醫(yī)學(xué)遺傳學(xué)英文課件：Cancer Genetics

1、Cancer Geneticspreventive double mastectomyCancer is a genetic diseaseCancersSporadically occurredHereditary occurredMutations of genesGenes mutation cause cancer encoding Proteins in signaling pathways for cell proliferation. Cytoskeletal components involved in contact inhibition. Regulators of the

2、 mitotic cycle. Components of programmed cell death machinery. Proteins responsible for detecting and repairing mutations.Types of mutations Activating gain-of-function mutations of one allele of a proto-oncogene. Loss of function of both allele or dominant negative mutation of one allele of a tumor

3、-suppressor gene. Chromosome translocation that cause misexpression of genes or create chimeric genes encoding proteins that have gained novel functional properties.Types of cancers Sarcomas: arisen in mesenchymal tissue: bone, muscle, or connective tissue; Carcinomas: originate in epithelial tissue

4、: the calls lining the intestine, bronchi, or mammary ducts; Hematopoietic and lymphoid malignancies: leukemias and lymphomas, in bone marrow, lymphatic system, and peripheral blood.Further classified by Site, tissue type, histological appearance, degree of malignancy. Types of cancersLungBreast (wo

5、men)ColonBladderProstate (men)Some common sarcomas:FatBoneMuscleLymphomas:Lymph nodesLeukemias:BloodstreamSome common carcinomas:Evolution of CancerNormalCellIncreased proliferationEarly neoplasiaProgressiveneoplasiaProgressiveNeoplasia May include mutations in DNA repair genesIncreasing Chromosomal

6、aneuplodyProgressiveNeoplasia ProgressiveNeoplasia carcinomacarcinomacarcinomamatastasismatastasismatastasismatastasismatastasisMutation In Gene A Mutation In Gene B Mutation In Gene C What Causes Cancer?Some viruses or bacteriaHeredityDietHormonesRadiationSome chemicalsPopulation-Based StudiesCANAD

7、A:LeukemiaRegions of Highest IncidenceBRAZIL:CervicalcancerU.S.:ColoncancerAUSTRALIA:SkincancerCHINA:LivercancerU.K.:LungcancerJAPAN:StomachcancerHeredity? Behaviors? Other Factors?1005050Stomach Cancer(Number of new cases per 100,000 people)U.S.JapanJapanese familiesin U.S.1007070Colon Cancer(Numbe

8、r of new cases per 100,000 people)U.S.JapanJapanese familiesin U.S.Three Patterns of Tumor Inheritance Heredity familial tumor syndrome (monogenic inheritance) Multigenic cancer genetic susceptibility (multigene involved) Somatic tumor cell gene rearrangement (acquired)Hereditary Familial Tumor Synd

9、rome Germline gene defect Vertical inheritance to descendents Mostly autosomal dominant inheritance Clinical characteristics (syndrome) More than 20 hereditary familial tumor gene clonedAccount for total tumor morbidity 1%Criteria of HFTS identification 1. Age of individual onset 2. Family aggregati

10、on 3. Clinical syndrome 4. Genes diagnosisExamples of HFTS involved Genes Transcriptional regulatory factor (regulate cell cycle) Rb、WTI、P53 DNA repair enzyme genes ERCC、FACC DNA ligase hmsH1、hmsH2 Cytoskeleton and cell adhesion genes APC、medlinInherited DNA repair gene mutations that increase cance

11、r riskDNA repair geneProteinRepair pathways affected*Cancers with increased riskataxia telangiectasia mutated ATMDifferent mutations in ATM reduce HRR, SSA or NHEJ leukemia, lymphoma, breast Bloom syndromeBLM HRR leukemia, lymphoma, colon, breast, skin, lung, auditory canal, tongue, esophagus, stoma

12、ch, tonsil, larynx, uterus breast cancer 1 & 2BRCA1 BRCA2HRR of double strand breaks and daughter strand gapsbreast, ovarian Fanconi anemia genes FANCA,B,C,D1,D2,E,F,G,I,J,L,M,N,O,PFANCA etc.HRR and TLSleukemia, liver tumors, solid tumors many areas Hereditary nonpolyposis colorectal cancer gene MSH

