Genetics - BIO310: Genetic Basis of Cancer PDF

Genetics– BIO310 Genetic Basis of Cancer  Genetic Basis of Cancer The key characteristics of cancer Oncogenes versus tumor-suppressor genes 49 Genetic Basis of Cancer Cancer is a disease characterized by uncontrolled cell division It is...

Genetics– BIO310 Genetic Basis of Cancer  Genetic Basis of Cancer The key characteristics of cancer Oncogenes versus tumor-suppressor genes 49 Genetic Basis of Cancer Cancer is a disease characterized by uncontrolled cell division It is a genetic disease at the cellular level Human cancers are classified according to the type of cell that has become cancerous ◦ More than 100 kinds have been identified 50  Characteristics of Cancer 1. Most cancers originate from a single cell ◦ A growth is clonal in origin ◦ A cancer cell divides to produce two cancer cells 2. Cancer is a multistep process ◦ Begins as a benign growth (not invasive) ◦ Additional genetic changes lead to cancerous growth 3. Cancers can be staged ◦ Malignant – invasive – Invades surrounding tissue ◦ Metastatic – Moves to a different site in body 52 Access the text alternative for these images 53 THE DEVELOPMENT AND CAUSES OF CANCER Causes of Cancer: Radiation and many chemical carcinogens act by damaging DNA and inducing mutations. Other chemical carcinogens contribute to the development of cancer by stimulating cell proliferation. Viruses also cause cancer in both humans and other species. Tumor Viruses Members of several families of animal viruses, called tumor viruses, are capable of directly causing cancer in either experimental animals or humans Tumor Viruses Table 22.7 TABLE 22.7 Examples of Viruses That May Cause Cancer Virus Description Retroviruses Rous sarcoma virus (RSV) Causes sarcomas in chickens Hardy-Zuckerman-4 feline Causes sarcomas in cats sarcoma virus DNA Viruses Hepatitis B, SV40, polyomavirus Causes liver cancer in several species, including humans Papillomavirus Causes benign tumors and malignant carcinomas in several species, including humans; causes cervical cancer in humans Herpesvirus Causes carcinoma in frogs and T-cell lymphoma in chickens. A human herpesvirus, Epstein-Barr virus, is a causative agent in Burkitt lymphoma, which occurs primarily in immunosuppressed individuals such as AIDS patients. 62 However, the majority (approximately 80%) of human cancers are not induced by viruses and apparently arise from other causes, such as radiation and chemical carcinogens. Cancer results from alterations in critical regulatory genes that control cell proliferation, differentiation, and survival.  Oncogenes Specific genes (called oncogenes) are capable of inducing cell transformation, thereby providing the first insights into the molecular basis of cancer. Therefore, the studies of viral oncogenes also led to the identification of cellular oncogenes, which are involved in the development of non-virus-induced cancers. The key link between viral and cellular oncogenes was provided by studies of the highly oncogenic retroviruses. Retroviral Oncogenes: The first oncogene to be identified was the src gene of RSV (Rous sarcoma virus). Subsequent studies have identified more than two dozen distinct oncogenes in different retroviruses.  Proto-Oncogenes: Proto-oncogenes are a group of genes that cause normal cells to become cancerous when they are mutated. Mutations in proto-oncogenes are typically dominant in nature, and the mutated version of a proto-oncogene is called an oncogene. The oncogenes are abnormally expressed or mutated forms of the corresponding proto-oncogenes. Tumor suppressor genes represent the opposite side of cell growth control, normally acting to inhibit cell proliferation and tumor development. Identification of Tumor Suppressor Genes: In contrast to oncogenes, tumor suppressor genes inhibit tumor development. The prototype tumor suppressor gene, Rb, was identified by studies of inheritance of retinoblastoma. Loss or mutational inactivation of Rb and other tumor suppressor genes, including p53, contributes to the development of a wide variety of human cancers. Functions of Tumor Suppressor Gene Products: The proteins encoded by most tumor suppressor genes act as inhibitors of cell proliferation or survival. The Rb, INK4, and p53 proteins are negative regulators of cell cycle progression. In addition, p53 is required for apoptosis induced by DNA damage and other stimuli, so its inactivation contributes to enhanced tumor cell survival. Inhibition of cell cycle progression by Rb and p 16 Rb inhibits progression past the restriction point in G1. Cdk4, 6/cyclin D complexes promote passage through the restriction point by phosphorylating and inactivating Rb. The activity of Cdk4, 6/cyclin D is inhibited by p16. Rb and p16 are tumor suppressors, whereas cyclin 01 and Cdk4 are oncogenes. Wild-type p53 is required for both cell cycle arrest and apoptosis induced by DNA damage. Cell cycle arrest is mediated by induction of the Cdk inhibitor p21 and apoptosis by induction of the proapoptotic Bcl-2 family members PUMA and Noxa Roles of Oncogenes and Tumor Suppressor Genes in Tumor Development: Mutations in both oncogenes and tumor suppressor genes