Cancer Genetics PDF
Preview Cancer Genetics
Cancer Treatment and Research Volume 155 SeriesEditor StevenT.Rosen Forfurthervolumes: http://www.springer.com/series/5808 Boris Pasche Editor Cancer Genetics 123 Editor BorisPasche,MD,PhD,FACP TheUABComprehensiveCancerCenter DivisionofHematology/Oncology TheUniversityofAlabamaatBirmingham Birmingham,AL,USA [email protected] ISSN0927-3042 ISBN978-1-4419-6032-0 e-ISBN978-1-4419-6033-7 DOI10.1007/978-1-4419-6033-7 SpringerNewYorkDordrechtHeidelbergLondon LibraryofCongressControlNumber:2010927443 ©SpringerScience+BusinessMedia,LLC2010 Allrightsreserved.Thisworkmaynotbetranslatedorcopiedinwholeorinpartwithoutthewritten permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY10013,USA),exceptforbriefexcerptsinconnectionwithreviewsorscholarlyanalysis.Usein connectionwithanyformofinformationstorageandretrieval,electronicadaptation,computersoftware, orbysimilarordissimilarmethodologynowknownorhereafterdevelopedisforbidden. Theuseinthispublicationoftradenames,trademarks,servicemarks,andsimilarterms,eveniftheyare notidentifiedassuch,isnottobetakenasanexpressionofopinionastowhetherornottheyaresubject toproprietaryrights. Whiletheadviceandinformationinthisbookarebelievedtobetrueandaccurateatthedateofgoing topress,neithertheauthorsnortheeditorsnorthepublishercanacceptanylegalresponsibilityforany errorsoromissionsthatmaybemade.Thepublishermakesnowarranty,expressorimplied,withrespect tothematerialcontainedherein. Printedonacid-freepaper SpringerispartofSpringerScience+BusinessMedia(www.springer.com) ThisbookisdedicatedtoDrs.JoanMassagué andKennethOffit.Dr.Massaguéisan outstanding scientist,mentor,androlemodelwho introduced metothefieldofTGF-βsignalingand cancergenetics.Dr.Offitisapioneerinthefield ofclinicalcancergeneticsandwasinstrumental inmycareerdevelopmentandprogression. Contents 1 EthicolegalAspectsofCancerGenetics . . . . . . . . . . . . . . . . 1 KennethOffitandPeterThom 2 TheInfluenceofCommonPolymorphismsonBreastCancer . . . . 15 DianaEcclesandWilliamTapper 3 HereditaryDiffuseGastricCancer . . . . . . . . . . . . . . . . . . 33 KasmintanSchraderandDavidHuntsman 4 GeneticsandGenomicsofNeuroblastoma . . . . . . . . . . . . . . 65 MarioCapassoandSharonJ.Diskin 5 TGF-βSignalingAlterationsandColonCancer . . . . . . . . . . . 85 NareshBellamandBorisPasche Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 vii Contributors NareshBellam DivisionofHematology/Oncology,DepartmentofMedicine, UABComprehensiveCancerCenter,TheUniversityofAlabama,Birmingham, AL35294-3300,USA MarioCapasso CEINGEAdvancedBiotechnologies,UniversityofNaples “FedericoII”,Naples,Italy SharonJ.Diskin OncologyDivision,CenterforChildhoodCancerResearch,The Children’sHospitalofPhiladelphia,Philadelphia,PA19104,USA DianaEccles HumanGeneticsandCancerSciencesDivisions,Schoolof Medicine,UniversityofSouthampton,SouthamptonUniversityHospitalsNHS Trust,SO166YD,UK DavidHuntsman DepartmentofPathologyandLaboratoryMedicine,Vancouver GeneralHospital,UniversityofBritishColumbia,BritishColumbiaCancer Agency,Vancouver,BC,CanadaV5Z4E6 KennethOffit ClinicalGeneticsService,MemorialSloan-KetteringCancer Center,NewYork,NY10021,USA BorisPasche DivisionofHematology/Oncology,DepartmentofMedicine,UAB ComprehensiveCancerCenter,TheUniversityofAlabama,Birmingham,AL 35294-3300,USA KasmintanSchrader DepartmentofPathologyandLaboratoryMedicineand DepartmentofMedicalGenetics,UniversityofBritishColumbia,British ColumbiaCancerAgency,Vancouver,BC,CanadaV5Z4E6 WilliamTapper HumanGeneticsandCancerSciencesDivisions,Schoolof Medicine,UniversityofSouthampton,SouthamptonUniversityHospitalsNHS Trust,SO166YD,UK PeterThom ClinicalGeneticsService,MemorialSloan-KetteringCancerCenter, NewYork,NY10021,USA ix Introduction BorisPasche Cancer genetics is a rapidly evolving field, which has revolutionized the practice of medicine in the past decade. Genetic testing for several high-penetrance tumor