SarcomasAssociatedWithGeneticCancerPredisposition ... · Sarcomas...

Sarcomas

Sarcomas AssociatedWith Genetic Cancer Predisposition

Syndromes: A ReviewMOHAMAD FARID, JOANNE NGEOW

Division of Medical Oncology, National Cancer Centre Singapore, SingaporeDisclosures of potential conflicts of interest may be found at the end of this article.

Key Words. Sarcoma x Hereditary x Cancer predisposition syndrome x Cancer genetics

ABSTRACT

Sarcomas are rare mesenchymal malignancies that demon-strate great clinical and biological heterogeneity. A variety ofsarcomas develop in the context of well-defined heritablecancer predisposition syndromes, associations that are oftenoverlooked, given the rarity and diversity of sarcomas and theequivalent relative infrequency of cancer genetic syndromes.This review describes in detail selected heritable cancerpredisposition syndromes that are known to be associatedwith sarcomas.Beyond themolecular and clinical features thatdefine each syndrome, disparities in clinical presentation,natural history, and treatment of syndrome-associatedcompared with otherwise histologically identical sporadicsarcomas will be described. The clinical approach to selectedsarcoma subsets with a view to identifying possible associa-tions with these syndromes will then be described. Althoughthe treatment of the majority of sarcomas will not differ

significantlybetweensporadic casesandthoseassociatedwithpredisposition syndromes, knowledge of features such asunique anatomic sites of affliction or excess toxicities withparticular cytotoxic therapies can facilitate alterations intherapeutic strategies to maximize efficacy and minimizetoxicity. In addition, recognition of cancer genetic predisposi-tion syndrome will allow patients and their relatives toundertake appropriate genetic counseling and testing, as wellas screening, surveillance, and interventional measures, asneeded. Situating sarcomas within the genetic endowment ofparticular patients—specifically that which confers a higherriskofmalignancy—will enable clinicians to bettermanage thepatient as a whole, complementing the great efforts currentlyroutinely undertaken to genomically characterize somatictumor changes with a view to achieving the dream ofpersonalized medicine. The Oncologist 2016;21:1002–1013

Implications for Practice: Sarcomas areuncommonmalignancies that often occur sporadically but can also arise in the setting of arecognized heritable cancer predisposition syndrome. Identification of such associations when present can facilitate refinementand optimization of treatment strategies for the sarcoma so as to minimize toxicity and maximize efficacy. Discerning geneticpredisposition can also facilitate institution of genetic counseling, as well as screening or surveillance schema for both the patientand his or her relatives, if required. Vigilance for these syndromes has the potential to significantly enhance the quality andcomprehensiveness of sarcoma clinical management.

INTRODUCTION

Sarcomas are neoplasms of mesenchymal origin that com-prise only 1% of adult malignancies, but a significantlygreater proportion (15%) of childhood cancers [1]. Sarcomasare extraordinarily heterogeneous, comprising more than 70distinct histological subtypes,with additional layers of biologicvariability conferred by differences in genetic complexity anddriver molecular aberrations, as well as particularities inclinical factors such as age of onset and anatomic site ofaffliction. These differences translate into great diversityin treatment regimens and outcomes that have renderedtransformative progress in the overall management ofsarcomas challenging. In the setting of localized disease,complete surgical excision, coupled in some instances with

adjuvant radiation, can be curative, with two thirds of patientssurviving more than 5 years [2]. In advanced disease, however,prognosis is dismal, with median survival of approximately 1year [3], speaking to the critical need for early detection toensure optimal outcomes.

An intriguing element in the care of patients with sarcomacenters on their association, in a fraction of cases, withheritable cancer predisposition syndromes (Table 1). Eversince the preeminent German pathologist Heinrich vonRecklinghausen described and systematically characterized themultiple neurofibromas of the syndrome we now call neuro-fibromatosis type 1 in the 1880s [4], a great deal has been learnedabout this and many other heritable cancer predisposition

Correspondence: JoanneNgeow,M.B.B.S.,M.R.C.P,M.P.H.,DivisionofMedicalOncology,NationalCancerCentreSingapore,11HospitalDrive, Singapore,Singapore169610.Telephone: 6564368000; E-Mail: [email protected]. Received February 28, 2016; accepted for publicationApril15, 2016; published Online First on July 8, 2016. ©AlphaMed Press 1083-7159/2016/$20.00/0 http://dx.doi.org/10.1634/theoncologist.2016-0079

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Table 1. Selected heritable cancer predisposition syndromes associated with sarcomas

Inherited syndrome Inheritance Genes Chief clinical features Associated sarcomas

FAP AD APC at 5q21-22 Thousands of colonicadenomatous polyps with coloncancer at age,40 years,osteomas, hepatoblastomas

Desmoid tumors

Beckwith-Wiedemann Sporadic/AD CDKAIC, KCNQ1OT1,LIT1, IGF2, and H19

Overgrowth syndrome:macroglossia, omphalocele,hemihypertrophy, gigantism

Embryonal RMS

Bloom AR RECQL3 on 15q26.1 Progeroid syndrome: growthretardation, sun sensitivity,telangiectasias, and other skinchanges

Osteosarcoma,embryonal RMS

Carney-Stratakis AD SDHB at 1p36, SDHC at1q21, SDD at 11q23

Dyad of paraganglioma and GIST GIST

Constitutional mismatch repairsyndrome

AR PSM2 at 7p/q22.1 Predisposition to hematologicmalignancies, CNS tumors,gastrointestinal tumors andpolyps, and other embryonictumors

Embryonal RMS

Costello AD HRAS at 11q15 /12p12.1

RASopathy: coarse facies, shortstature, cardiac anomalies,developmental delay, andcongenital myopathy

Embryonal RMS

Familial GIST AD KIT, PDGFRA at 4q12 Multifocal GISTs in setting ofinterstitial cells of Cajalhyperplasia

GIST

Familial pleuropulmonaryblastoma (DICER 1 syndrome)

AD DICER1 at 14q23.13 Predisposition topleuropulmonary blastomas andother dysplastic/malignantlesions

Embryonal RMS

Familial rhabdoid predispositionsyndrome

AD SMARCB1/INI1 at22q11.33

Renal or extrarenal malignantrhabdoid tumors, CNS tumors

Malignant rhabdoidtumor

Gorlin syndrome/nevoid basalcell carcinoma syndrome

AD PTCH at Xp11.23 / 9q22 Multiple basal cell carcinomas,odontogenic keratocysts,palmar/plantar pits, calcificationof the falx cerebri, ribabnormalities

