximately30% of defectiveHRresultsfromlossofBRCA1-2function,while
the remainder is caused by inherited or acquired defects in other genes of the HR
pathway. TCGA described four subtypes: (i) immunoreactive, (ii) differentiated, (iii)
proliferative, and (iv) mesenchymal. In contrast to the findings of the TCGA for
endometrial cancer, thus far, this ovarian classification has not been shown to be of
prognosticortherapeuticvalue.
OvarianCarcinosarcoma
Limited data on ovarian carcinosarcoma show that TP53 is mutated in 25–67% of cases,
Kirstenratsarcoma(KRAS)in15%andphosphatidylinositol3-kinase, catalytic subunit α
(PIK3CA) in 19–40%, Phosphatase and tensin homolog (PTEN) in 40%, and AT-rich
interactive domain (ARID1A) in 32% (135–137). As with uterine carcinosarcoma, these
analyses do not differentiate the sarcomatous and carcinomatous components of these
biphasictumors,whichmayskewtheresults.
Low-GradeSerousCarcinoma
Low-grade serous carcinomas display the p53 wild-type protein, in contrast to high-grade
serousovariancarcinomas,butupto65%ofcaseshavemutationsinKirstenratsarcoma
(KRAS) and rapidly activated fibrosarcoma (BRAF) (138,139). Mutations in the
serine/threonine kinase BRAF may occur in patients without concurrent KRAS mutations
suggestingcomplementaryfunctionintheactivationofthemitogen-activatedproteinkinase
(MAPK)signalingpathway.BRAFmutationusuallydoesnotaffecttheprognosis,while
thepresenceofKRAShasbeendescribedasanadverseprognosticfactorinlow-grade