susceptibilitygenessuchasBRCA1,BRCA2,andAPChaveallowedtheidentifica- tion of individuals at high riskfor breast and colon cancers that can be effectively preventedwithearlyscreening. SomaticallyacquiredgeneticchangessuchasoverexpressionoftheERBB2gene in breast cancer and mutations of the KRAS or BRAF genes in colorectal cancer are observed in a significant fraction of patients. These genetic alterations can be effectivelytargetedwithantibodiessuchastrastuzumabandcetuximab.Treatment withthesegeneticallytargetedagentsincreasespatientsurvival. Because genetic information allows for the exact identification of individuals, the widespread expansion of genetic testing is potentially fraught with ethical and legalissues.Thefirstchapterofthisbook,whichiswrittenbyDrs.OffitandThom, providesaninsightfuloverviewoftheethicalaspectsofcancergenetics. Systematic studies of common genetic variants are facilitated by the fact that individualswhocarryaparticularSNPalleleatonesiteoftenpredictablycarryspe- cificallelesatothernearbysites.Thiscorrelationisknownaslinkagedisequilibrium (LD);aparticularcombinationofallelesalongachromosomeistermedahaplotype. Thecorrelationsbetweencausalmutationsandthehaplotypesonwhichtheyarose havelongservedasatoolforhumangeneticresearch:firstfindinganassociationto ahaplotypeandthensubsequentlyidentifyingthecausalmutation(s)thatitcarries. With the sequencing of the human genome and development of high-throughput genomic methods, it has become clear that the human genome generally displays moreLDthanundersimplepopulationgeneticmodels,andthatLDismorevaried across regions, and more segmentally structured, than had previously been sup- posed.TheseobservationsindicatedthatLD-basedmethodswouldgenerallyhavea greatvalue(becausenearbySNPsweretypicallycorrelatedwithmanyoftheneigh- bors),andalsothatLDrelationshipswouldneedtobeempiricallydeterminedacross B B.Pasche( ) DivisionofHematology/Oncology,DepartmentofMedicine,UABComprehensiveCancer Center,TheUniversityofAlabama,Birmingham,AL35294-3300,USA e-mail:[email protected] xi xii Introduction thegenomebystudyingpolymorphismsathighdensityinpopulationsamples.This hasprovidedtherationaleforthedevelopmentoftheInternationalHapMapproject (www.hapmap.org).Novelgenotypingtechnologiescombinedwiththeknowledge generated by the HapMap project have provided the necessary tools to interrogate theassociationofgeneticvariantsfromtheentiregenomewithriskforvariousdis- eases. The influence of such common polymorphisms on breast cancer, one of the leadingcausesofcancerdeath,isthoroughlyreviewedinthesecondchapterwritten byDrs.EcclesandTapper. In the third chapter, Drs. Schrader and Huntsman provide the latest genetic knowledgerelatedtogastriccancerandfocusongeneticcause,identification,and managementofararebutdeadlysyndrome,hereditarygastriccancer. Recent advances in cancer genetics are not limited to adult tumors. In the fourthchapter,Drs.CapassoandDiskinprovideatimelyupdateontherecentand exciting genetic discoveries related to one of the most common pediatric cancer, neuroblastoma. Inthefifthandlastchapter,Drs.BellamandPaschereviewthelatestdiscoveries related to constitutively altered TGF-β signaling in colorectal cancer risk, a novel phenotypethatmayaccountforalargeproportionofcolorectalcancers. Chapter 1 Ethicolegal Aspects of Cancer Genetics KennethOffitandPeterThom Abstract In the wake of efficacious preventive interventions based on hereditary cancer risk assessment, a number of ethical and legal challenges have emerged. These include issues such as appropriate testing of children and embryos, the “duty to warn” relatives about familial risk, reproductive genetic testing, the risk of genetic discrimination, and equitable access to testing. These and other issues will be discussed within the framework of a bioethical model, with reference to recentcaselaw. 