Embryonal RMS

Hereditary retinoblastoma AD RB1 at 13q14.2 Retinoblastoma, often bilateraland in early childhood (,5 yearsage)

Osteosarcomas, STS

HLRCC AD FH at 1q42 Cutaneous and uterineleiomyomas, type2papillaryRCC

Uterine leiomyosarcoma

LFS AD TP53 at 17p13.1, CHEK2at 22q12

Predisposition to early onset ofmultiple cancers, mostcommonly premenopausalbreast cancer, STS, CNS tumors,osteosarcomas, adrenocorticalcarcinomas, and leukemias

Osteosarcomas, RMS, STS

Mosaic variegated aneuploidy AR BUB1B at15q15 Intrauterine growth restriction,microcephaly, predisposition tocancer (Wilms tumor,hematologic malignancies).

Embryonal RMS

Multiple osteochondromas AD EXT1 at 8q24, EXT2 at11p11.

Multiple osteochondromas Chonodrosarcomas

NF1 AD NF1 at 17q11.2 Cafe-au-lait spots,neurofibromas, irisharmartomas (Lisch nodules),optic gliomas, skeletalabnormalities

MPNST, GIST, RMS

Nijmegen breakage syndrome AR NBS1 at 8q21.3 Chromosomal instabilitysyndrome associated withmicrocephaly, growthretardation, immunodeficiency,and tumor predisposition

Embryonal RMS

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syndromes. Although the initial characterization of thesesyndromes involved careful clinical observation and annota-tion only, epochal advances in molecular biology and bio-informatics have enabled us to interrogate these syndromes toamuch greater degree of genetic detail and depth, refining ourunderstanding and classification of these syndromes at everystep. For example, Li-Fraumeni syndrome was first definedin 1969 based on the observation of early onset cancerstransmitted in autosomal-dominant fashion in four families [5];germline mutation of TP53 was discovered to be the geneticaberration responsible for this syndrome more than 20 yearslater [6]. The clinical and genetic features of this syndromecontinue to be refined to this day, with a recent publicationreporting a long and detailed follow-up of more than 300affected TP53mutation carriers, suggesting significant updatesto clinical criteria for diagnosis andputative clinical implicationsof mutational subtypes [7].

Although there are ample data detailing the clinical andgenetic features of individual syndromes, as well as well-defined therapeutic strategies for individual sarcomasubtypes,there are no guidelines, as far as we know, to aid cliniciansin evaluating for familial syndromes or cancer predispositionwhen managing sarcoma patients. Accurate identification ofsuch syndromes through both clinical evaluation and targetedspecific investigations allows clinicians to adapt their therapyto the particular needs of patientswith genetic predisposition,if any, and plan appropriate genetic counseling and surveil-lance for the patients and their relatives.

In this review,weaim todescribe themostcommoncancerpredisposition syndromes associated with sarcomas (Table 2)

and suggest a sound and clinically practical approach to thequestion of inherited cancer predisposition when treatingsarcomas. Although we recognize the existence of manymorebenign soft-tissuetumors thanmalignantones, anda significantnumber of nonheritable tumor-associated syndromes, they arebeyond the scope of this review; we shall focus only onmalignant mesenchymal tumors arising in the setting ofrecognizably heritable cancer predisposition syndromes.

HEREDITARY CANCER PREDISPOSITION SYNDROMES

ASSOCIATEDWITH SARCOMAS

Li-Fraumeni SyndromeLi-Fraumeni syndrome (LFS) is an autosomal dominant disorderassociated with germline loss-of-function mutations in TP53,one of the cell’s chief bulwarks to the development of neo-plasia, whose loss of function as a tumor suppressor is implicatedin .50% of all cancers. In the classic clinical definition of thissyndrome, the proband had to have a sarcoma diagnosis before45 years of age [5]; subsequent modifications of this criteria haveallowed for any of the multiple cancers associated with LFS toafflicttheproband,namely,sarcoma,braintumor,premenopausalbreast cancer, adrenocortical carcinoma, leukemia, or bronchoal-veolar lung cancer [7]. Approximately 80% of families meetingclassic LFS criteria harbor germline TP53mutations. A key issuewith using such criteria is that diagnosis of the syndromepostdates diagnosis of the primary malignancies, with noopportunity for preventive intervention; thus, obtaining acomplete family history in every patientwith a newdiagnosisof sarcoma is critical. Based on data from the International

Table 1. (continued)

Inherited syndrome Inheritance Genes Chief clinical features Associated sarcomas

Noonan syndrome AD PTPN11 at 12q24, SOS1at 2-22

RASopathy associated withdysmorphic facies, short stature,neck webbing, cardiacanomalies, deafness, andbleeding diathesis

Embryonal RMS, giant celltumor of bone, granularcell tumor, PVNS

Rothmund-Thomson syndrome II AR REQL4 at 8q24.3 Characterized by poikiloderma,as musculoskeletal (shortstature, radial defects, andhypoplastic patellae) and organabnormalities (esophagealatresia, cataracts, andmyelodysplasia)

Osteosarcoma

Rubinstein-Taybi AD CREBBP at 16p13.1 Multiple congenital anomalies,developmental delay,microcephaly, and dysmorphicfeatures

Embryonal RMS, LMS

Tuberous sclerosis AD TSC1 at 9q34, TSC2 at16p13.3, TSC3 at12q22-24.1

Hamartomas of multiple organs,angiomyolipomas, other renaltumors (cysts and RCCs),lymphangiomyomatosis, andangiofibromas

PEComa tumor (Pacoima),chordomas

Werner AR WRN at 8p11.2-12 Progeroid syndrome with tightatrophic skin and bird-like facies,early onset atherosclerosis,diabetes, and osteoporosis

Osteosarcoma,embryonal RMS

Abbreviations: AD, autosomal dominant; APC, adenomatous polyposis coli; AR, autosomal recessive; CNS, central nervous system; FAP, familialadenomatous polyposis; FH, fumarate hydratase; GIST, gastrointestinal stromal tumor; HLRCC, hereditary leiomyomatosis and renal cancer; LFS,Li-Fraumeni syndrome; LMS, leiomyosarcoma; MPNST, malignant peripheral nerve sheath tumor; NF1, neurofibromatosis type 1; PDGFRA,platelet-derivedgrowthfactor receptorA;PEComa,perivascularepithelioidcell tumor;PVNS,pigmentedvillonodularsynovitis;RCC, renal cell carcinoma;RMS, rhabdomyosarcoma; STS, soft-tissue sarcoma; TSC1, tuberous sclerosis complex 1.

