基因组学与癌症风险评估(A Cancer Journal for Clin.pdf

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1、Genetics,Genomics,and Cancer Risk AssessmentState of the Art and Future Directions in the Era of Personalized MedicineJeffrey N.Weitzel,MD1;Kathleen R.Blazer,EdD,MS,CGC2;Deborah J.MacDonald,PhD,RN,APNG3;Julie O.Culver,MS,CGC4;Kenneth Offit,MD,MPH5AbstractScientific and technologic advances are revol

2、utionizing our approach to genetic cancer risk assessment,cancer screen-ing and prevention,and targeted therapy,fulfilling the promise of personalized medicine.In this monograph,we reviewthe evolution of scientific discovery in cancer genetics and genomics,and describe current approaches,benefits,an

3、dbarriers to the translation of this information to the practice of preventive medicine.Summaries of known hereditarycancer syndromes and highly penetrant genes are provided and contrasted with recently discovered genomic variantsassociated with modest increases in cancer risk.We describe the scope

4、of knowledge,tools,and expertise required forthe translation of complex genetic and genomic test information into clinical practice.The challenges of genomic coun-seling include the need for genetics and genomics professional education and multidisciplinary team training,the needfor evidence-based i

5、nformation regarding the clinical utility of testing for genomic variants,the potential dangers posedby premature marketing of first-generation genomic profiles,and the need for new clinical models to improve access toand responsible communication of complex disease risk information.We conclude that

6、 given the experiences and les-sons learned in the genetics era,the multidisciplinary model of genetic cancer risk assessment and management willserve as a solid foundation to support the integration of personalized genomic information into the practice of cancermedicine.CA Cancer J Clin 2011;61:327

7、-359.VC2011 American Cancer Society.IntroductionScientific and technologic advances in genomics are revolutionizing our approach to genetic counseling andtesting,targeted therapy,and cancer screening and prevention,fulfilling the promise of personalized medicine.Features of genetic counseling that p

8、ose emerging challenges to oncology and other health care providers includethe focus on the family as well as the individual,the emerging role of testing for common as well as rare genomicmarkers of cancer susceptibility,and the role of the oncologist in the communication of nononcologic healthrisks

9、.For physicians,genetic counselors,nurses,and other members of a multidisciplinary cancer care team,thefuture of personalized medicine is now;however,the current enthusiasm about personalized genomics followsseveral decades of scientific discovery and clinical translation in human genetics.By analyz

10、ing the lessons learned1Chief,Division of Clinical Cancer Genetics,Department of Population Sciences,City of Hope,Duarte,CA;2Assistant Director,Cancer Genetics EducationProgram,Division of Clinical Cancer Genetics,Department of Population Sciences,City of Hope,Duarte,CA;3Assistant Professor,Division

11、 of ClinicalCancer Genetics,Department of Population Sciences,City of Hope,Duarte,CA;4Assistant Director,Cancer Screening&Prevention Program,Division ofClinical Cancer Genetics,Department of Population Sciences,City of Hope,Duarte,CA;5Chief,Clinical Genetics Service,Program in Cancer Control,Prevent

12、ion,and Population Research,Memorial Sloan-Kettering Cancer Center,New York,NY.Corresponding author:Jeffrey N.Weitzel,MD,Division of Clinical Cancer Genetics,City of Hope,1500 East Duarte Rd,Duarte,CA 91010;jweitzelcoh.org;orKenneth Offit,MD,Program in Cancer Control,Prevention,and Population Resear

13、ch,Memorial Sloan-Kettering Cancer Center,New York,NY 10021-6007;offitkmskcc.orgDISCLOSURES:Supported in part by National Cancer Institute grant R25CA112486 and grant RC4CA153828 from the National Cancer Institute and the Officeof the Director,National Institutes of Health to Jeffrey Weitzel and Cit

14、y of Hope,and also by support to Kenneth Offit from the Robert and Kate Niehaus ClinicalCancer Genetics Initiative,the Sharon Levine Corzine Fund at Memorial Sloan-Kettering Cancer Center,the Lymphoma Foundation,and the Esther and HymanRapport Philanthropic Trust.We are grateful to Peter Thom,MS,for

15、 his help with designing Figure 1;to Dr.Stephen Gruber for his critical reading of the article;and to Tracy Sulkin andShawntel Payton for assistance with preparation of the article.We also thank participants in the City of Hope Community Cancer Genetics and ResearchTraining Intensive Course(National