contribute to the progressive development of human cancers. Accumulated damage to multiple such genes results in the abnormalities of cell proliferation, differentiation, and survival that characterize the cancer  Oncogenes vs. Tumor Suppressor Genes Genes that are involved in cancers are classified as Oncogenes ◦ Mutant gene that is overexpressed and contributes to cancerous growth Tumor suppressor genes ◦ Gene that prevents cancers ◦ Loss-of-function in a tumor-suppressor gene can allow cancerous growth to occur 76 Proto-Oncogenes Normal, nonmutated gene with the potential to become an oncogene is a proto- oncogene Gain-of-function mutation that produces an oncogene usually has one of three effects ◦ Amount of protein is increased ◦ Change in the structure of the protein to make it overly active ◦ Protein expressed in a cell type where it is not normally expressed 78 TABLE 22.6 Examples of Proto-Oncogenes That Can Mutate into Oncogenes* Gene Cellular Function of Encoded Protein Growth factors sis Platelet-derived growth factor int-2 Fibroblast growth factor Growth factor receptors erbB Growth factor receptor for EGF (epidermal growth factor) fms Growth factor receptor for NGF (nerve growth factor) Intracellular signaling proteins ras GTP/GDP-binding protein raf Serine/threonine kinase src Tyrosine kinase abl Tyrosine kinase Transcription factors myc Transcription factor jun Transcription factor fos Transcription factor 82 Ras Protein Ras protein is a GTPase The ras gene is a proto-oncogene that when mutated can be an oncogene Missense mutations in ras genes are found in a large number of different cancers ◦ Example: Some mutations decrease the ability of the Ras protein to hydrolyze GTP ◦ Results in more of the GTP-bound active form of the protein, keeping the signaling pathway turned on – and stimulating the cell to divide 83 84 Mutations Changing Proto-oncogenes to Oncogenes There are four types of mutation frequently found that change a proto-oncogene into an oncogene: 1. Missense mutation 2. Gene amplification 3. Chromosomal translocation 4. Viral integration 85 Tumor-Suppressor Genes Using rb and p53 as examples, describe how tumor-suppressor genes prevent cancer and explain what happens when their function is lost Two main categories of tumor-suppressor genes Genetic changes that inactivate tumor-suppressor genes Different ways in which loss of tumor-suppressor genes can lead to cancer 93 Retinoblastoma Tumor suppressor genes prevent cancerous growth The first human tumor-suppressor gene identified was the retinoblastoma gene ◦ Causes a tumor of the retina in the eye There are two types of retinoblastoma 1. Inherited, which occurs in the first few years of life 2. Non inherited, which occurs later in life 94 Two-Hit Model for Retinoblastoma Alfred Knudson proposed a “two-hit” model for retinoblastoma which has been confirmed ◦ Retinoblastoma requires “two” mutations to occur ◦ People with the inherited form already have one hit, or mutation ◦ All they need is one more mutation for cancer to occur ◦ People with the non inherited form must have two hits, or mutations ◦ The non inherited form occurs much later in life, and only rarely 95 Rb Protein Regulates Cell Division More recent studies have revealed how the Rb protein suppresses proliferation of cancer cells ◦ Rb regulates transcription factor, E2F, which activates genes required for cell cycle progression ◦ Binding of Rb to E2F inhibits its activity and prevents the cell from progressing through cell cycle ◦ If no functional Rb protein is present, a cell can alway progress through the cell cycle 96 97 p53 The p53 gene was the second tumor-suppressor gene discovered About 50% of all human cancers are associated with defects in the p53 gene A primary role for the p53 protein is to determine if a cell has incurred DNA damage ◦ If so, p53 will promote cellular pathways that ◦ Activate genes that promote DNA repair ◦ Activate genes that arrest cell division and repress genes that are required for cell division ◦ Activate genes that promote apoptosis – programmed cell death 98 Apoptosis Apoptosis is a process that involves cell shrinkage, chromatin condensation and DNA degradation resulting ultimately in programmed cell death It is facilitated by proteases known as caspases ◦ Sometimes referred to as “the cell’s executioners” In apoptosis, the cell is broken down into small vesicles ◦ Eventually phagocytized by cells of the immune system 99 TABLE 22.8 Functions of Selected Tumor-Suppressor Genes Gene Function Genes that negatively regulate cell division rb The Rb protein is a negative regulator of E2F (see Figure 22.14). The inhibition of E2F prevents the transcription of certain genes required for DNA replication and cell division. p16 The protein kinase p16 negatively regulates cyclin-dependent kinases and thereby controls the transition from the G1 phase of the cell cycle to the S phase. NF1 The NF1 protein stimulates Ras to hydrolyze its GTP to GDP. Loss of NF1 function causes the Ras protein to be overactive, which promotes cell division. APC APC is a negative regulator of a cell-signaling pathway that leads to the activation of genes that promote cell division. Genes that maintain genome integrity p53 p53 is a transcription factor that acts as a checkpoint protein and positively regulates a few specific target genes and negatively regulates others in a general manner. It acts as a sensor of DNA damage. It can prevent advancement through the cell cycle and also can promote apoptosis. BRCA-1, BRCA-2 BRCA1 and BRCA2 proteins are both involved in the cellular defense against DNA damage. These proteins facilitate DNA repair and can promote apoptosis if repair is not achieved. 