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Functional Genomics talk Westwood) (T. BIO477 Cancer Part I- Oct. 20, 2007 Part II- Oct. 27, 2007 Tim Westwood Reading Weinberg, R. A. (2007). The Biology of Cancer. Garland Science, New York. Chapter 2- The Nature of Cancer Chapter 3- Tumor Viruses Chapter 4- Cellular Oncogenes 1 Functional Genomics talk Westwood) (T. Outline A. Introduction - types, properties of cancer cells, history, epidemiology B. The “3” causes of cancer 1. Microbes 2. Mutagens (irritants) 3. Genetics C. Epidemiology of Cancer D. Mutagens and Carcinogens - Ames test E. Tumour Viruses and Oncogenes 1. Rous sarcoma virus 2. DNA and RNA Tumor viruses 3. Retroviruses and the discovery of oncogenes 2 Functional Genomics talk Westwood) (T. Table 3.2 The Biology of Cancer (© Garland Science 2007) 3 Functional Genomics talk Westwood) Table 23-1. Variation Between Countries in the Incidence of Some Common Cancers From: Molecular Biology of the Cell,4th ed. 2002. B. Alberts et al. Garland Press, N.Y., N.Y. (T. SITE OF ORIGIN OF CANCER HIGH-INCIDENCE POPULATION LOCATION INCIDENCE* LOW-INCIDENCE POPULATION LOCATION INCIDENCE* * Incidence = number of new cases per year per 100,000 population Lung USA (New Orleans, blacks) 110 India (Madras) 5.8 Breast Hawaii (Hawaiians) 94 Israel (non-Jews) Prostate USA (Atlanta, blacks) 91 China (Tianjin) 1.3 Uterine cervix Brazil (Recife) 83 Israel (non-Jews) 3.0 Stomach Japan (Nagasaki) 82 Kuwait (Kuwaitis) 3.7 Liver China (Shanghai) 34 Canada (Nova Scotia) 0.7 Colon USA (Connecticut, whites) 34 India (Madras) 1.8 Melanoma Australia (Queensland) 31 Japan (Osaka) 0.2 Lip Canada (Newfoundland) 15 Japan (Osaka) 0.1 Kidney Canada (NWT and Yukon) 15 India (Poona) 0.7 Leukemia Canada (Ontario) 12 India (Nagpur) 2.2 14.0 Table 2.5 part 1 of 2 The Biology of Cancer (© Garland Science 2007) 4 Functional Genomics talk Westwood) (T. Figure 2.20 The Biology of Cancer (© Garland Science 2007) 5 Functional Genomics talk Westwood) (T. 6 Functional Genomics talk Westwood) (T. Figure 23-17. The Ames test for mutagenicity. The test uses a strain of Salmonella bacteria that require histidine in the medium because of a defect in a gene necessary for histidine synthesis. Mutagens can cause a further change in this gene that reverses the defect, creating revertant bacteria that do not require histidine. To increase the sensitivity of the test, the bacteria also have a defect in their DNA repair machinery that makes them especially susceptible to agents that damage DNA. A majority of compounds that are mutagenic in tests such as this are also carcinogenic and vice versa. From: Molecular Biology of the Cell,4th ed. 2002. B. Alberts et al. Garland Press, N.Y., N.Y. 7 Functional Genomics talk Westwood) (T. Figure from: Genes and the Biology of Cancer. H. Varmus and R. Weinberg. 1993. Sci. Am. Library, W.H. Freeman. N.Y, N.Y. Table 2.8 The Biology of Cancer (© Garland Science 2007) 8 Functional Genomics talk Westwood) (T. Figure 3.2 The Biology of Cancer (© Garland Science 2007) Table 23-2. Viruses Associated with Human Cancers VIRUS ASSOCIATED TUMORS AREAS OF HIGH INCIDENCE warts (benign) worldwide carcinoma of the uterine cervix worldwide liver cancer (hepatocellular carcinoma) Southeast Asia, tropical Africa Burkitt's lymphoma (cancer of B lymphocytes) West Africa, Papua New Guinea nasopharyngeal carcinoma southern China, Greenland DNA Viruses Papovavirus family Papillomavirus (many distinct strains) Hepadnavirus family Hepatitis-B virus Herpesvirus family Epstein-Barr virus 9 Functional Genomics talk Westwood) (T. RNA viruses Retrovirus