16、 Cancer Institute grant R25CA112486;PI:J.N.W.)for providing insights about the challenges and rewards of providing geneticcancer risk assessment in community-based practices and the Cancer Genetics Community of Practice.VC2011 American Cancer Society,Inc.doi:10.3322/caac.20128.Available online at ht

17、tp:/VOLUME 61_NUMBER 5_SEPTEMBER/OCTOBER 2011327CA CANCER J CLIN 2011;61:327359during the development of genetic cancer risk assess-ment(GCRA)and management,we will define thescope of the challenges currently faced by practi-tioners seeking to integrate genomic technologiesinto medical practice.The

18、Genetics of Hereditary Cancers:The First Decades of Discovery andTranslationToday,personalized medicine,informed by a molec-ular understanding of disease,has resulted in newclassification systems as well as more effective pre-ventive and therapeutic interventions.The NationalCancer Institute(NCI)def

19、ines personalized medi-cine as a form of medicine that uses informationabout a persons genes,proteins,and environment toprevent,diagnose,and treat disease.1Simply put,the field of genetics refers to the study of singlegenes,and the emerging field of genomics refersto the study of all of a persons ge

20、nes.2While thecomputational challenges of genomics are daunting,the translation of genomics to clinical care derivessquarely from genetics practice.Indeed,single ormultiplexed genetic profiles(DNA analysis of a sin-gle gene or set of genes)have been applied to pre-symptomaticriskassessment,aswellast

21、odiagnostic,prognostic,and therapeutic applicationin several fields,notably cancer care.In oncology,the use of presymptomatic genetic testing andtargeted therapies tailored to the genetic profiles oftumors is part of the recommended evaluation forcancers of the colon,lung,breast,and other sites.3-7T

22、hediscussionpresentedhereassumesthatpersonalized genomics must meet the same evidenti-ary standards as other components of personalizedmedicine.Thus,it is important to state at the outsetthat the perspective offered here does not recognizea special claim to the personal utility of genomictests for m

23、edical conditions outside of a medicalcontext.Requirements for the clinical validity andutility of genomic tests are discussed elsewhere,3,8and the roles for alternate models of providerdelivery of genetic and genomic information areFIGURE 1.Timeline of Cancer Genetics to Genomic Discovery.Depicted

24、is a snapshot of scientific developments capturing a century of experience in thetranslation of research in genetics and genomics to the practice of cancer medicine.Rb indicates retinoblastoma tumor suppressor gene;APC,adenomatouspolyposis coli;PARP,poly(ADP-ribose)polymerase.Genetics,Genomics,and C

25、ancer Risk Assessment328CA:A Cancer Journal for CliniciansTABLE 1.Genes Associated With Hereditary Cancer PredispositionSYNDROME(OMIM ENTRY)PRIMARY COMPONENT TUMORSaINHERITANCEGENESHEREDITARY BREAST CANCER SYNDROMESHereditary breast and ovarian cancer(113705,600185,605724-FANCD1)Breast cancer,ovaria

26、n cancerDominantBRCA1,BRCA2Prostate cancer,pancreatic cancer,melanomaDominantBRCA2Fanconi anemia(FANCD1)in bialleliccarriers,medulloblastomaRecessiveBRCA2Partner and localizer ofBRCA2(610355)SeeBRCA2aboveDominantPALB2(FANCN)BRCA1-interacting protein 1(605882,609054-BRIP1)SeeBRCA1above;Fanconi anemia

27、(FANCJ)in biallelic carriersRecessiveBRIP1Li-Fraumeni syndrome(151623)Breast cancer,sarcomas(soft tissue/osteosarcoma),brain tumors,adrenocorticalcarcinomaDominantp53Cowden syndrome(158350-PTEN,612105-Killin)Breast,thyroid,endometrial cancersDominantPTEN,KILLINBannayan-Riley-Ruvalcaba syndrome(15348

28、0)Breast cancer,meningioma,thyroid follicularcell tumorsDominantPTENAtaxia telangiectasia(208900)LeukemiaRecessiveATMOther hereditary breast cancer(604373)Breast cancer(2-fold risk)DominantCHEK2HEREDITARY GASTROINTESTINAL MALIGNANCIESLynch syndrome(also known as HNPCC)(120435,613244-EPCAM/TACSTD1)Co

29、lon,endometrial cancers;gastric,hepatobiliary,ovarian,pancreatic,renal,pelvis,small bowel,and ureteral cancersDominantMLH1,MSH2(includingEPCAM),MSH6,PMS2Includes Turcot syndrome(276300)GlioblastomaFamilial adenomatous polyposis,includingattenuated phenotype(175100)Colon cancer;gastric,duodenal,ampul