100 Tumor-Suppressor Genes Tumor-suppressor genes fall into two general categories ◦ Negatively regulate cell division ◦ Rb ◦ Maintain genome integrity ◦ Genome maintenance = cellular mechanisms that either prevent mutations from occurring or prevent mutant cells from dividing or surviving ◦ Checkpoint proteins detect genetic abnormalities and prevent cell division ◦ DNA repair enzymes 101 102  Epigenetics Epigenetics is the study of heritable traits, or a stable change of cell function, that happen without changes to the DNA sequence. The Greek prefix epi- "over, outside of, around" in epigenetics implies features that are "on top of" or "in addition to" the traditional (DNA sequence based) genetic mechanism of inheritance. Epigenetic factors can also lead to cancer. The term also refers to the mechanism of changes: functionally relevant alterations to the genome that do not involve mutation of the nucleotide sequence. Examples of mechanisms that produce such changes are DNA methylation and histone modification, each of which alters how genes are expressed without altering the underlying DNA sequence. Association Between Epigenetics and Disease An association between epigenetic changes and human disease can occur in three ways: ◦ Epigenetic changes directly contribute to disease symptoms ◦ Disease symptoms may arise first, then cause epigenetic changes to occur ◦ Association is indirect because a third factor is involved ◦ For example Toxic agent causes disease and genetic changes, but genetic changes do not contribute to the disease 122 Epigenetic Changes Common in Cancer Cells Several types of chromatin modifications are found to be abnormal in cancer cells: ◦ DNA methylation ◦ Covalent modification of histones ◦ Chromatin remodeling Why do these occur? ◦ Mutations may occur in genes that encode chromatin modifying proteins ◦ Environmental agents may alter the functions of chromatin- modifying proteins 123 Mutations in Genes that Encode Chromatin-Modifying Proteins Examples: ◦ Mutation in a genes that lead to inhibition of chromatin-modifying proteins ◦ Mutation may also lead to increased function of chromatin- modifying proteins These mutations may have widespread effects on gene expression 124 TABLE 22.10 Mutations in Genes That Encode Chromatin-Modifying Proteins and Their Occurrence in Different Types of Cancers Particular Cancer(s) in Type of Protein Encoded Which Mutant Gene Is Type of Modification by Mutant Gene Protein Function Observed DNA methylation DNA methyltransferase Methylated DNA Acute myeloid leukemia Histone modification Histone Attaches acetyl groups Colorectal, breast, and acetyltransferase to histones pancreatic cancer Histone modification Histone Attaches methyl groups Renal and breast methyltransferase to histones cancer Histone modification Histone demethylase Removes methyl groups Multiple myeloma and from histones esophageal cancer Histone modification Histone kinase Attaches phosphate Medulloblastoma, groups to histones glioma Chromatin remodeling SWI/SNF complex Alters the positions of Lung, breast, prostate, histones and pancreatic cancer 125 Environmental Agents that Alter the Functions of Chromatin-Modifying Proteins Some environmental agents directly alter the functions of chromatin-modifying proteins ◦ For some examples the association is causative ◦ For other examples scientists are still trying to determine if epigenetic changes caused by environmental agents result in cancer 126 TABLE 22.11 Environmental Agents That Are Associated with Cancer and Are Known to Cause Epigenetic Changes Particular Cancers Associated Environmental Agent Occurrence with Agent Polycyclic aromatic Tobacco smoke, automobile exhaust, Lung, breast, stomach, and skin hydrocarbons charbroiled food cancer Benzene Tobacco smoke, automobile exhaust Leukemia, lymphoma, multiple myeloma Endocrine disruptors (e.g., Insecticides, fungicides, herbicides, and some Breast, prostate, and thyroid diethylstilbestrol) types of plastic cancer Cadmium Tobacco products, production of batteries Lung and breast cancer Nickel Occupational exposure in mining, welding, and Lung and nasal cancer electroplating, and in the manufacturing of jewelry, stainless steel, and batteries Arsenic Lead alloy, feed additive in agriculture, Skin, bladder, kidney, and liver insecticides cancer 127 Cancer Treatments Aimed at Epigenetic Changes Researchers are investigating drugs that may inhibit cancer cells by affecting DNA methylation or covalent histone modifications 5-azacytidine and decitabine are DNA methyltransferase inhibitors; have shown some promising results in treatment of leukemia; mechanisms not completely understood 128