©AlphaMed Press 2016TheOncologist®

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Table2.

Clinicalandgeneticfeaturesofselectedsarcomahistologicalsubtypes

associated

withgeneticpredispositionsyndromes

Inherited

syndrome

(modeofinheritan

ce)

Clinicalfeaturesof

inherited

syndrome

Dem

ograp

hic

Uniqueclinicalfeaturesof

thesarcoma(compared

withsporadiccases)

Associated

gene

(s)

Other

associated

malignan

ttumors

Rem

arks

GIST Carney-Stratakis(AD)

Dyadofparagangliomain

conjunctionwithGIST

1%ofGISTalmostexclusively

inpediatric

population

Stom

achorsm

all-bow

elGIST

SDH

FamilialGIST

,1%

ofGIST

Multifo

calityofGIST,ICC

hyperplasia

KITorPD

GFR

NF1

(AD)

2of7criteria:

Sixor

morecafe-au-lait

spotsor

hyperpigmented

macules,axillaryor

inguinal

freckles

(.2freckles),tw

oor

moretypical

neurofibromas

orone

plexiform

neurofibroma,

opticnerveglioma,tw

oor

moreirishamartomas(Lisch

nodu

les),sph

enoid

dysplasiaor

typicallon

g-bo

neabno

rmalitiessuch

aspseudoarthrosis,first-

degree

relative

withNF1

,1%

ofGIST7%

ofNF1

developGIST

IntestinalGIST,multifo

cal,

indolentbiology

NF1

MPN

ST

Osteo

sarcoma

LFS(AD)

Probanddiagnosedwith

sarcomaage,45

years,

first-degreerelative

with

anycancerage,45

years,

anyfirst-orsecond-degree

relative

withanycancer

age,45

yearsorsarcoma

anyage

13%ofLFSdevelop

osteo

sarcoma

Locationsimilarto

sporadic,age

youngerthan

generalpopulation

TP53

Sarcomas,premen

opausal

breastcancer,brain

tumors,adrenocortical

carcinomas,leu

kemia

Screen

ingforLFS

cancers

Hered

itary

retinoblastoma(AD)

Malignantretinaltumor

presentingage,5years

Locationsimilarto

sporadic,age

youngerthan

generalpopulation

RB1

STS,melanoma,brain

tumors,breastcancer

Gen

etictestingoffamilies

asmore

intensive

surveillance

leadsto

less

morbidtherapy;

mosaicism

possible

RTS

IIPoikiloderm

aishallm

ark;the

rash

spreadsto

extrem

ities

andbuttocks,and

then

enterschroniclifelong

phase.Otherfeatures

includeskeletaldysplasia,

sparse

eyebrows/lashes,

shortstature,cataracts,and

dentalabnorm

alities

32%ofRTS

IIpatients

developosteo

sarcoma,at

ameanageof11

years

REQ

L4UPS

BCCandSCCMDS/AML

lymphom

a;gastric

carcinom

aREQL4

encodesaDNA

helicase;othersyndrom

esinvolvingmutations

insame

gene

have

similarclinical

features(e.g.,Baller-Gerold

syndromeorRA

PADILINO

syndrome);recom

mendation

forbaselineskeletalsurvey

byage5,exam

inationfor

cataracts

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Table2.

(continued

)

Inherited

syndrome

(modeofinheritan

ce)

Clinicalfeaturesof

inherited

syndrome

Dem

ograp

hic


thesarcoma(compared

withsporadiccases)

Associated

gene

(s)

Other

associated

malignan

ttumors

Rem

arks

Werner

syndrome

Phenotypethat

mim

icspremature

aging;

prematurely

agedap

pearan

cein

2ndan

d3rd

decades.

Bilateralcataracts,

scleroderm

a-like

skin

chan

ges,short

stature,p

remature

graying,an

dloss

of

scalphair

Largestnumber

inJapan;

freq

uen

cystrongly

influen

cedbylocalfounder

mutationsand

consanguinity;7.7%

of

Werner

syndromedevelop

osteo

sarcoma

WRN

Thyroidcarcinoma,

melanoma,STS,

hem

atolymphoid

malignancies

WRNen

codes

aDNA

helicase

Chondrosarcoma

Chondrosarcoma(AD)

Multiple

osteo

chondromas,

withat

least2

osteo

chondromas

inthe

juxta-ep

iphysea

lreg

ion

oflongbones

observed

radiograp

hically

First2decades

oflife

EXT1

orEXT2

STS LFS(AD)

Probanddiagnosedwith

sarcomaage,45

years,


with

anycancerage,45

years,

anyfirst-orsecond-degree

relative

withanycancer

age,45

yearsorsarcoma

anyage

11%–17

%ofLFSdevelop

STS

TP53

Sarcomas,

premen

opau

salb

reast

cancer,brain

tumors,

adrenocortical

carcinomas,leu

kemia

UPS

NF1

(AD)

2of7criteria:

Sixormore

cafe-au-lait

spotsorhyperpigmen

ted

macules,axillaryor

inguinalfreckles

(.2

freckles),tw

oormore

typicalneu

rofibromas

or

oneplexiform

neurofibroma,

opticnerveglioma,tw

oormore

irisham

artomas

(Lisch

nodules),sphenoid

dysplasiaortypical

long-boneab

norm

alities

such

aspseudoarthrosis,


withNF1

50%ofMPN

STsare

NF1-associated

;10%

of

NF1sdevelopMPN

ST

Conflictingdataon

progn

osticim

pactof

NF1

onMPNST

(possibly

associatedwith

inferiorprogn

osis

comparedwithsporadic

MPNST

)

