CancerSlide 2Knudson’s “two-hit” hypothesisSlide 4Slide 5“An easily understood, workable falsehood is more useful than a complex, incomprehensible truth.”Cancer is a disease of genomic instabilitySlide 8Slide 9Slide 10Slide 11Slide 12One: “self-sufficiency in growth”Slide 14A forward genetic screenSlide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Yeast Cdc28p and human CDK1Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Burkitt’s lymphomaImmediate early genes: myc, jun, fosA summaryTwo: insensitivity to anti-growth signals and evasion of apoptosis“Malignancy of somatic cell hybrids” B. Ephrussi et al., Nature (1969) 224:1314Our two best friendsSlide 38Slide 39Slide 40Tumor suppressors: a summarySlide 42Causes and treatmentsSmoking (lung cancer)Diagnostics of sporadic cancerAflatoxin (liver cancer)Sunlight (skin cancer)Ounce of preventionp53Spontaneous meCpG deamination (colon cancer)A Russian proverb that aptly describes most current cancer treatment modalities“Chemo” drugs“Fused transcript of abl and bcr genes in chronic myelogenous leukaemia” Shtivelman et al. Nature 315: 550-4 (1985).Slide 54Slide 55“… 400 mg of oral imatinib daily “Slide 57Trastuzumab (Herceptin).Tarceva OKd for new use by FDA Lung cancer drug from Genentech to treat pancreas SF Chronicle – 11-3-05Slide 60Genetic predisposition to cancerSlide 62And you thought LOD scores were boring“A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1” (1994) Miki et al. Science 266: 66.7Very important distinction“Breast and Ovarian Cancer Risks Due to Inherited Mutations in BRCA1 and BRCA2” King MC et al. (2003) Science 302: 574.Prophylactic bilateral mastectomy (and/or oopherectomy) for BRCA1/2 mutation carriersSlide 69The biggest puzzle of them all“Hereditary Cancer Testing”1MCB 140 12-6-06Cancer2MCB 140 12-6-06http://seer.cancer.gov/publications/raterisk/rates28.htmlCancer Site 1974-76 1977-79 1980-82 1983-90Brain & Other Nervous 22.3 24.4 25 27.3Breast (females) 74.3 74.5 76.2 80.4Cervix Uteri 68.5 67.7 66.9 67.4Colon & Rectum 49.5 51.7 54.2 59.2Esophagus 4.7 5.1 6.7 9.2Hodgkin's Disease 71.1 73 74.3 78.9Kidney & Renal Pelvis 51.3 50.8 51.4 56.3Larynx 65.4 66.8 68 67Leukemias 34.2 36.6 37.4 38.3Liver & Intrahep 3.8 3.7 3.4 6Lung & Bronchus 12.3 13.3 13.3 13.4Melanoma of Skin 79.7 81.5 82.1 85.1Multiple Myeloma 24.4 26.1 28 27.7Ovary 36.5 38.1 38.9 41.8Pancreas 2.6 2.5 3.1 3.2Prostate 66.7 70.9 73.1 79.6Stomach 15.1 16.7 17.5 18.5Testis 78.6 87.2 91.7 93.3Thyroid 91.9 92.5 94.2 94.6Urinary Bladder 72.4 74.8 77.9 79.8All Sites 49.3 49.8 50.6 53.9Five year survival rates, in %.Number of people diagnosed with cancer: 1,284,900Number of people who will die of cancer: 550,0003MCB 140 12-6-06Knudson’s “two-hit” hypothesis“Knudson's analysis of the age-specific incidence of retinoblastoma led him to propose that two "hits" or mutagenic events were necessary for retinoblastoma development. Retinoblastoma occurs sporadically in most cases, but in some families it displays autosomal dominant inheritance. In an individual with the inherited form of the disease, Knudson proposed that the first hit is present in the germline and thus in all cells of the body. However, the presence of a mutation at the susceptibility locus was argued to be insufficient for tumor formation, and a second somatic mutation was hypothesized to be necessary for promoting tumor formation.”18.244MCB 140 12-6-06Knudson, 1971:“two-hit” model18.245MCB 140 12-6-066MCB 140 12-6-06“An easily understood, workable falsehood is more useful than a complex, incomprehensible truth.”7MCB 140 12-6-06Cancer is a disease of genomic instability= it is profoundly nontrivial to take a mature cancer cell line and divine the iterative sequence of steps that led to its formation8MCB 140 12-6-06Dr. Thomas Ried, NCI/NIH: SKY of hormal human cell9MCB 140 12-6-06HeLaDr. Thomas Ried, NCIHeLaDr. Thomas Ried, NCI11MCB 140 12-6-06Hanahan and Weinberg (2000) Cell 100: 57–70.12MCB 140 12-6-0613MCB 140 12-6-06One:“self-sufficiency in growth”•The majority of cells in the adult human (60,000 billion of them) are mitotically quiescent – most in G0, but some elsewhere (G2)•Some are unequivocally postmitotic (neurons, muscle cells)•The decision to exit quiescence and begin proliferation is VERY tightly regulated14MCB 140 12-6-061967 (Hartwell) – screen in budding yeast for cell division control (cdc) mutants.15MCB 140 12-6-06A forward genetic screenA phenomenon a list of genes involved in the phenomenon an understanding of mechanism1. Take organism2. Mutagenise3. Isolate mutants relevant to phenomenon under study4. Determine what genes are affected (mutated) in each mutant5. Determine the order of action of gene products in the process under study16MCB 140 12-6-0617MCB 140 12-6-06A.818MCB 140 12-6-06mitosisG1Begin DNAreplicationEnd DNAreplicationG2S phaseGene Xdoes its“thing”19MCB 140 12-6-0618.320MCB 140 12-6-06Permissive: Restrictive:Cells at all points in cell cycle Cells all arrest at the point in the cellcycle where mutated gene exertsits function!21MCB 140 12-6-0622MCB 140 12-6-0618.623MCB 140 12-6-06Yeast Cdc28p and human CDK124MCB 140 12-6-0618.525MCB 140 12-6-06http://www.nature.com/celldivision/milestones/index.html26MCB 140 12-6-06Hanahan and Weinberg (2000) Cell 100: 57–70.27MCB 140 12-6-0628MCB 140 12-6-0618.23Mike BishopHarold “Hal” Varmus29MCB 140 12-6-0630MCB 140 12-6-06“neomorph” – “gain-of-function” dominant allele31MCB 140 12-6-0632MCB 140 12-6-06Burkitt’s lymphomaThe mutation in Burkitt’s lymphoma puts Myc downstream of the Ig enhancer – this overexpressed Myc and thus creates a hypermorph.This is a dominant mutation – a “hypermorph.”33MCB 140 12-6-06Immediate early genes: myc, jun, fos34MCB 140 12-6-06A summaryTo make a transition to malignancy, a cell must be under the erroneous impression that it is receiving a signal from the body to leave quiescence and begin proliferating.This typically occurs via a dominant mutation in a “protooncogene”:1.A growth factor receptor (ret).2.A G-protein downstream of #1 (ras).3.A transcription factor downstream of #2 (myc).The mutation creates a constitutively active form of the protein (i.e., it’s a neomorph or a hypermorph).35MCB 140 12-6-06Two: insensitivity to anti-growth signals and evasion of apoptosisMutations in protooncogenes are dominant (they yield
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