Agro/Ansc/Bio/Gene/Hort 305 Fall, 2017 MEDICAL GENETICS AND CANCER Chpt 24, Genetics by Brooker (lecture outline) #17

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1 Agro/Ansc/Bio/Gene/Hort 305 Fall, 2017 MEDICAL GENETICS AND CANCER Chpt 24, Genetics by Brooker (lecture outline) #17 INTRODUCTION - Our genes underlie every aspect of human health, both in function and dysfunction. - Knowledge of how genes work together and interact with the environment is very important - It will have a profound impact on the way many diseases are diagnosed, treated and prevented. It will bring about revolutionary changes in medicine. Indeed, such changes are already beginning. Currently, several hundred genetic tests are in clinical use: e.g., sickle-cell anemia, Huntington disease, cystic fibrosis Genetic tests are also available to detect predisposition to certain forms of cancer. - Approximately 4,000 genetic diseases afflict people. Many of these are the direct result of a mutation in one gene. - Genes also play roles in the development of diseases that have a complex pattern of inheritance e.g., Diabetes, asthma, mental illness and Cancer - Unraveling the complexities of these diseases will be a challenge for some time to come. GENETIC ANALYSIS OF HUMAN DISEASES - The study of human genetic diseases provides insights regarding our traits; e.g., by analyzing people with hemophilia, researchers have identified genes that participate in blood clotting - Thousands of human diseases have a genetic basis. This section focuses on the diseases that result from defects in single genes. The mutant genes that cause these diseases often obey simple Mendelian inheritance patterns. Pedigree Analysis: The pattern of inheritance of monogenic disorders, can be deduced by analyzing human pedigrees. To use this method, a geneticist must obtain data from large pedigrees with many affected individuals. Tay-Sachs Disease (TSD). TSD is inherited in an autosomal recessive manner Four common features of autosomal recessive inheritance are as follows: 1. Frequently, an affected offspring will have two unaffected parents 2. When two unaffected heterozygotes have children, the percentage of affected children is (on average) 25% 3. Two affected individuals will have 100% affected children 4. The trait occurs with the same frequency in both sexes - Disorders that involve defective enzymes typically have an autosomal recessive mode of inheritance. The heterozygote carrier has 50% of the normal enzyme. This is sufficient 1

2 for a normal phenotype. Hundreds of genetic diseases are inherited this way. In many cases, the mutant genes responsible have been cloned and mapped. (Table 24.1) Huntington Disease (HD) HD is inherited in an autosomal dominant manner. Five common features of autosomal dominant inheritance are as follows: 1. An affected offspring usually has one or both affected parents 2. An affected individual, with only one affected parent, is expected to produce (on average) 50% affected offspring 3. Two affected, heterozygous will have (on average) 25% unaffected offspring 4. The trait occurs with the same frequency in both sexes 5. For most dominant disease-casing alleles, the homozygote is more severely affected with the disorder. - Disorders that involve alteration in structural proteins typically have an autosomal dominant mode of inheritance. The heterozygote has 50% of the normal protein which is not sufficient for a normal phenotype. Numerous genetic diseases are inherited this way. In many cases, the mutant genes responsible have been cloned and mapped. (Table 24.2) A third mode of inheritance is X-linked recessive inheritance. This type of inheritance poses a special problems for males. Males have only a single copy of most X- linked genes. They are termed hemizygous.therefore a female heterozygous for an X- linked recessive gene will pass this trait to half her sons. Hemophilia Three common features of X-linked recessive inheritance are as follows: 1. Males are much more likely to exhibit the trait 2. The mothers of affected males often have brothers or fathers who are affected with the same trait 3. The daughters of affected males will produce (on average) 50% affected sons (Table 24.3) Many Genetic Disorders are Heterogeneous. Heterogeneity refers to the phenomenon that a disease is caused by mutations in different genes. Consider the disease hemophilia - Blood clotting involves a cellular cascade that involved several different proteins. Therefore, a defect in any of these proteins can cause the disease. - Hemophilia B is caused by a defect in the clotting factor IX. It is also an X-linked recessive disorder - Another mechanism that may lead to genetic heterogeneity occurs when proteins are composed of many different subunits. Consider the disease thalassemia. - This potentially life-threatening disease involves defects in hemoglobin. Hemoglobin is a tetrameric protein, composed of two α and two β chains 2