NF1

GIST

MPN

ST

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Agency for Research on Cancer TP53 database, sarcomasrepresent 17.4% of all cancers in TP53 germline mutationcarriers and 36.8% of all cancers in patients younger than 20years [8]. The most commonly encountered subtypes wereosteosarcomas (40.4%), sarcoma not otherwise specified(17%), rhabdomyosarcoma (16.5%), leiomyosarcoma (9.1%),and liposarcoma (4.9%). The actual proportion of individualswith early onset sarcomas who demonstrated evidence ofhaving LFS, however, is small, at approximately 3% [9, 10].There is evidence to suggest particular susceptibility of TP53-deficient cells to toxicity and development of malignancywhen subjected to the cytotoxic effects of ionizing radiation[11, 12]; such patients may thus benefit from radiation-sparing approaches to therapy, if feasible.There are also datato suggest that screening protocols for patients from familieswith LFSmay facilitate earlier detection ofmalignancywithpotentially improved overall outcomes [13]. Althoughgermline TP53 loss-of-function mutations result in cancerpredisposition, recent evaluation of elephant genomesrevealed that the presence of multiple extra copies of TP53may protect against cancer development [14]; this mayshed some light specifically on the relatively low rates ofcancer in elephants compared with humans, and moregenerally on Peto’s paradox, the observation that cancerrisk does not scale proportionately with size in the animalkingdom [15].

Neurofibromatosis Type 1AlsoknownasvonRecklinghausen’sdisease,neurofibromatosistype 1 (NF1) is an autosomal dominant disorder affecting 1 in3,000 live births, making it the most common human cancerpredispositionsyndrome.It ismostdistinctivelycharacterizedbythe development of widespread nerve sheath tumors, termedneurofibromas, and multiple areas of cutaneous hyperpigmen-tation, or cafe-au-lait spots. Other clinical features includeaxillary freckling,opticgliomas, irishamartomas (Lischnodules),bonedysplasia, andpositive family history; thediagnosis ofNF1is made when any two of these seven clinical criteria are met.The syndrome is genotypically defined by loss-of-functionmutations to the NF1 gene encoding the tumor suppressorneurofibromin,whichleadstountrammeledmitogenicsignalingdown the mitogen-activated protein kinase (MAPK) pathway.Patients with NF1 syndrome have an 8%–13% lifetime risk ofdevelopingmalignant peripheral nerve sheath tumor (MPNST),an aggressive, genetically complex soft-tissue sarcoma thatcomprises 2%of all sarcomas [16]. NF1 syndrome has also beenassociated with the development of gastrointestinal stromaltumors (GISTs), the mesenchymal tumor deriving from theinterstitial cells of Cajal that line the gastrointestinal tract. DatafromaSwedishcancer registry showedthat7%ofNF1patientsdevelop GIST; NF1-associated GISTs comprise approximately1.5% of all GIST cases [17]. These GISTs are often associatedwith an indolent biology and have a predilection for the smallbowel. They are part of approximately 10% of GISTs notmutated for either cKIT or platelet-derived growth factorreceptor A (PDGFRA), a group that, unsurprisingly, displaysdecreased sensitivity to the tyrosine kinase inhibitor thattargets these two oncogenes, imatinib. In the pediatric popula-tion, rhabdomyosarcoma has also been noted to occur 20 timesmore frequently among NF1-affected children compared withTa

ble2.

(continued

)

Inherited

syndrome

(modeofinheritan

ce)

Clinicalfeaturesof

inherited

syndrome

Dem

ograp

hic


thesarcoma(compared

withsporadiccases)

Associated

gene

(s)

Other

associated

malignan

ttumors

Rem

arks

FAP(AD)

7.5%

ofd

esmoidtumors

haveFA

P;15

%ofFA

Pwill

developdesmoidtumors;

averageageat

diagnosis:

32years

Thepercentage

of

intra-abdominaldisease

amongFA

P-associated

desmoidtumorsis80

%,

compared

with5%

for

sporadicdesmoidtumors.

Intra-abdominaldisease

isassociated

withsignificant

morbidity,usuallyrelated

tobowelobstruction

APC

Colorectalcarcinoma,

hep

atoblastoma

Aggressivefibromatosis

Hered

itary

leiomyomatosisand

renalcellcancer

syndrome(AD)

Cutaneo

usoruterine

leiomyomas

1.5%

ofleiomyosarcomas

inpatientsaged

,45

years

oldareassociated

witha

germ

lineFH

mutation

FHTypeIIpapillaryRCC

Leiomyosarcoma

Abbreviations:AD,autosomaldominant;AML,angiomyolipoma;APC

,aden

omatouspolyposiscoli;BCC,basalcellcarcinoma;FA

P,familialaden

omatouspolyposis;FH

,fumaratehydratase;G

IST,gastrointestinalstromal

tumor;ICC,intrahep

aticcholangiocarcinoma;LFS,Li-Fraumen

isyndrome;MDS,myelodysplasticsyndrome;MPN

ST,m

alignantperipheralnerve

sheath

tumor;NF1,neu

rofibromatosistype1;PD

GFR,platelet-derived

growth

factorreceptor;RCC,ren

alcellcarcinoma;RTS,Rothmund-Thomsonsyndrome;SCC,squam

ouscellcarcinoma;STS,softtissuesarcoma;UPS,unclassified

pleomorphicsarcoma.


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children without NF1, with the urogenital system being themostcommonly affected anatomic site [18].

Hereditary Retinoblastoma SyndromeHereditary retinoblastoma syndrome is an autosomal domi-nant condition causedby a germlinemutation in theRB1 gene,a tumor suppressor that regulates cell-cycle progression andmodulates the transcription of a large number of target genesinvolved in apoptosis, autophagy, and chromosomal stability,among other roles [19]. Hereditary retinoblastoma is geno-typically defined by a germline mutation in the tumor sup-pressor RB1, with a “second hit” causing inactivation of bothalleles and the development of malignancy. This most oftenoccurs before 1 year of age, in the embryonic retina of botheyes, occurring with a penetrance of approximately 90%. Ap-proximately 13% of patients with unilateral disease, how-ever, also carry a germline mutation in RB1 [20]. Long-termsurvivors have a significantly increased risk of second primarynonocular malignancies, comprised primarily of bony tumors,soft-tissue sarcomas, and melanomas, with leiomyosarcomasand osteosarcomas accounting for more than half of thesesecond primary tumors [21]. Notably, up to 40% of thesesecond primary neoplasms occur outside the radiation field,speaking to the multiple factors beyond radiation for theprimary retinoblastoma, including alkylator chemotherapyand underlying genetic susceptibility, as causes for the secondmalignancy. Indeed, there is ample molecular evidence for anassociation of karyotypically complex sarcomas seen in associa-tion with hereditary retinoblastoma with defects in the RB1pathway, providing a mechanistic biological explanation forthe association of sarcomas with this syndrome beyondradiation-associated etiology [22, 23]. Patients presentingwith newly diagnosed sarcoma thus need to be screened forpersonal history of childhood cancers like retinoblastoma.The age of presentation in hereditary retinoblastoma survivorsvaries; bone sarcomasusually develop in survivors between the1st and 2nd decade of life, whereas soft-tissue sarcomas canarise between 10 and 50 years after retinoblastoma diagnosis[24]. Survivors of hereditary retinoblastoma also have elevatedrisks of epithelial tumors of bladder, lung, and breast [25], sodiagnosis of sarcomas synchronously or metachronously withthese cancers should trigger an evaluation for hereditaryretinoblastoma.

