Cancer MCB 140 12 6 06 1 Five year survival rates in Number of people diagnosed with cancer 1 284 900 Number of people who will die of cancer 550 000 Cancer Site Brain Other Nervous Breast females Cervix Uteri Colon Rectum Esophagus Hodgkin s Disease Kidney Renal Pelvis Larynx Leukemias Liver Intrahep Lung Bronchus Melanoma of Skin Multiple Myeloma Ovary Pancreas Prostate Stomach Testis Thyroid Urinary Bladder All Sites 1974 76 22 3 74 3 68 5 49 5 4 7 71 1 51 3 65 4 34 2 3 8 12 3 79 7 24 4 36 5 2 6 66 7 15 1 78 6 91 9 72 4 49 3 1977 79 24 4 74 5 67 7 51 7 5 1 73 50 8 66 8 36 6 3 7 13 3 81 5 26 1 38 1 2 5 70 9 16 7 87 2 92 5 74 8 49 8 http seer cancer gov publications raterisk rates28 html 1980 82 25 76 2 66 9 54 2 6 7 74 3 51 4 68 37 4 3 4 13 3 82 1 28 38 9 3 1 73 1 17 5 91 7 94 2 77 9 50 6 1983 90 27 3 80 4 67 4 59 2 9 2 78 9 56 3 67 38 3 6 13 4 85 1 27 7 41 8 3 2 79 6 18 5 93 3 94 6 79 8 53 9 MCB 140 12 6 06 2 Knudson s two hit hypothesis Knudson s analysis of the agespecific 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 24 MCB 140 12 6 06 3 Knudson 1971 two hit model 18 24 MCB 140 12 6 06 4 MCB 140 12 6 06 5 An easily understood workable falsehood is more useful than a complex incomprehensible truth MCB 140 12 6 06 6 Cancer 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 formation MCB 140 12 6 06 7 Dr Thomas Ried NCI NIH SKY of hormal human cell MCB 140 12 6 06 8 HeLa HeLa Dr Thomas Ried NCI MCB 140 12 6 06 9 Dr Thomas Ried NCI Hanahan and Weinberg 2000 Cell 100 57 70 MCB 140 12 6 06 11 MCB 140 12 6 06 12 One 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 regulated MCB 140 12 6 06 13 1967 Hartwell screen in budding yeast for cell division control cdc mutants MCB 140 12 6 06 14 A forward genetic screen A phenomenon a list of genes involved in the phenomenon an understanding of mechanism 1 Take organism 2 Mutagenise 3 Isolate mutants relevant to phenomenon under study 4 Determine what genes are affected mutated in each mutant 5 Determine the order of action of gene products in the process under study MCB 140 12 6 06 15 MCB 140 12 6 06 16 A 8 MCB 140 12 6 06 17 mitosis G1 G2 Gene X does its thing Begin DNA replication End DNA replication S phase MCB 140 12 6 06 18 18 3 MCB 140 12 6 06 19 Permissive Restrictive Cells at all points in cell cycle Cells all arrest at the point in the cell cycle where mutated gene exerts its function MCB 140 12 6 06 20 MCB 140 12 6 06 21 18 6 MCB 140 12 6 06 22 Yeast Cdc28p and human CDK1 MCB 140 12 6 06 23 18 5 MCB 140 12 6 06 24 http www nature com celldivision milestones index html MCB 140 12 6 06 25 Hanahan and Weinberg 2000 Cell 100 57 70 MCB 140 12 6 06 26 MCB 140 12 6 06 27 Mike Bishop Harold Hal Varmus 18 23 MCB 140 12 6 06 28 MCB 140 12 6 06 29 neomorph gain of function dominant allele MCB 140 12 6 06 30 MCB 140 12 6 06 31 Burkitt s lymphoma The 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 MCB 140 12 6 06 32 Immediate early genes myc jun fos MCB 140 12 6 06 33 A summary To 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 MCB 140 12 6 06 34 Two insensitivity to anti growth signals and evasion of apoptosis Mutations 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 MCB 140 12 6 06 35 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 …
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