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BIOL 311 Human Genetics Fall 2006 Lecture: Cancer Genetics: Oncogenes Reading Chap. 17 and Chapters 3 and 4 Weinberg, R. A. (2007) The Biology of Cancer. Garland Science, New York, NY. Outline: 1. Cancer as a genetic disease 2. Discovery of oncogenes 3. Activation of oncogenes 4. Cancer testing and profiling 1. Cancer as a genetic disease Cancer runs in families: Hereditary cancers of the breast, colon and retina Agents that damage DNA increase risk of cancer Many mutagens are carcinogens Cancers involve multiple mutations in different genes Oncogenes: Genes that promote cancer. Encode proteins involved in growth, cell signaling, gene regulation, or that prevent cell death. Mutation leads to dominant gain of function. Tumor suppressors: Genes that in normal form prevent cancer. Encode transcription factors, proteins that control cell cycle, DNA repair enzymes. Mutation leads to recessive loss of function. 2. Discovery of oncogenes 1960's study of oncogenic retroviruses retroviruses: RNA is genetic material Encode reverse transcriptase, enzyme that makes DNA from RNA Genome contains genes for envelop proteins (env), reverse transcriptase (pol), coat proteins (gag) An additional gene is (oncogene) present in oncogenic retroviruses, for example src oncogene is present in Rous sarcoma virus, an oncogenic retrovirus associated with sarcoma (muscle tumor) in chickens Normal cells contain proto-oncogenes: normal forms of genes for proteins adopted by oncogenic retroviruses. 1 Oncogenes are mutated or overexpressed versions of cellular proteins Function Example Growth factors sis, platelet derived growth factor Receptors erb-B, epidermal growth factor receptor Cell signaling proteins Transcription factors Cell cycle proteins Cell death proteins ras, G-protein fos, jun, myc mdm2 bcl-2 Assay for detecting activated oncogenes, ultimately used to clone human ras Transfection of mouse fibroblasts with DNA from cancers; identify "transformed cells", cells with more cancer-like characteristics. Isolate and clone DNA for oncogene. Special trick for identifying the human oncogene from transfected mouse cells--human DNA contains Alu family repeats, mouse DNA does not. 3. Ways in which oncogenes can become activated amplification hundreds of extra copies made i.e. erb-b2 (her-2/neu) growth factor receptor associated with some breast cancers point mutation single base on DNA is changed i.e. ras causes GTP binding protein to remain in "on" position and to not cycle to GDP form translocation chromosome rearrangement involving non-homologous chromosomes i.e. bcr-abl fusion oncoprotein associated with chronic myeloid leukemia translocation involves abl gene on chromosome 9 and bcr gene on chromosome 22 Fig. 17-4 Philadelphila chromosome Leukemia: cancer of blood forming stem cells Burkitt's lymphoma, solid tumor of lymphocytes T(8:14) translocation of myc into Ig heavy chain gene, associated with 75-85% of patients; other cases associated with different translocations 4. Cancer testing and profiling molecular methods of diagnosis test DNA of cancer cells vs. normal cells karyotype analysis, cancer cells vs. normal cells molecular profiles for diagnosis/treatment 2 microarrays Fig. 17-18 a. identify tissue of origin (primary tumor) based on molecular markers b. molecular profiles may distinguish tumor types c. drug sensitivity profiles particular genotypes may be resistant to certain drugs d. predict clinical outcome 3