30、larycancersDominantAPCIncludes Turcot syndrome(276300)MedulloblastomaMYH-associated polyposis(608456)Colon cancerRecessiveMYHMismatch repair cancer syndrome(276300)Colon,CNS,hematologic,and other cancersRecessiveMLH1,MSH2 MSH6,PMS2Hereditary diffuse gastric cancer(137215)Gastric cancer;lobular breas

31、t cancerDominantCDH1Juvenile polyposis(174900)Gastrointestinal cancers;Pancreatic cancerDominantSMAD4(DPC4),BMPR1APeutz-Jeghers syndrome(175200)Colon,small bowel,breast,ovarian,andpancreatic cancersDominantSTK11Hereditary pancreatic cancer(600185,260350)Pancreatic cancer;breast and ovarian cancersDo

32、minantBRCA2,PALB2Hereditary melanoma pancreatic syndrome(606179)Pancreatic cancer,melanomaDominantCDKN2A(p16)Hereditary pancreatitis(167800)Pancreatic cancerDominantPRSS1Familial gastrointestinal stromal syndrome(606764)Gastrointestinal stromal tumorsDominantKITOligodontia-colorectal cancer syndrome

33、(608615)Colon cancerDominantAXIN2GENODERMATOSES WITH CANCER PREDISPOSITIONMelanoma syndromes(155600,155601,609048,608035)Malignant melanomaDominantCDNK2(p16),CDK4,CMMBasal cell carcinoma/nevus syndrome/Gorlinsyndrome(109400)Basal cell cancers;medulloblastoma,ovarian cancerDominantPTCHCowden syndrome

34、See aboveDominantPTENNeurofibromatosis 1(162200)Neurofibrosarcoma,pheochromocytoma,opticgliomas,meningiomasDominantNF1CA CANCER J CLIN 2011;61:327359VOLUME 61_NUMBER 5_SEPTEMBER/OCTOBER 2011329TABLE 1.(Continued)SYNDROME(OMIM ENTRY)PRIMARY COMPONENT TUMORSaINHERITANCEGENESNeurofibromatosis 2(101000)

35、Vestibular schwannomaDominantNF2Tuberous sclerosis(191100)Renal cancer,multiple bilateral renalangiomyolipoma,myocardial rhabdomyoma,ependymoma,giant cell astrocytomaDominantTSC1,TSC2Carney complex(160980,605244)Myxoid subcutaneous tumors,primaryadrenocortical nodular hyperplasia,testicularSertoli c

36、ell tumor,atrial myxoma,pituitaryadenoma,mammary fibroadenoma,thyroidcarcinoma,schwannomaDominantPRKAR1AMuir-Torre syndrome(variant of Lynchsyndrome;158320)Sebaceous neoplasia(adenoma,keratoacanthoma,carcinoma);see Lynchsyndrome above for other component tumorsDominantMLH1,MSH2,MSH6Xeroderma pigment

37、osum(278730,278700,278720,278760,274740,278780,278750,133510)Skin cancer,melanoma,leukemiaRecessiveXPA-G,POLHRothmund-Thomson syndrome(268400)Basal and squamous cell carcinoma,osteogenicsarcomaRecessiveRECQL4LEUKEMIA/LYMPHOMA PREDISPOSITION SYNDROMESBloom syndrome(210900)Leukemia,carcinoma of the to

38、ngue,squamouscancers,Wilms tumorRecessiveBLMFanconi anemia,several complementationgroups(227650)Leukemia;squamous cancers;hepatoma;andbrain,skin,vulvar,and cervical cancers;seehereditary breast cancer above(FANCD1,J)RecessiveFANCA,B,C,D2,E,F,G,I,L,M,N(FANCH is FANCA)Shwachman-Diamond syndrome(260400

39、)Myelodysplasia,acute myelogenous leukemiaRecessiveSBDSNijmegen breakage syndrome(251260)Lymphoma,glioma,medulloblastoma,rhabdomyosarcomaRecessiveNBS1Canale-Smith syndrome(601859)LymphomaDominantFAS,FASLHodgkin lymphoma(236000)Hodgkin lymphomaRecessiveKLHDC8BIMMUNODEFICIENCY SYNDROMESWiskott-Aldrich