3 α-thalassemia: The defect is in the α-globin subunit β-thalassemia: The defect is in the β-globin subunit - Unfortunately, heterogeneity can greatly confound pedigree analysis - Genetic Testing: Genetic testing refers to the use of tests to discover if an individual has a genetic abnormality. Genetic screening refers to population-wide genetic testing (Table 24.4) - In many cases, single-gene mutations that affect proteins, can be examined at the protein level - Biochemical assays may be available for enzymes. - An alternative approach is to detect single-gene mutations at the DNA level. Researchers must have previously identified the mutant gene using molecular techniques e.g., Duchenne muscular dystrophy, Huntington disease. - The most common class of human genetic abnormality is the change in chromosome number. Most of these result in spontaneous abortions. However, about 1 in 200 live births are aneuploid or have unbalanced chromosomal alterations. Chromosomal abnormalities can be detected with a karyotype. (Table 24.4) In the U.S., genetic screening for certain disorders has become common medical practice. - Genetic testing has also been conducted on specific population in which a genetic disease is prevalent, e.g., Tay-Sachs disease in the Aschenazi Jews - - Genetic testing can be performed prior to birth. There are two main types of procedures: 1. Amniocentesis: Fetal cells are obtained from the amniotic fluid. 2. Chorionic villi sampling: Fetal cells are obtained from the chorion (fetal part of the placenta). Can be performed earlier during pregnancy than amniocentesis. However, it poses a slightly greater risk of miscarriage. Genetic testing and screening are medical practices with many social and ethical dimensions. Do people have the right to know about their genetic makeup? Does it do more harm than good? Another issue is privacy. In this century we will become more aware of our genetic makeup and the causes of genetic diseases. It will be necessary therefore, to establish guidelines for the uses of genetic testing. GENETIC BASIS OF CANCER - Cancer is a disease characterized by uncontrolled cell division. It is a genetic disease at the cellular level. More than 100 kinds of human cancers are known. These are classified according to the type of cell that has become cancerous. - Cancer characteristics 1. Most cancers originate in a single cell. In this regard, a cancerous growth can be considered to be clonal. 2. At the cellular and genetic levels, cancer is usually a multistep process. It begins with a precancerous genetic change (i.e., a benign growth). Following additional genetic changes, it progresses to cancerous cell growth. 3

4 3. Once a cellular growth has become malignant, the cells are invasive (i.e., they can invade healthy tissues). They are also metastatic (i.e., they can migrate to other parts of the body) % of cancers are inherited % are not. - A small subset of these is the result of spontaneous mutations and viruses - However, at least 80% of cancers are related to exposure to mutagens. These alter the structure and expression of genes. - An environmental agent that causes cancer is termed a carcinogen - A few viruses are known to cause cancer in plants, animals and humans. Spontaneous mutations can cause cancer, however, most cancers are caused by environmentally induced mutations. These mutations may involve two types of genes: oncogenes and tumor-suppressor genes. An oncogene, which is derived from a normal proto-oncogene, is an abnormally activated gene that stimulates cell growth. By comparison, a tumor-suppressor gene normally inhibits cell growth, but if rendered inactive, unconstrained cell growth may ensue. A master tumor-suppressor gene, called p53, plays a critical role in monitoring DNA damage and preventing the division of cells that have been damaged. Oncogenes and Their Effects on Cell Division: In eukaryotes, the cell cycle is regulated in part by polypeptide hormones known as growth factors. Growth factors bind to cell surface receptors and initiate a cascade of cellular events leading ultimately to cell division. Epidermal growth factor (EGF) is a growth hormone - An oncogene may promote cancer by keeping the cell growth signaling pathway permanently ON. This can occur in two ways: 1. The oncogene may be overexpressed. This yields too much of the encoded protein 2. The oncogene may produce an aberrant protein. Proto-Oncogenes Can Be Converted into Oncogenes: A proto-oncogene is a normal cellular gene that can incur a mutation to become an oncogene. How this occurs is a fundamental issue in cancer biology. By studying proto-oncogenes, researchers have found that this occurs in four main ways: 1. Missense mutations 2. Gene amplifications 3. Chromosomal translocations 4. Viral integration Tumor-Suppressor Genes and Their Effects on Cell Division: Tumor-suppressor genes prevent the proliferation of cancer cells. If they are inactivated by mutation, it becomes more likely that cancer will occur. The first identification of a human tumorsuppressor gene involved studies of retinoblastoma- a tumor of the retina of the eye - There are two types of retinoblastoma: 1. Inherited, which occurs in the first few years of life 2. Noninherited, which occurs later in life - Alfred Knudson proposed a two-hit model for retinoblastoma. 4

5 The p53 Gene: The Master Tumor-Suppressor Gene. 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 three types of cellular pathways to prevent the division of cells with damaged DNA. Other Types of Tumor-Suppressor Genes - During the past three decades, researchers have identified many tumor-suppressor genes. Some encode proteins that have direct effects on the regulation of cell division. Others play a role in the proper maintenance of the genome. Some tumor-suppressor genes encode proteins that function in the sensing of genome integrity. These proteins can detect abnormalities such as DNA breaks and improperly segregated chromosomes. Many of these proteins are called checkpoint proteins. They check the integrity of the genome and prevent cells from progressing past a certain point of the cell cycle if there is damage. Most Cancers Involve Multiple Genetic Changes - Many cancers begin with a benign mutation that, with time and more mutations leads to malignancy. Furthermore, a malignancy can continue to accumulate genetic changes that make it even more difficult to treat. Inherited Forms of Cancers - As mentioned earlier, about 5% to 10% of all cancers involve germ-line mutations. - People who have inherited such mutations have a predisposition to develop cancer - Genetic testing exists for certain types of cancer - Most inherited forms of cancer involve a defect in tumor-suppressor genes - Some inherited forms of cancer are due to the activation of an oncogene. - Other inherited forms of cancer are associated with defect in DNA repair enzymes 5