family Human T-cell leukemia virus type I (HTLV-1) adult T-cell leukemia/lymphoma Japan, West Indies Human immuno-deficiency virus (HIV, the AIDS virus) Kaposi's sarcoma (HIV-indirect; HPV, herpesvisrus-direct) Central and Southern Africa From: Molecular Biology of the Cell,4th ed. 2002. B. Alberts et al. Garland Press, N.Y., N.Y. Table 15.2. Tumor Viruses Virus family Human tumors Genome size (kb) DNA tumor viruses Hepatitis B viruses Liver cancer 3 SV40 and polyomavirus None 5 Papillomaviruses Cervical carcinoma, Kaposi’s sarcoma 8 Adenoviruses None Herpesviruses (e.g. Epstein-Barr virus) Burkitt's lymphoma, nasopharyngeal carcinoma, Kaposi's sarcoma 35 100–200 RNA tumor viruses Retroviruses Adult T-cell leukemia 9 10 Functional Genomics talk Westwood) (T. Figure 5-73. The life cycle of a retrovirus. The retrovirus genome consists of an RNA molecule of about 8500 nucleotides; two such molecules are packaged into each viral particle. The enzyme reverse transcriptase first makes a DNA copy of the viral RNA molecule and then a second DNA strand, generating a double-stranded DNA copy of the RNA genome. The integration of this DNA double helix into the host chromosome is then catalyzed by a virus-encoded integrase enzyme. This integration is required for the synthesis of new viral RNA molecules by the host cell RNA polymerase, the enzyme that transcribes DNA into RNA Figure 15.17. A typical retrovirus genome The DNA provirus, integrated into cellular DNA, is transcribed to yield genome-length RNA. This primary transcript serves as the genomic RNA for progeny virus particles, and as mRNA for the gag and pol genes. In addition, the full-length RNA is spliced to yield mRNA for env. The gag gene encodes the viral protease and structural proteins of the virus particle, pol encodes reverse transcriptase and integrase, and env encodes envelope glycoproteins. From: The Cell, a Molecular Approach. 2nd ed. 2000. G. Cooper. Sinauer Assoc., Sunderland, MA 11 Functional Genomics talk Westwood) (T. Figure 15.18. Cell transformation by RSV and ALV Both RSV and ALV infect and replicate in chicken embryo fibroblasts, but only RSV induces cell transformation. From: The Cell, a Molecular Approach. 2nd ed. 2000. G. Cooper. Sinauer Assoc., Sunderland, MA Figure 15.19. The RSV genome RSV contains an additional gene, src, that is not present in ALV and encodes the Src protein-tyrosine kinase. From: The Cell, a Molecular Approach. 2nd ed. 2000. G. Cooper. Sinauer Assoc., Sunderland, MA 12 Functional Genomics talk Westwood) (T. Figure 3.20 The Biology of Cancer (© Garland Science 2007) Fig. 3.22 Capture of src by avian leukosis virus The Biology of Cancer (© Garland Science 2007) 13 Functional Genomics talk Westwood) (T. Table 15.3. Retroviral Oncogenes Oncogene abl Virus Species Abelson leukemia Mouse erbA Avian erythroblastosis-ES4 Chicken erbB Avian erythroblastosis-ES4 Chicken ets Avian erythroblastosis-E26 Chicken fes Gardner-Arnstein feline sarcoma Cat fms McDonough feline sarcoma Cat fos FBJ murine osteogenic sarcoma Mouse fps Fujinami sarcoma Chicken jun Avian sarcoma-17 Chicken kit Hardy-Zuckerman feline sarcoma Cat mos Moloney sarcoma Mouse mpl Myeloproliferative leukemia Mouse myb Avian myeloblastosis Chicken myc Avian myelocytomatosis Chicken p3k Avian sarcoma-16 Chicken qin Avian sarcoma-31 Chicken raf 3611 murine sarcoma Mouse rasH Harvey sarcoma Rat rasK Kirsten sarcoma Rat rel Reticuloendotheliosis Turkey ros UR2 sarcoma Chicken sea Avian erythroblastosis-S13 Chicken sis Simian sarcoma Monkey ski Avian SK Chicken src Rous sarcoma Chicken From: The Cell, a Molecular Approach. 