GIST Predisposition SyndromesFamilial GISTsyndromes, unsurprisingly, involve aberrations inthe genes pathogenically linked to the development of GIST.Approximately 80% of sporadic GISTs aremutated for the cKIToncoprotein; there are now more than 20 kindreds reportedwith germline KIT mutations and associated familial GIST,inherited in an autosomal dominant fashion [26]. In additiontobeingpredisposed todevelopingGIST,patientsmaydeveloppigment changes of the skin, urticaria pigmentosa, myentericplexus hyperplasia, and dysphagia. There have also beenseveral reported kindreds of GIST in patients with germlinemutations of PDGFR, a genemutated in approximately 10% ofsporadic GISTs [27]. Another form of familial GIST can arise thesetting of Carney-Stratakis syndrome, which clinically mani-fests as a dyad of paragangliomas and GISTs, arising from agermline mutation in one of the subunits of succinate

dehydrogenase (SDH), a mitochondrial enzyme complexcritical to cellular metabolism [28]. SDH-deficient GISTs as agroup form approximately half of the 10% of GISTs not mu-tated for cKIT or PDGFR, with the majority of pediatric GISTs(comprising ,5% of all GISTs) being SDH-deficient [29]. Aproportion of these GISTs in children and young adults areassociated with pulmonary chondromas and/or paraganglio-mas, referred to as the Carney triad, a nonheritable syndromenot to be confused with Carney-Stratakis syndrome.There arecurrently no data to suggest that familial GISTs should bemanaged any differently than sporadic GISTs.

Familial Adenomatous PolyposisFamilial adenomatous polyposis is primarily an inheritedcolorectal cancer syndrome characterized by the develop-ment of hundreds to thousands of adenomas throughout thelarge bowel.The autosomal-dominant syndrome is caused bygermline mutation of adenomatous polyposis coli (APC). Thistumor suppressor is involved in modulating the levels ofb-catenin, a protein involved in mitogenic signaling. Thepenetrance of familial adenomatous polyposis (FAP) is nearly100%, with virtually all patients developing colorectal cancerby the 4th decade of life, if not detected early through sur-veillance endoscopy and treated with prophylactic surgery.Patients with FAP are also predisposed to developing otherneoplasms, including desmoid tumors or aggressive fibroma-tosis.These are sarcomas of intermediate malignant potentialthat, although not associated with the development of widelymetastatic disease, are locally invasive and predisposed torepeated local recurrences that can lead to morbidity andmortality. The absolute lifetime risk of developing desmoidtumors in FAP is 15% [30]. A Dutch study of more than 500patients revealed the incidence of FAP among patients withdesmoid tumors to be 7.5%, with 85%of these FAP-associateddesmoids diagnosed in the setting of known FAP [31]. FAP-associated desmoids differ from sporadic desmoids bothgenetically and phenotypically. Unlike APC-mutated FAP-associated desmoids, sporadic desmoids are most often theresult of mutations in the b-catenin gene, CTNNB1. Up to80% of FAP-associated desmoids arise intra-abdominally,as opposed to only 5% of sporadic desmoids, the majority ofwhich arise extra-abdominally, in part explaining the in-creased morbidity of FAP-associated desmoids comparedwith those arising sporadically, aswell as their status as one ofthe leading causes of death in FAP [32].Themorbidity of suchFAP-associated intra-abdominal or mesenteric desmoids isoften prominent, leading to interventions like surgery andsystemic therapy. This is distinct from extra-abdominaldesmoids, which can often be managed expectantly, espe-cially if disease bulk andanatomical factors are favorable [33].

Tuberous Sclerosis ComplexTuberous sclerosis complex is an autosomal dominant multi-system disorder that almost invariably affects the centralnervous system. Epilepsy occurs in 80%–90% of patients and isoften difficult to control; almost half of patients will have somedegree of intellectual disability [34]. The main genetic defectinvolves loss-of-function germlinemutations of tumor suppres-sor genes tuberous sclerosis complex 1 (TSC1) and TSC2, criticalnegativeregulatorsof themTORsignalingpathway.Thesegenes



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encode proteins that inhibit the RAS family GTPase Rheb, theactivator of the mechanistic target of rapamycin 1 complex, akey regulator of protein synthesis. This syndrome is alsoassociated with several abnormal proliferations, includingintracranial tumors (subependymal nodules and subependy-mal giant cell astrocytomas) and a range of extracranialtumors, including angiomyolipomas (AMLs) of the kidney,clear cell “sugar” tumor of the lung, and lymphangioleiomyo-matosis (LAM) of the lung [35]. These extracranial tumors canbe subsumed under the pathological category perivascularepithelioid cell tumor (PEComa).These are histopathologicallywell-definedentitiesthatappear tobedrivenbymTORpathwayoveractivity, for which use of mTOR pathway antagonists hasshown satisfactory responses and improvements in outcomes[36, 37]. Their incidence is approximately 200 cases worldwideper year, and they can arise from almost any organ. MostPEComas other than AML and LAM are sporadic, with only asmall subset associated with the TSC [38].