1 Introduction While genetic information is clearly medical information, its uses and abuses may reach beyond the patient to the family and society. For these and other rea- sons, predictive genetic information, including the counseling that accompanies presymptomaticgenetictesting,wasintroducedintothepracticeofclinicaloncol- ogy as a special case requiring special considerations [1, 2]. At the time of the firstwidespread introduction of genetic testingforadult-onsetbreast,ovarian, and coloncancer,“geneticexceptionalism”wasfelttoberequiredbecauseoftheunique psychological, social, economic, and even political consequences of genetic infor- mation.Now,morethanadecadelater,itcanbearguedthatgeneticexceptionalism is no longer necessary. Moreover, the similarities between genetic and nongenetic predictive testing appear much greater than the differences [3]. In this review, the distinguishingcharacteristicsandspecialethicalandlegalimplicationsofpredictive genetictestsforcancerriskwillbeconsidered.Theconclusionwhichwillemerge isthatbreakingdowngeneticexceptionalismremainsanimportantgoal.However, achieving this goal will require continued physician and provider education and B K.Offit( ) ClinicalGeneticsService,MemorialSloan-KetteringCancerCenter,NewYork,NY10021,USA e-mail:offi[email protected] B.Pasche(ed.),CancerGenetics,CancerTreatmentandResearch155, 1 DOI10.1007/978-1-4419-6033-7_1,(cid:2)C SpringerScience+BusinessMedia,LLC2010 2 K.OffitandP.Thom also greater societal involvement in shaping the ethical discussions and case law thatwilldeterminethewaygenetictestsforcancerriskarebeingincorporatedinto thepracticeofpreventiveoncology. 2 MoralTheory:TheGroundingofBiomedicalEthics Themoralimplicationsofmedicaldecisionsandtheuseofnewlyintroducedtech- nologies have been examined by biomedical ethicists, and professional societies have entered into this dialogue by formulating uniform “codes” of professional ethics. Recent codes, including those of the AMA and the Office for Human ResearchProtections(OHRP),reflecttheinfluenceofmodernethicaltheoryinthe area of human genetic information [4, 5]. OHRP recommendations have become a critical resource for institutional IRBs and constitute basic reading for cancer risk counselors. Other professional organizations and advisory bodies have pro- vided guidelines that bear on ethical and legal aspects of cancer genetic testing [1,2,6–8].However,onmanyimportantissues(e.g.,thedutytowarnfamilymem- bersatriskandreproductiveusesofgenetictests),cliniciansandIRBsareexpected toreachdecisionsbasedonthefundamentaltenetsofbiomedicalethics.Intheclin- ical setting, principle-driven normative ethics grounded in moral theory can guide individual ethical quandaries and have been specifically applied to cancer genetic testing[9]. Intheirclassicintroductiontobiomedicalethics,BeauchampandChildress[10] define the principles central to the current view of ethical conduct in medicine. These concepts include respect for individual autonomy of the patient; the imper- ative to do no harm (nonmaleficence); the concept of beneficence and justice; and specific obligations of the health professional relating to truth telling, privacy, confidentiality,andmorallycorrectbehavior. 3 Autonomy The principle of autonomy is perhaps the most fundamental to genetic medicine. Strictly defined, autonomy refers to self-rule, but in bioethical parlance this con- cept is more broadly defined. It refers to the right of the individual to act freely, when provided adequate information, without coercion or interference. The con- ceptofautonomyhasalsobeeninvokedtojustifytheindividual’srightnottoknow medical information. Cancer genetic counseling, with its emphasis on education andempowerment,isfullyconsistentwiththeconceptofautonomy,implyingfully informed choice, free from coercion. The context of testing presumptively nonau- tonomous children and embryos raises special concerns, which will be discussed below.
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