2nd ed. 2000. G. Cooper. Sinauer Assoc., Sunderland, MA 14 Functional Genomics talk Westwood) (T. The Biology of Cancer (© Garland Science 2007) Figure 24-4. The identification and molecular cloning of the rasD oncogene. Addition of DNA from a human bladder carcinoma to a culture of mouse 3T3 cells causes about one cell in a million to divide abnormally and form a focus, or clone of transformed cells. To clone the oncogene responsible for transformation, advantage is taken of the fact that most human genes have nearby repetitive DNA sequences called Alu sequences. DNA from the initial focus of transformed mouse cells is isolated, and the oncogene is separated from adventitious human DNA by secondary transfer to mouse cells. The total DNA from a secondary transfected mouse cell is then cloned into bacteriophage λ; only the phage that receives human DNA hybridizes with an Alu probe. The hybridizing phage should contain part or all of the transforming oncogene. This expected result can be proved by showing either that the phage DNA can transform cells (if the oncogene has been completely cloned) or that the cloned piece of DNA is always present in cells transformed by DNA transfer from the original donor cell. From: Molecular Cell Biology. 4th ed. 2000. Lodish et al. W.H. Freeman, NY, NY. 15 Functional Genomics talk Westwood) (T. From: Molecular Biology of the Cell,4th ed. 2002. B. Alberts et al. Garland Press, N.Y., N.Y. Figure 23-24. Cancer-critical genes fall into two readily distinguishable categories, dominant and recessive. Oncogenes act in a dominant manner: a gain-of-function mutation in a single copy of the cancer-critical gene can drive a cell toward cancer. Tumor suppressor genes, on the other hand, generally act in a recessive manner: the function of both alleles of the cancer-critical gene must be lost to drive a cell toward cancer. In this diagram, activating mutations are represented by solid red boxes, inactivating mutations by hollow red boxes. Figure 23-27. Three ways in which a proto-oncogene can be made overactive to convert it into an oncogene. From: Molecular Biology of the Cell,4th ed. 2002. B. Alberts et al. Garland Press, N.Y., N.Y. 16 Functional Genomics talk Westwood) (T. Fig. 3.23. Insertional mutagenesis. The Biology of Cancer (© Garland Science 2007) Table 15.4. Representative Oncogenes of Human Tumors Oncogene Type of cancer Activation mechanism abl Chronic myelogenous leukemia, acute lymphocytic leukemia Translocation akt Ovarian and pancreatic carcinomas Amplification bcl-2 Follicular B-cell lymphoma Translocation D1 Parathyroid adenoma, B-cell lymphoma Translocation erbB-2 Breast and ovarian carcinomas Amplification gip Adrenal cortical and ovarian carcinomas Point mutation gli Glioblastoma Amplification 17 Functional Genomics talk Westwood) (T. hox-11 Acute T-cell leukemia Translocation lyl Acute T-cell leukemia Translocation c-myc Burkitt's lymphoma Translocation c-myc Breast and lung carcinomas Amplification L-myc Lung carcinoma Amplification N-myc Neuroblastoma, lung carcinoma Amplification PDGFR Chronic myelomonocytic leukemia Translocation PML/RA Rα Acute promyelocytic leukemia Translocation rasH Thyroid carcinoma Point mutation rasK Colon, lung, pancreatic, and thyroid carcinomas Point mutation rasN Acute myelogenous and lymphocytic leukemias, thyroid carcinoma Point mutation ret Multiple endocrine neoplasia types 2A and 2B Point mutation ret Thyroid carcinoma DNA rearrangement SMO Basal cell carcinoma Point mutation From: The Cell, a Molecular Approach. 2nd ed. 2000. G. Cooper. Sinauer Assoc., Sunderland, MA 18