40、 syndrome(301000)Hematopoietic malignanciesX-linked recessiveWASSevere combined immune deficiency(102700,300400,312863,601457,600802,602450)B-cell lymphomaX-linked recessiveRecessiveIL2RG,ADA,JAK3,RAG1,RAG2,IL7R,CD45,ArtemisX-linked lymphoproliferative syndrome(308240)LymphomaX-linked recessiveSH2D1

41、AGENITOURINARY CANCER PREDISPOSITION SYNDROMESHereditary prostate cancer(176807,601518)Prostate cancerDominantHPC1,HPCX,HPC2/ELAC2,PCAP,PCBC,PRCASimpson-Golabi-Behmel syndrome(312870)Embryonal tumors,Wilms tumorX-linked recessiveGPC3Von Hippel-Lindau syndrome(193300)Hemangioblastomas(retina and CNS)

42、,renal cellcancer(clear cell),pheochromocytomas,endolymphatic sac tumorsDominantVHLBeckwith-Wiedemann syndrome(130650)Wilms tumor,hepatoblastoma,adrenalcarcinoma,gonadoblastomaDominantCDKN1C,NSD1Wilms tumor syndrome(194070)Wilms tumorDominantWT1Wilms tumor,aniridia,genitourinaryabnormalities,mental

43、retardation(WAGR)(194072)Wilms tumor,gonadoblastomaDominantWT1Birt-Hogg-Dube syndrome(135150)Renal tumorsDominantFLCNPapillary renal cancer syndrome(605074)Papillary renal tumorDominantMET,PRCCGenetics,Genomics,and Cancer Risk Assessment330CA:A Cancer Journal for CliniciansTABLE 1.(Continued)SYNDROM

44、E(OMIM ENTRY)PRIMARY COMPONENT TUMORSaINHERITANCEGENESConstitutional t(3;8)translocation(603046)Renal cell cancerDominantTRC8Rhabdoid predisposition syndrome(601607)Rhabdoid tumors(see below)DominantSNF5/INI1Testicular tumors(273300)Seminoma,embryonal carcinoma,teratoma,choriocarcinoma,endodermal si

45、nus tumorDominantKIT,STK11,FGFR3CNS/VASCULAR CANCER PREDISPOSITION SYNDROMESHereditary paraganglioma(115310,600857,185470,602413,602690,16800,613019,613403)Paraganglioma,pheochromocytomaDominantSDHA,SDHB,SDHC,SDHD,SDH5,TMEM127Retinoblastoma(180200)Retinoblastoma,osteosarcomaDominantRB1Rhabdoid predi

46、sposition syndrome(601607)Rhabdoid tumors,choroid plexus tumors,medulloblastomaDominantSNF5/INI1SARCOMA/BONE CANCER PREDISPOSITION SYNDROMESMultiple exostoses(133700,133701)ChondrosarcomaDominantEXT1,EXT2Leiomyoma/renal cancer syndrome(605839)Papillary(type II)renal cell carcinoma,uterineleiomyosarc

47、omasDominantFHCarney complexSee aboveDominantPRKAR1AWerner syndrome(277700)Sarcoma/osteosarcoma,meningiomaRecessiveWRNENDOCRINE CANCER PREDISPOSITION SYNDROMESMEN1(131100)Pancreatic islet cell tumors,pituitary adenomas,parathyroid adenomasDominantMEN1MEN2(171400)Medullary thyroid cancers,pheochromoc

48、ytoma,parathyroid hyperplasiaDominantRETHyperparathyroidism(145000,145001,610071)Parathyroid carcinomas,Wilms tumor,pancreaticadenocarcinoma,renal cortical adenoma,papillary renal cell carcinoma,Hurthle cellthyroid carcinomaDominantHRPT1,HRPT2,HRPT3MISCELLANEOUS SYNDROMESChordoma(215400)Chordomas,sk

49、ull(sphenooccipital,nasopharyngeal)and spine(sacrococcygeal,vertebral)DominantCHDMCostello syndrome/faciocutaneoskeletalsyndrome(218040)Epithelioma,bladder carcinoma,rhabdomysarcoma,vestibular schwannomaDominantHRASDyskeratosis congenita(127550)Squamous cell carcinomaDominantTERC,TERT,TINF2Mosaic va

50、riegated aneuploidy(257300)Wilms tumor,nephroblastoma,rhabdomysarcoma,leukemiaRecessiveBUB1BADA indicates adenosine deaminase;APC,adenomatous polyposis coli;ATM,ataxia telangiectasia mutated;AXIN2,axis inhibition protein 2;BLM,Bloom syn-drome,RecQ helicase-like;BMPR1A,bone morphogenetic protein rece