Hereditary Leiomyomatosis and Renal Cell CarcinomaHereditary leiomyomatosis is an autosomal dominant syn-drome, characterized predominantly by the development ofcutaneous and uterine leiomyomata, as well as renal tumors,most distinctively papillary renal cell carcinoma (RCC) in afraction of patients, one of the more aggressive forms ofrenal cancer. The underlying genetic aberration is a germlinemutation in the fumarate hydratase (FH) gene, which encodesthe tricarboxylic acid cycle enzyme that converts fumarate tomalate, an important step in oxidative phosphorylation andcellular energetics. Loss of function of fumarate hydrataseleads to a shift to aerobic glycolysis and accumulation offumarate, which leads to overactivity of hypoxia-induciblefactor-1a and increased transcription of its target genes suchasvascular endothelial growth factor [39].Thedevelopmentofuterine leiomyosarcoma has only been reported very in-frequently amonghereditary leiomyomatosis and renal cancer(HLRCC) patients [40]. A Finnish study of early onset uterineleiomyosarcoma showed that 1.5% of seemingly sporadic,nonsyndromic cases of uterine leiomyosarcoma evaluatedharbored FH germlinemutations [41]. Among HLRCC patients,the majority of families with RCCs—and the only cases ofuterine leiomyosarcoma—have been reported in Finland [42,43]. A genome-wide linkage-analysis study failed to findevidence for a genetic modifier for RCC risk [42].This apparentclustering is thus probably explained by differences inrecruitment methodology across various reported series,predisposing to ascertainment bias, in addition to chancevariation in the prevalence of rare diseases betweendifferent small cohorts.

MANAGEMENT OF SPECIFIC SARCOMAS ACCOUNTING FOR

POSSIBILITY OF INHERITED CANCER PREDISPOSITION

The optimal family history for in the evaluation of any newpatient with cancer is the three-generation pedigree used ingenetic counseling. It is recognized, however, that such acomprehensive evaluation is logistically challenging in a busyclinical oncology practice. Consistent with recent AmericanSocietyof Clinical Oncologyguidelines for collection anduseofcancer family history for oncology care providers [44], wewould advocate a minimum adequate family history as family

history of cancer in first- and second-degree relatives. For eachrelative with cancer, minimum data required are the type ofprimary cancer, the age at diagnosis of each primary cancer,and whether the relative is along the maternal or paternallineage.

As a general rule, the primary treatment of patientswhosesarcoma arises as part of an inherited cancer predispositionsyndrome does not differ significantly from that of the samesarcomaarising sporadically. For thevastmajorityof sarcomas,surgical extirpation with adequate margins remains thecornerstone of care. That being said, there should be aheightened concern for the short- and long-term toxicity ofcytotoxic agents (chemotherapy and radiotherapy) in thetreatment of patients with particular syndromes (LFS andhereditary retinoblastoma syndrome), the value of whichneeds to be framed against each individual patient’s prognosisin totality. The recognition of particular genotype-phenotypecorrelations can certainly facilitate surveillance, diagnosis, andtherapy of the patient’s sarcoma, as well as other manifesta-tions of the syndrome, both neoplastic and otherwise. Clearly,early apprehension of particular syndromes with well-definedinheritance will facilitate appropriate genetic counseling toguide fertility and surveillance protocols both for the patientand his or her relatives.

For the vastmajority of sarcomas, surgical extirpationwith adequate margins remains the cornerstone ofcare. That being said, there should be a heightenedconcern for the short- and long-term toxicity ofcytotoxic agents (chemotherapy and radiotherapy) inthe treatment of patients with particular syndromes(LFS and hereditary retinoblastoma syndrome), thevalue of which needs to be framed against eachindividual patient’s prognosis in totality.

GISTIn spite of its relative cytogenetic and genomic simplicity, aswell as its status as thearchetypal oncogene-addicted tumor,GIST represents a molecularly complex family of tumors,rather than a uniform biological entity [45]. Validated clinico-pathologicrisk factors, suchassize,mitotic rate,anatomicorigin,and tumor rupture, are more important than genotype inprognosticatingresected localizedGIST [46]; however, genotypeis importanttoconsider indecidingonuseofadjuvanttherapyassome genotypes predict for imatinib insensitivity. KIT is thegenemost commonlymutated, affecting 80% of GISTpatients.In primary disease, KIT-mutant GISTs can have varying prog-noses, but are generally imatinib-sensitive. PDGFRA-mutantGISTs (10%) are generally associated with more favorableprognosis compared with KIT-mutant GISTs [43]. However, thePDGFRA exon 18 d842V mutation, affecting approximatelyhalf of GIST cases mutated for PDGFRA, confers Imatinibresistance—these patients should not receive imatinib. The10% of GIST patients wild-type for KIT and PDGFRA dem-onstrate an evolving complexity, with the best characterizedgroups being the MAPK-pathway mutated and SDH-deficientGISTs. These GISTs are also generally predisposed to indolent


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biologies and relative imatinib resistance, although thesedata necessarily accrue from very small patient series[47]. Imatinib-resistant KIT-mutated GIST is almost alwaysdriven by secondarymutations in KIT, for which second-linetherapies have varying activities depending on the natureof the secondarymutation.The utility of genotype-directedtherapy in this setting is limited by clonal heterogeneity andongoing evolution of the resistant tumors.

Patients with GIST should have a history and physicalexamination to evaluate for signs and symptoms of functionalgastrointestinal symptoms, cutaneous signs or thoracic lesions,suggestive of familial GIST or Carney-Stratakis syndrome. Thetreatment for GIST in the setting of these syndromeswould notbe different from that as described for sporadic GIST.

OsteosarcomaOsteosarcomas are the most common primary bone tumor.They are genomically complex tumors, defined pathologicallyby their characteristic feature of laying down new bone orosteoid. There are two peaks in incidence, the first in the 2ndand 3rd decades of life, arising in the long bones mostcommonly the distal femur, and the second in the 6th and 7thdecades of life, in this setting more commonly secondary toan environmental insult, such as chronic inflammation (e.g.,secondary to Paget’s disease of bone) or radiotherapy forcancer.