13、2 MSH6 MLH1 PMS2MSH2 MSH6 MLH1PMS2MMRcolorectal, endometrial, ovariain, gastrointestinal tract (stomach and small intestine, pancreas, biliary tract), urinary tract, brain (glioblastomas), and skin (keratoacanthomas andsebaceous adenomas) Li-Fraumeni syndrome gene TP53P53Direct role in HRR, BER, NER

14、 and acts in DNA damage response for those pathways and for NHEJ and MMR sarcomas, breast cancers, brain tumors, and adrenocortical carcinomas MRE11AMRE11HRR and NHEJ breastMUTYHMUTYH glycosylase BER of A paired with 8-oxo-dGcolorectal, duodenal, ovarian, bladder and skin cancers Nijmegen breakage s

15、yndrome NBS (NBN)NHEJlymphoid cancers NTHL1NTHL1BER for Tg, FapyG, 5-hC, 5-hU in dsDNAColon cancer, endometrial cancer, duodenal cancer, basal-cell carcinomaRECQL4RECQ4Helicase likely active in HRR basal cell carcinoma, squamous cell carcinoma, intraepidermal carcinoma Werner syndrome gene WRN Werne

16、r syndromeHRR, NHEJ, long patch BERsoft tissue sarcoma, colorectal, skin, thyroid, pancreas Xeroderma pigmentosum genes XPA-GXPA-XPG NER repairs skin cancer (melanoma and non-melanoma) XPV (also called polymerase H)DNA polymerase eta (Pol )Translesion synthesis (TLS)skin cancers (basal cell, squamou

17、s cell, melanoma)Genetic Susceptibility of Cancers (1) 1. Conception of susceptibility 2. Characteristics : a. Environmental dependent b. Multigene involved c. Genetic change is slight, both structurally and functionally (i.e. SNP) d. Slightly prone to familial aggregation、 high incident populationG

18、enetic Susceptibility of Cancers (2)EnvironmentHeredityGenetic Susceptibility of Cancers (3)Features of Environmental Carcinogen1. Three types environment carcinogen a chemical b physical c biological2. Common features a nonfatal injury b time、body site、way、duration、dose of exposure c strongly rely

19、on individual susceptibility ( metabolism、compensation、repair、immunity)Genetic Susceptibility of Cancers (4) 1. SNP (Single Nucleotide Polymorphism)point mutation2. Distribution frequency in human genome 1%, 1/1000bp 3. Some SNPs are related to disease susceptibility Sites of SNPs intron exon promot

20、eraa changeno aa changeForms of SNPs influence on function Influence on responsible expression (response to special environment) Influence on secondary structure alteration (protein binding , antigen presentation) Influence on gene activity (dominance recessive, gene dosage effect) Isogenetic combin

21、ed effect (fatal) Influence on shearing (intron boundary) Genetic Susceptibility of Cancers (5) Category of candidate genesChemical metabolic enzymes systemDNA damage-repair systemImmunological recognition-regulation-reaction systemBiological factors vs cellular interaction factorsApoptosis genes Ge

22、netic Susceptibility of Cancers (6) Significance of defining Susceptible Gene1. High-risk population identifying2. Intervention and prevention of cancers3. Early diagnosis and treatment4. Molecular mechanisms of carcinogenesis 5. Supplement to HGPGenetic variation of individualsWe are all 99.99% ide

23、ntical in our genomes BUTAdapted from Third Wave2012201420082010200620022007From $2B to $1K Human Genome 2,000,000 x dropDramatic Decrease of Cost in Sequencing a Human Genome!NGS SequencersRoche 454GS FLX TitaniumLife TechnologiesSOLiD 5500 xlPacific BiosciencesSMART PacBioRSIon TorrentIon Proton S

24、equencerHelicos Biosciences HeliscopeMinIONIon Torrent PGMMiSeq DXHiSeq 2500HiSeq X TenCRISPR(clustered regularly interspaced short palindromic repeats)Leader: 300-500 bp, AT rich, promoter.Spacers: 26-72 bp, exogenous DNA, targetingRepeats: 21-48 bp, form hairpin for targetingCAS genes: CRISPR asso

25、ciated, for cuttingCRISPR mechanismPAM: (protospacer adjacent motif), Cas9 2nd signalCRISPR applicationOncogenes and Tumor Suppressor Genes in Tumor Cell Features of Oncogenes and Tumor Suppressor Genes Genes in charge of proliferation、 differentiation、apoptosisOncogene A mutant gene altered functio

