11MCB 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” model18.2425MCB 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 cell39MCB 140 12-6-06HeLaDr. Thomas Ried, NCIHeLaDr. Thomas Ried, NCI11MCB 140 12-6-06Hanahan and Weinberg (2000) Cell 100: 57–70. 12MCB 140 12-6-06413MCB 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 Æa list of genes involved in the phenomenon Æan 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 12-6-06517MCB 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!621MCB 140 12-6-0622MCB 140 12-6-0618.623MCB 140 12-6-06Yeast Cdc28p and human CDK124MCB 140 12-6-0618.5725MCB 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” Varmus829MCB 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.”933MCB 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 neomorphs and hypermorphs), and thus heterozygosity is sufficient for cancer.The second major class of genes mutated in cancer – the “tumor suppressors” – are ablated via recessive mutations (but see below!), and thus both alleles must be lost (LOH) for cancer to proceed.The name “tumor suppressor” stems from the fact that introducing a wild-type allele of one of them into a cancer cell will arrest its growth.36MCB 140 12-6-06“Malignancy of somatic cell hybrids” B. Ephrussi et al., Nature (1969) 224:1314 The studies of Ephrussi et al. and Harris provided compelling evidence that the ability of cells to form a tumor is a recessive trait. They observed that the growth of murine tumor cells in syngeneic animals could be suppressed when the malignant cells were fused to nonmalignant cells, although reversion to tumorigenicity often occurred when the hybrids were propagated for extended periods in culture. The reappearance of malignancy was found to be associated with chromosome losses. Stanbridge and his colleagues studied hybrids made by fusing human tumor cell lines to normal, diploid human fibroblasts. Their analysis confirmed that hybrids retaining both sets of parental chromosomes were suppressed, with tumorigenic variants arising only rarely after chromosome losses in the hybrids. Moreover, it was demonstrated that the loss of specific chromosomes, and not simply chromosome loss in general, correlated with the reversion to tumorigenicity. The observation that the loss of specific chromosomes was associated with the reversion to malignancy suggested that a single chromosome (and perhaps even a single gene) might be sufficient to suppress tumorigenicity. To directly test this hypothesis, single chromosomes were transferred from normal cells to tumor cells, using the technique of microcell-mediated
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