Approximately 10% of osteosarcomas are associated withgenetic cancer predisposition syndromes [48]. The mostprominent are LFS and hereditary retinoblastoma syndrome,a finding, when considered togetherwith the known presenceof defects in TP53 and RB function in sporadic osteosarcomas[49] speaks to the importance of these tumor suppressors inosteosarcomagenesis. Another group of syndromes associ-atedwithosteosarcomas is theDNAhelicasemutation-relatedsyndromes, autosomally recessive inherited syndromeswherepatients usually present with developmental and physicalabnormalities; in this setting, osteosarcoma is usually di-agnosed even earlier, in the 1st decade of life [50]. Otherwise,there are no known clinical differences in prognosis andtreatment between osteosarcomas presenting in the settingof genetic predisposition or sporadically.Treatment comprisescombination chemotherapy combined with complete surgicalexcision, with the extent of chemotherapy-induced tumornecrosis being prognostic for eventual outcomes.The utility ofradiation therapy is limited, so the need for vigilance to avoidradiation is less prominent. Most patients who present withosteosarcoma will be in the adolescent and young adult agegroup (16–39 years old)—if the tumor arises in the setting ofgenetic cancerpredisposition, thesepatientsmaybenefit fromgenetic testing and subsequent surveillance. Thus, all patientsshould havea thorough family history andphysical examinationto exclude phenotypic presenceof syndromes. Li Fraumenimaynot present with any phenotypic features if there is no familyhistory, so it may arguably be of value to refer all newlydiagnosed osteosarcomas for genetic counseling to discuss theevaluation for germline TP53mutation.

RhabdomyosarcomaRhabdomyosarcomas are skeletal muscle tumors composedof several histologic variants, of which the most common in

children and young adults is embryonal rhabdomyosarcoma(ERMS), followed by alveolar rhabdomyosarcoma (ARMS).ERMS is composed of cells with features of embryonal skeletalmuscle cells. Up to 80% of cases arise in the 1st decade of life.The head and neck and genitourinary system are the mainanatomic sites of involvement, with less than 10% of casesaffecting the extremities. ARMS are highly cellular tumorscontainingamonomorphouspopulationofprimitive cellswithfeatures of arrested myogenesis [1]. Approximately 80% ofARMSarecharacterizedbytranslocationsthateither juxtaposePAX3 (chromosome 2) or PAX7 (chromosome 1), with FOXO1on chromosome 13, to generate chimeric fusion genes [51].A very small subset of ERMS and ARMS are associated withinherited cancer predisposition syndromes.These include LFS,hereditary retinoblastoma syndrome, Beckwith-Wiedemannsyndrome, and RASopathies such as Costello syndrome andneurofibromatosis type 1 [52]. The majority of syndromicrhabdomyosarcoma (RMS) has been ERMS, and those withmorphologic features of ARMS often lack the PAX-FOXO1translocations. Treatment of ERMS and ARMS is multimodal,often involving surgery, radiation, andmultiagent chemother-apy according to clinicopathologic prognostication schemaand therapeutic regimens developed by the IntergroupRhabdomyosarcoma Study Group as part of the Children’sOncology Group.

Soft-Tissue SarcomasAs described, the general principles of therapy for soft-tissuesarcomas arising from the extremity, viscera, retroperito-neum, or head and neck region apply equally to sporadic orinheriteddisease. In the absence ofmetastasis, themost criticalelement of treatment is complete surgical removal withadequate margins, with consideration of adjuvant radiationtherapy to optimize local control [53]. The value of radiationhowever, needs to be balanced against the heightened risk ofsecondmalignant neoplasms in these patients, over and abovetheir inherent increased risk for developing malignancy, whichhas been repeatedly demonstrated in patients with heredi-tary retinoblastoma syndrome and LFS [54, 55]. The role ofadjuvant chemotherapy in completely resected soft-tissuesarcoma remains controversial. A meta-analysis evaluating18 trials revealed absolute risk reductions in recurrence anddeath of 12% and 11%, respectively, with the use of adjuvantdoxorubicin in combination with ifosfamide [56]; despite this,the most recently reported large randomized trial using thesame combination involving 351 patients, two thirds of whomhad extremity sarcoma, revealed no benefit in recurrence freesurvival or overall survival [2]. The weight of clinical opinion isgenerally against the widespread use of adjuvant chemother-apy in the treatment of localized sarcomas. In addition, DNA-damaging chemotherapy, especially alkylators, have beenimplicated in contributing to increased riskof secondmalignantneoplasms in hereditary retinoblastoma syndrome [57].

Pertaining to specific sarcomas, patients with MPNSTshould be evaluated clinically for signs of NF1 syndrome.Fluorodeoxyglucose-positron emission tomography has beenstudied to differentiate benign neurofibromas from MPNST inpatients with NF1 with promising results; one study demon-strated reliable and replicabledifferentiationwith relatively highspecificity [58]. After curative treatment of an NF1-associated



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MPNST, if feasible, consideration should be made for closeclinicoradiologicmonitoringwith PET-CT todetectmalignanttransformation of neurofibromas earlier, to facilitate earlyintervention [59]. Patients with PEComa or angiomyolipomashould be evaluated for clinical evidence of tuberoussclerosis complex. Patients with leiomyosarcoma shouldhave clinical evaluation (cutaneous examination and thoracicexamination) for hereditary leiomyomatosis with renal cellcarcinoma.

Aftercurative treatmentofanNF1-associatedMPNST,if feasible, consideration should be made for closeclinicoradiologic monitoring with PET-CT to detectmalignant transformationofneurofibromasearlier, tofacilitate early intervention.

Soft-tissue sarcomas should be evaluated clinically forpast personal history of, and treatment for anymalignancy, toassess for the possibility of cancer predisposition syndromessuch as LFS and hereditary retinoblastoma. If patients meetclinical criteria for these syndromes, genetic counselingshouldbe initiated, and theappropriate confirmatorygenetictests should be instituted. Patients with desmoid tumorsshould have a clinical evaluation for history and features ofFAP. In the Dutch study described earlier, the odds ratio forbeing associated with FAP when compared against extra-abdominal desmoids, was 4.8 for abdominal wall and 18.9 forintra-abdominal desmoids [31]. In the absence of a familyhistory or clinical symptoms suggestive of FAP, we wouldsuggest genetic counseling for evaluation of germline APCmutation in all patients under 60 years old with abdominaldesmoids.