26、n or expression abnormal stimulation of cell division and proliferation. The activating mutation can be: itself; regulatory elements; or genomic copy number unregulated function or overexpression of the oncogene. Dominant effect. OncogenesMutated/damaged oncogeneOncogenes accelerate cell growth and

27、divisionCancer cellNormal cellNormal genes regulate cell growthProto-Oncogenes and Normal Cell GrowthReceptorNormal Growth-Control PathwayDNACell proliferationCell nucleusTranscriptionfactorsSignaling enzymesGrowth factorOncogenes areMutant Forms of Proto-OncogenesCell proliferation driven by intern

28、al oncogene signalingTranscriptionActivated gene regulatory proteinInactive intracellular signaling proteinSignaling protein from active oncogeneInactive growth factor receptorTumor Suppressor GenesNormal genes prevent cancerRemove or inactivate tumor suppressor genesMutated/inactivated tumor suppre

29、ssor genesDamage to both genes leads to cancerCancer cellNormal cellTumor Suppressor GenesAct Like a Brake PedalTumor Suppressor Gene ProteinsDNACell nucleusSignalingenzymesGrowth factorReceptorTranscriptionfactorsCell proliferationTumor suppressor Gate-keepers: directly involved in regulation of th

30、e cell cycle or growth inhibition. eg, p53. Caretakers: involved in repairing DNA damage and maintaining genomic integrity, eg, WRN. The Structure of p531393IIIIIIIVVTransactivation DomainDNA Binding DomainTetramerization DomainNLSINLSII NLSIIINC* * DNA-Binding Regulatory RegionTumor suppression Tra

31、nscriptional activator and repressor Mutations in almost every kind of tumors Stress Response of p53StressDNA damagep53ActivateTargetsCell growth arrestApoptosisSenescenceActivation Phosphorylation AcetylationStabilizationMajor Post-translational Modification of p53Mdm2p531. Ubiquitination2. Phospho

32、rylation3. Acetylationp53Pp53AATM/ATRCBP/p300Mdm2DNA DamageMDM2APPhosphorylationAcetylationp53CBP/p300PCAFTFsTFsTFsp53p53PCAFTFsCBP/p300RNAPolymerase IIAAAAPPMDM2p53Growth ArrestCellular SenescenceApoptosisWRN is a member of RecQ familyWRN physically and functionally interacts with many proteinsWRN

33、Telomere maintenanceTRF1TRF2POT1 DNA replicationpol RPAPCNAFEN1TopoI DNA DSB repair HRNHEJp53MRNRad51Rad52BLMBRCA1Ku70/Ku80DNA- PKcsX4L4 DNA BERpol PPAR-1Werner syndrome Autosomal recessive disorders. Werners syndrome is named after Otto Werner, a German scientist, described the syndrome as part of

34、his doctoral thesis in 1904.Werner syndrome patients typically develop normally until they reach puberty. Following puberty they age rapidly, by age 40 they often appear several decades older. Numerous features of premature ageing: graying and loss of hair, wrinkling and ulceration of skin, atherosc

35、lerosis, osteoporosis, and cataracts. Short stature due to lack of usual growth spurt during puberty. Predisposition for cancerMostly associated with soft tissue sarcomas, osteosarcoma.Werner syndrome patientWilliam and Wilkens Publishing Inc.Chromosome translocation cause misexpression of genes or

36、create chimeric genes encoding proteins that have gained novel functional properties. Philadelphia chromosome translocation, t(9;22)(q34;q11). Form BCR-ABL causes Chronic myelogenous leukemia (CML). Imatinib (Gleevec) treat CML by inhibiting tyrosine kinase activity.Ph1 translocation:t(9;22)(q34;q11

37、)Cancer PreventionCancer viruses or bacteriaCarcinogenic radiationCarcinogenic chemicalsAvoid Tobacco15x10 x5xNon-smokerCigarettes Smoked per DayLung Cancer Risk Increases with Cigarette ConsumptionLung Cancer Risk0 15 30Protect Yourself From Excessive SunlightLimit Alcohol and Tobacco 40 x30 x20 x10 xAlcoholic D