Cancer and genetic influences

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Cancer and genetic influences: overview & oncogenes

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  • Cancer is abnormal cellular
  • Oncogenes in it’s normal form the gene is called proto-oncogene. Most proto-oncogene are components of signal transduction pathways. ,translate extracellular signals into changes in gene expression by increasing the blood supply to the tumor or inhibit apoptosis.
  • One of the the first activated oncogenes discovered by DNA Transformation process , encodes a small guanosine triphosphate binding protein 3 members of the family the H-RAS , K-RAS And N-RAS , Serves as on / off switch to activate or inhibit molecules when bound to GTP , the effect of protein effect is ended by self directed cleavage of GTP.
  • RAS associated with plasma membrane
  • RAS activation is done by another mechanism which is done via neclueotide substitution Note the conversion of oncogene to proto-oncogene is
  • Proto-Oncogenes are converted to oncogenes by means of : 1-Point mutation. 2- chromosome translocation ( breakpoint can occur within 2 introns of 2 genes producing chimeric protein with novel properties ) .
  • B lymphocytes are one of the fastest growing malignancies (B cell solid tumor ) Slid tumors are type of cancer intiated in the tissues The outer surfaces is dealt with radiotherapy whilst the vesrical is dealt with chemotherapy
  • Cancer and genetic influences

    1. 1. Cancer and geneticCancer and genetic influencesinfluences 1. overview & oncogenes1. overview & oncogenes Lec 24Lec 24
    2. 2. What is cancer?What is cancer? A name used to describe a form ofA name used to describe a form of neoplasianeoplasia  Uncontrolled cell proliferation leading to a mass or tumorUncontrolled cell proliferation leading to a mass or tumor (neoplasm)(neoplasm)  Occurs due to imbalance between cellular proliferation andOccurs due to imbalance between cellular proliferation and cellular deathcellular death Normal growthNormal growth NeoplasmNeoplasm Mutations in genesMutations in genes controllingcontrolling -prolif or cell cycle.-prolif or cell cycle. -cytoskeletal-cytoskeletal inv’ed with contactinv’ed with contact inhibitioninhibition -programmed cell-programmed cell deathdeath -detecting and-detecting and repairing DNArepairing DNA damagedamage
    3. 3. What is cancer?What is cancer? In addition, the neoplasm must alsoIn addition, the neoplasm must also be malignantbe malignant NOTE: Tumors that do not invade or spread are not cancerous, butNOTE: Tumors that do not invade or spread are not cancerous, but referred to asreferred to as benignbenign growth no longergrowth no longer controlled and can nowcontrolled and can now invade neighboringinvade neighboring tissues and/or spread totissues and/or spread to more distant sitesmore distant sites (metastasis)(metastasis)
    4. 4. Major types of cancerMajor types of cancer CarcinomaCarcinoma  Derived from epithelial cells, which line surface of skin andDerived from epithelial cells, which line surface of skin and organs, digestive tract, airways and mammary ductsorgans, digestive tract, airways and mammary ducts  Most common cancer type (89-90% of all reported cases)Most common cancer type (89-90% of all reported cases) SarcomaSarcoma  Derived from mesenchymal tissue – muscle, bone, cartilage, fat,Derived from mesenchymal tissue – muscle, bone, cartilage, fat, connective tissuesconnective tissues HematopoieticHematopoietic  Leukemia – derived from white blood cells or their precursorsLeukemia – derived from white blood cells or their precursors  Lymphoma – involves cells of the lymphatic systemLymphoma – involves cells of the lymphatic system  Myelomas – involves white blood cells responsible for theMyelomas – involves white blood cells responsible for the production of antibodies (B lymphocytes or B-cells)production of antibodies (B lymphocytes or B-cells)
    5. 5. Cancer prefixesCancer prefixes Examples:Examples: Osteosarcoma – cancerOsteosarcoma – cancer arising in bonearising in bone Hepatocarcinoma –Hepatocarcinoma – cancer arising in the livercancer arising in the liver
    6. 6. Stages of tumor progressionStages of tumor progression more growth – abnormalmore growth – abnormal cellular appearance; maycellular appearance; may become disorganizedbecome disorganized uncontrolled cell division leading to an excess of cells cells become primitive incells become primitive in capability – invasivecapability – invasive potential existspotential exists ability to invadeability to invade &/or metastasize&/or metastasize
    7. 7. Characteristics of cancer cellsCharacteristics of cancer cells Cytoskeletal changesCytoskeletal changes Cell adhesion altered – cells able to moveCell adhesion altered – cells able to move Changes in structure of nucleusChanges in structure of nucleus Secretion of enzymes that enable them to invadeSecretion of enzymes that enable them to invade neighboring tissuesneighboring tissues Unlimited number of cell divisionsUnlimited number of cell divisions Growth in the absence of “go” signalsGrowth in the absence of “go” signals Avoidance of cell deathAvoidance of cell death Tumors stimulate the growth of blood vesselsTumors stimulate the growth of blood vessels (angiogenesis)(angiogenesis)