SARCOMA SUBTYPES NOT CLASSICALLY ASSOCIATEDWITH

INHERITED CANCER PREDISPOSITION

In spite of the fact that the vast majority of individual sarcomacases arise sporadically, quite a few histological subtypes, asthus far described, can arise within the context of one orseveral inherited cancer predisposition syndromes. A numberof sarcoma subtypes, however, have not, to the best of ourknowledge, been systematically or recurrently linked with anysuch syndromes. This may very well represent no more thanthe workings of chance—rarely diagnosed sarcoma subtypesnot arising in rarely prevalent cancer predisposition syn-dromes. Yet there are several relatively more commonsarcomas that are comparatively more conspicuous in theirabsence fromthecatalogsof sarcomasarising in the settingofcancer predisposition. These include liposarcoma, synovialsarcoma, angiosarcoma, and Ewing sarcoma.

Liposarcomas (LPS) are adipocytic malignancies that makeup approximately 20% of soft-tissue sarcomas (STS). Theycomprise well-differentiated/dedifferentiated (WD/DD LPS;64%),myxoid/round cell (MRLPS; 28%), andpleomorphic (8%)varieties [60]. WD/DD LPS most often arises in the retroper-itoneum of adults in the 5th or 6th decade of life and isassociated with amplification of the 12q14-15 chromosomalregion, resulting in increased activity ofMDM2, HMGA2, andCDK4. MR LPS commonly afflicts the extremities of adults in

the third and fourth decades of life and harbors gene fusionsinvolving DDIT3, most commonly from the reciprocal trans-location involving chromosomes 12 and 16 to generate theFUS-DDIT3 chimeric fusion protein. The majority of liposarco-mas are predisposed primarily to repeated local recurrencesand treated mainly with multiple surgical extirpations, wherepossible.

Synovial sarcomas, making up 6% of STS, predominantlyaffect young adults in the 3rd decade of life. They areassociated with reciprocal translocations involving the Xchromosome and chromosome 18, leading to the formationof an SS18-SSX oncogenic fusion protein [61]. They can arisefrom any anatomical site, although they most commonlyoccur in the extremities. These are aggressive malignanciesthat have a predilection for distant relapses after surgicalresection, primarily in the lungs. Although more sensitive tochemotherapy thanmost soft-tissue sarcomas, responses areusually short-lived, and prognosis in the setting of advanceddisease is generally poor.

Angiosarcomas, comprising 1%–4% of STS, primarilyafflict adults in the 5th decade of life and beyond.These aretumors of endothelial origin that can arise from themultiple anatomic sites including head and neck, skin,heart, breast (most often in the postradiation therapysetting), bone, liver, or spleen, and in association withchronic lymphedema (Stewart-Treves syndrome) [62].Angiosarcomas are genetically complex tumors with nowell-characterized defining recurrent molecular aberrations.They are extremely aggressive biologically with dismal overalloutcomes and feweffective treatment options in the settingofadvanced disease.

Ewing sarcoma or primitive neuroectodermal tumor,making up 6%–8% of primary malignant bone tumors, has apeak incidence in the2nddecadeof life.These are small, roundblue cell tumors whose cell of origin is unknown, defined bychromosomal translocation giving rise to EWSR1-ETS fusionproteins that drive the malignant phenotype. Ewing sarcomasare exquisitely sensitive to chemotherapy and radiationtherapy, with satisfactory cure rates achieved by usingintensive multimodal therapy in the setting of localizeddisease [63].

To thebest ofour knowledge, there are no specific definingfeatures linking the members of sarcoma subtypes notclassically associated with hereditary cancer predisposition.They include both genetically simpler sarcomas characterizedby specific recurrent molecular aberrations (chromosomaltranslocations, mutations, and amplifications) and usuallysimple karyotypes, as well as genetically complex sarcomaswith nonspecific genetic alterations and complex unbalancedkaryotypes.There isnodoubtthatthemembersof thisgroupofsarcomaswill continuallychangeasweprogressively refinethetaxonomy of sarcomas in ways that are more biologically andtherapeutically meaningful and as we improve the techniquesused to evaluate and annotate patients with inherited cancerpredisposition.

CONCLUSIONThe clinical management of sarcomas can be very heteroge-neous, deriving from the numerous biologically distinctentities that are subsumed within this group, each with


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different natural histories and varying sensitivities to antineo-plastic therapy—the oncologist treating sarcomas will need tobe aware of the many different sarcoma subtypes and theirdisparate therapeutic strategies.The association of particularsarcomas with various heritable cancer predispositionsyndromes adds yet another layer of complexity to thisalready-formidable matrix. Yet as we hope we have shown,apprehension of these associations will be critical for theoptimal management of the patient, both specific to thetreatment of the sarcoma, as well to his or her overall healthstate and wellbeing. As we continue to make exponentialinroads into cancer genomics and bioinformatics, it is likelythat these relationships will only becomemoremuddled andcomplicated, with the same qualitative genetic aberrationconferring different risks of sarcoma and other diseases

depending onmultiple other factors. Itwill be critical for us asa community to effectively grapple with such burgeoningcomplexity and resolvenewdata in real timewith thedictatesof clinical medicine, so that our patients with this raremalignancy can enjoy the best care science andmedicine hasto offer.

AUTHOR CONTRIBUTIONSConception/Design:Mohamad Farid, Joanne NgeowCollection and/or assembly of data:Mohamad Farid, Joanne NgeowData analysis and interpretation:Mohamad Farid, Joanne NgeowManuscript writing:Mohamad Farid, Joanne NgeowFinal approval of manuscript:Mohamad Farid, Joanne Ngeow

DISCLOSURES

The authors indicated no financial relationships.

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CME This article is available for continuing medical education credit at CME.TheOncologist.com.

For Further Reading:John T. Mullen, Thomas F. DeLaney, Andrew E. Rosenberg et al. b-Catenin Mutation Status and Outcomes in SporadicDesmoid Tumors. The Oncologist 2013;18:1043–1049.

Implications for Practice:Mutations in the gene-encoding b-catenin, CTNNB1, are highly prevalent in sporadic desmoid tumors, yet whethermutation status and/or type predict outcome is not certain. In contrast to recently published studies fromother groups,wedid not detect a significant difference in recurrence risk according to either the CTNNB1 mutation status or the specificmutation. Accordingly, the impact of CTNNB1 mutation status in the treatment algorithm of these enigmatic tumors isuncertain at present. However, with the acquisition of further data, and as the efforts to target b-catenin as a therapymature, knowledge of the CTNNB1mutation status may eventually permit amuchmore rational, individualized treatmentapproach to desmoid tumors.


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