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Genetics Objectives 20 A. Cancer Biology: 1. Unique characteristics of cancer for malignant phenotype: a. Uncontrolled, limitless proliferation b. Impaired apoptosis pathways c. Differentiation arrest and clonal expansion d. Invasion and metastasis e. Angiogenesis 2. Histopathologic classifications of human cancer: a. Carcinoma: epithelial tissues in adults b. Sarcoma: mesenchymal tissues in children c. Leukemia/lymphoma: hematopoietic tissues in both children and adults 3. Differentiation arrest and clinical behavior: tumor progression occurs with differentiation arrest, and clinically, this can be used to determine the tumor tissue of origin. This can be advantageous in PCR screening because cancer cells will all leave the same characteristic banding pattern, and can be detected in low amounts with PCR amplification. Clonal evolution and clinical behavior: as tumors progress from a single cell, they become heterogeneous with higher than normal mutation rates. Cells that have defects in DNA repair and an ability to tolerate severe chromosomal defects are selected for by clonal evolution, and increases malignancy of the developing tumor. However, this malignant phenotype also makes tumor cells more susceptible to DNA damaging chemotherapeutic agents because they continue progressing through the cell cycle with a fatal amount of damaged DNA. 4. Mechanisms of cancer resulting in altered DNA: cancer causes alter DNA in many fashions: a. Excision repair: Xeroderma Pigmentosa b. Mismatch repair: Hereditary Non Polyposis Colon Cancer c. Cell cycle checkpoint: Ataxia Telangiectasia d. Chromosome instability: Fanconi’s Anemia, Bloom’s Syndrome e. Mutagenicity: UV rays, X-rats, Aflatoxin, Tobacco smoke f. Stimulation of growth: Estrogen g. Chronic inflammaion: Asbestos h. Viral oncogenesis: Papillomaviruses, Hepatitis B and C, Epstein-Barr virus, HTLV-1, HIV B. Oncogenes and Tumor Suppresor Genes: 1. Oncogene: a gene that leads to tumorigenesis Proto-oncogenes and contribution to oncogenesis: proto-oncogenes are oncogene precursors that when overactivated, lead to increased susceptibility to tumorigenesis 2. Tumor suppressor gene identification: identified using RFLP analysis looking for loss of heterozygosity Tumor suppressor inactivation and cancer development: a tumor suppressor gene prohibits uncontrolled proliferation; loss of function of this gene results in uncontrolled proliferation and development of cancer 3. Oncogenic tumorigenesis: oncogenic tumorigenesis occurs when a protooncogene is activated, and activity of a protein signaling cascade increases. This occurs in humans in three manners: a mutation in the coding sequence leading to a hyperactive protein made in normal amounts (RAS, RET), gene amplification of a normal protein made in large amounts (MYC, ERB-B2), or a chromosomal rearrangement leading to either hyperactive proteins or mass production of a normal protein (BCR-ABL, MYC, BCL-2) Tumor suppressor tumorigenesis: caused when a tumor suppressor gene is inactivated, and activity of a protein signaling cascade increases. This occurs in humans in many ways: transcriptional regulation (Rb), transcription factor loss (p53, BRCA-1), altered cadherin signaling (APC), GTP-ase activator (NF-1), inhibition of transcription elongation (VHL), and problems in DNA repair (hereditary non-polyposis colon cancer) Note: Refer to the table on page 10 of lecture for a good comparison of oncogenic and tumor suppressor tumorigenic characteristics 4. Genetic instability origin and contribution to oncogenesis: genetic instability originates from mutations that allow the cell to divide when the chromosome is altered. This allows cells to survive for more generations because normally, cells will age and incur chromosomal damage before apoptosis. In cancer, when this occurs, the cells block apoptosis and continue to divide, making the cells capable of infinite cell divisions and tumorigenesis. Note: the notes reference two major causes of genetic instability: o p53: a cell cycle checkpoint that arrests the cell cycle when DNA damage is detected. In the absence of p53, the cell can proliferate with DNA damage, leading to genetic instability o Telomerase: if a cell line is proliferating rapidly, the telomeres of the cell shorten, and the cell will ultimately have severe DNA damage due to chromosomal joining during mitosis and subsequent breakage of chromosomes during anaphase. Telomerase activation protects against this by adding base pairs back to telomers after cellular division, thus protecting cancerous cells from severe DNA damage that would ultimately result in cell death. C. Molecular Oncology: 1. Multi-step carcinogenesis: since cancer is not often caused by a single mutation in a proto-oncogene or tumor suppressor gene, carcinogenesis must be described on a wide spectrum ranging from relatively benign hyperplasia to severe carcinoma. The “steps” between hyperplasia and carcinoma represent the multistep process of carcinogenesis Implications for prevention/treatment: since advanced malignancies are difficult to treat, it is important to treat cancer early, and with preventative agents in at-risk populations. 2. Molecular complexity of pathogenesis and therapeutic hindrance: since advanced malignancies have a host of cells with different mutations, often one type of therapy proves unsuccessful, leaving behind malignant cells not targeted by the therapy. Also, in advanced malignancies, cells may no longer require initiation of genetic defects, and targeting cancerous cells in this manner may be rendered ineffective. 3. Clinical application of molecular genetics for diagnosis/staging of cancer: PCR assays screening for tumor-specific genetic alterations has allowed for earlier, more accurate diagnoses while detecting smaller amounts of cancerous cells. 4. Cancer treatment development for tumor-specific genetic alterations: knowledge of a tumor-specific genetic alteration can alter therapy based on the specific genetic alteration. Procedures that utilize this knowledge include manufacturing of antibodies specific for a tumor-specific antigen, molecularly targeted drugs that affect tumor-specific molecules, and gene therapy that inserts a specific, normal gene in place of a tumor-specific mutated gene.