    8. 8. Cancer in familiesCancer in families Many forms have higher incidence in relatives thanMany forms have higher incidence in relatives than in general populationin general population Nearly 50 mendelian disorders where risk ofNearly 50 mendelian disorders where risk of cancer is very high among relativescancer is very high among relatives For other cancers, the increased incidence is 2-3For other cancers, the increased incidence is 2-3 fold higher for 1fold higher for 1 oo relatives – complex disorderrelatives – complex disorder
    9. 9. Cancer as a genetic diseaseCancer as a genetic disease whether sporadic or familial, cancer is fundamentally duewhether sporadic or familial, cancer is fundamentally due to mutation in various genes controlling cell growth or cellto mutation in various genes controlling cell growth or cell deathdeath once initiated, the cancer evolves by accumulatingonce initiated, the cancer evolves by accumulating additional mutations in other genesadditional mutations in other genes leads to an ever-worsening cascade of mutationsleads to an ever-worsening cascade of mutations Original clone of neoplastic cells can evolve intoOriginal clone of neoplastic cells can evolve into numerous sublineages with different but overlappingnumerous sublineages with different but overlapping mutationsmutations Tumor suppressor geneTumor suppressor gene ProtooncogeneProtooncogene
    10. 10. Classifying the genes involvedClassifying the genes involved in cancerin cancer OncogenesOncogenes –– mutant forms of genes (proto-mutant forms of genes (proto- oncogenes) that positively regulate cell proliferationoncogenes) that positively regulate cell proliferation and cell survivaland cell survival -usu dominant, gain-of-fn mutations-usu dominant, gain-of-fn mutations Tumor suppressorsTumor suppressors – genes which function to block– genes which function to block tumor development by negatively regulating cellulartumor development by negatively regulating cellular growth-growth-usu need loss of both copiesusu need loss of both copies Cellular maintenance genesCellular maintenance genes – responsible for the– responsible for the detection and repair of genetic damage in cellsdetection and repair of genetic damage in cells
    11. 11. OncogenesOncogenes in altered (mutated) form, gene expression leads toin altered (mutated) form, gene expression leads to abnormal stimulation of cell division and proliferationabnormal stimulation of cell division and proliferation have a dominant effect at the cellular level – a singlehave a dominant effect at the cellular level – a single mutant allele is enough to change cellular phenotypemutant allele is enough to change cellular phenotype from normal to malignant (gain of function)from normal to malignant (gain of function) Mutations: gene, regulatory region, copy #Mutations: gene, regulatory region, copy # normalnormal mutantmutant
    12. 12. OncogenesOncogenes in its normal form, thein its normal form, the gene is called agene is called a proto-oncogeneproto-oncogene Most proto-oncogenesMost proto-oncogenes are components ofare components of signal transductionsignal transduction pathways:pathways: translate extracellulartranslate extracellular signals into changes insignals into changes in gene expressiongene expression Increase blood supplyIncrease blood supply to the tumor or inhibitto the tumor or inhibit apoptosisapoptosis
    13. 13. RET, METRET, MET Receptor tyrosine kinasesReceptor tyrosine kinases -transduce an extracellular-transduce an extracellular signal inwardsignal inward -bind a ligand, conformational-bind a ligand, conformational change that results in kinasechange that results in kinase activity, leading to phosphor-activity, leading to phosphor- lation of cellular proteinslation of cellular proteins -pt mut’s cause receptors to-pt mut’s cause receptors to be constitutively activebe constitutively active RET mut-multiple endocrineRET mut-multiple endocrine neoplasianeoplasia MET mut-hereditary papillaryMET mut-hereditary papillary renal carcinomarenal carcinoma Ras, AblRas, Abl MycMyc
    14. 14. RAS family of proto-oncogenesRAS family of proto-oncogenes One of the first activated oncogenes discovered by theOne of the first activated oncogenes discovered by the DNA transformation assayDNA transformation assay Encodes a small guanosine triphosphate (GTP) –Encodes a small guanosine triphosphate (GTP) – binding protein (G-protein)binding protein (G-protein) 3 members of this family; H-RAS, K-RAS, N-RAS3 members of this family; H-RAS, K-RAS, N-RAS Serves as an “on/off” switch to activate or inhibitServes as an “on/off” switch to activate or inhibit downstream molecules when bound to GTPdownstream molecules when bound to GTP The protein’s effect is ended by self-directed cleavageThe protein’s effect is ended by self-directed cleavage of GTPof GTP
    15. 15. RAS family of proto-oncogenesRAS family of proto-oncogenes Ras associates with the plasma membraneRas associates with the plasma membrane Ras relays signals from the cell surface receptors toRas relays signals from the cell surface receptors to the nucleus, functioning as athe nucleus, functioning as a switchswitch  ‘‘Active’ when GTP is boundActive’ when GTP is bound  ‘‘Inactive when the hydrolyzed GDP is boundInactive when the hydrolyzed GDP is bound
    16. 16. RAS mutation in humanRAS mutation in human cancerscancers H-RAS mutated in 10% of all bladder cancer K-RAS mutations in about 50% of colorectal cancers, 70-90% of pancreatic cancers and 30% of lung adenocarcinomas as well as in ovarian, breast skin liver and kidney N-RAS mutations have been detected in 20- 30% of acute nonlymphocytic leukemias
    17. 17. RAS oncogene activation byRAS oncogene activation by nucleotide substitutionnucleotide substitution Conversion to oncogene usually due to a pointConversion to oncogene usually due to a point mutation in the gene where:mutation in the gene where:  the ras protein is able to signal continuously, even inthe ras protein is able to signal continuously, even in absenceabsence of GTPof GTP  the ras protein isthe ras protein is unable to hydrolyze GTPunable to hydrolyze GTP toto turn “off” the signalturn “off” the signal Leads to the continuous activation of multipleLeads to the continuous activation of multiple downstream signaling pathways inducing celldownstream signaling pathways inducing cell proliferationproliferation Mutations in the 3 RAS genes are found in 10-15% ofMutations in the 3 RAS genes are found in 10-15% of all human cancersall human cancers
    18. 18. Oncogenes are also activatedOncogenes are also activated by chromosome translocationsby chromosome translocations Breakpoint can occur withinBreakpoint can occur within introns of two genes: chimericintrons of two genes: chimeric protein with novel properties –protein with novel properties – Chronic MyelogenousChronic Myelogenous Leukemia-Leukemia-UncontrolledUncontrolled proliferation of white bloodproliferation of white blood cellscells Arises in a bone marrow stemArises in a bone marrow stem cell that is a precursor to thecell that is a precursor to the granulocytes andgranulocytes and megakaryocytesmegakaryocytes These cells contain a chr 9;22These cells contain a chr 9;22 translocation – “Philadelphiatranslocation – “Philadelphia Chromosome”Chromosome” Protooncogene ABL, a tyrosine kinase, is moved from its normal position on 9 to 22. Result: increased activity
    19. 19. Chronic MyelogenousChronic Myelogenous Leukemia (CML)Leukemia (CML) Proto-oncogene ABLProto-oncogene ABL (tyrosine kinase) moves(tyrosine kinase) moves from 9q to thefrom 9q to the “breakpoint cluster region“breakpoint cluster region (BCR) on 22q(BCR) on 22q Chimeric protein hasChimeric protein has increased tyrosine kinaseincreased tyrosine kinase activity but alteredactivity but altered structure and functionstructure and function Requires secondaryRequires secondary mutation to move intomutation to move into crisis phasecrisis phase Effective drug therapyEffective drug therapy developed to target noveldeveloped to target novel proteinprotein
    20. 20. Oncogenes are also activatedOncogenes are also activated by chromosome translocationsby chromosome translocations Breakpoint can occur withinBreakpoint can occur within introns of two genes: chimericintrons of two genes: chimeric protein with novel properties –protein with novel properties – Chronic MyelogenousChronic Myelogenous LeukemiaLeukemia Alternately, translocation mayAlternately, translocation may place proto-oncogeneplace proto-oncogene downstream of a strongdownstream of a strong constitutive promoter fromconstitutive promoter from another gene – proto-another gene – proto- oncogene is now expressed atoncogene is now expressed at inappropriate time/place –inappropriate time/place – Burkitt LymphomaBurkitt Lymphoma
    21. 21. Burkitt LymphomaBurkitt Lymphoma B-cell tumorB-cell tumor MYC proto-oncogeneMYC proto-oncogene (transcription factor)(transcription factor) translocated from 8q24translocated from 8q24 to 14q32, distal of the Igto 14q32, distal of the Ig heavy chain locusheavy chain locus Ig enhancers orIg enhancers or activating sequences actactivating sequences act on MYC – allowing foron MYC – allowing for unregulated expressionunregulated expression and uncontrolled celland uncontrolled cell growthgrowth
    22. 22. http://tooldoc.wncc.edu/Infections/lymphoma.JPG • Solid tumor of B-lymphocytes • Predominantly affecting young children in Africa, • one of the fastest growing malignancies in humans. • manifested most often as a large jaw lesion expands rapidly over a period of a few weeks to invade the orbit. • Visceral involvement, usually an abdominal mass • Treatment of the jaw and eye areas is by radiotherapy,while visceral involvement requires systemic chemotherapy. In all cases, translocation of MYC is the cause

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