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Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display MEDICAL GENETICS AND CANCER
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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 22-2 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display
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INTRODUCTION 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 Cancer Unraveling the complexities of these diseases will be a challenge for some time to come 22-3 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display
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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 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22.1 GENETIC ANALYSIS OF HUMAN DISEASES 22-4
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For traits and diseases, geneticists want to know the relative contributions from genetics and environment Geneticists cannot conduct human crosses to elucidate the genetic basis for diseases Instead, they must rely on analyses of families that already exist Several observations are consistent with the idea that a disease is caused, at least in part, by genes Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Observations of Human Diseases 22-5
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1. When an individual exhibits a disease, the disorder is more likely to occur in blood relatives than in the general population 2. Identical twins share the disease more often than fraternal twins Identical twins are also called monozygotic twins They are formed from the same sperm and egg Fraternal twins are also called dizygotic twins They are formed from separate pairs of sperm and egg Geneticists evaluate the concordance of a disorder, which is the degree to which it is inherited Concordance refers to the percentage of twin pairs in which both twins exhibit the disorder or trait 3. The disease does not spread to individuals sharing similar environmental situations Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-6
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4. Different populations tend to have different frequencies of the disease 5. The disease tends to develop at a characteristic age Many genetic disorders exhibit a specific age of onset 6. The human disorder may resemble a genetic disorder that is already known to have a genetic basis in an animal Refer to Figure 22.1 7. A correlation is observed between a disease and a mutant human gene or a chromosomal alteration If a disease correlates with several of these 7 observations, it is very likely that the disease has a genetic basis Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-7
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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 In this section, we will examine a few large pedigrees that involve diseases inherited in different ways But first, let’s review Figure 2.10 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Pedigree Analysis 22-8
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Figure 2.10 22-9
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Tay-Sachs Disease (TSD) Affected individuals appear healthy at birth, but then develop neurodegenerative symptoms at 4 to 6 months Cerebral degeneration, blindness and loss of motor function TSD patients typically die at 3 or 4 years of age TSD is about 100 times more frequent in Ashkenazi (eastern Europe) Jewish populations than in others TSD is the result of a mutation in the gene that encodes the enzyme hexosaminidase A (Hex A) HexA breaks down a category of lipids called GM2 gangliosides An excessive accumulation of this lipid in cells of the CNS causes the neurodegenerative symptoms TSD is inherited in an autosomal recessive manner Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-10
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Figure 22.2 A family pedigree of Tay-Sachs disease 22-11
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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 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-12
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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 for a normal phenotype Hundreds of genetic diseases are inherited this way In many cases, the mutant genes responsible have been clone and mapped Refer to Table 22.1 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-13
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Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-14
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Huntington Disease (HD) The major symptom of the disease is the degeneration of certain types of neuron in the brain This leads to personality changes, dementia and early death (usually in middle age) HD is the result of a mutation in a gene that encodes a protein termed huntingtin The mutation adds a polyglutamine tract to the protein This causes an aggregation of the protein in neurons HD is inherited in an autosomal dominant manner Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-15
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Figure 22.3 A family pedigree of Huntington disease 22-16
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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 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-17
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Disorders that involve alteration in structural proteins typically have an autosomal dominant mode of inheritance The heterozygote has 50% of the normal protein This is not sufficient for a normal phenotype Numerous genetic diseases are inherited this way In many cases, the mutant genes responsible have been clone and mapped Refer to Table 22.2 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-18
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Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-19
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A third mode of inheritance is X-linked recessive inheritance This type of inheritance poses a special problems for males Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-20 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
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Hemophilia The major symptom of the disease is that the blood cannot clot properly when a wound occurs For hemophiliacs, common accidental injuries pose a threat of severe internal or external bleeding Hemophilia A (also called classical hemophilia) is caused by a defect in an X-linked gene that encodes the clotting factor VIII This disease has also been called the “Royal disease”, because it has affected many members of European royal families Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-21
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Figure 22.4 The inheritance pattern of hemophilia A in the royal families of Europe 22-22
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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 Refer to Table 22.3 for a few examples Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-23
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Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-24
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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 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Many Genetic Disorders are Heterogeneous 22-25
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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 a and two b chains a-thalassemia The defect is in the a-globin subunit b-thalassemia The defect is in the b-globin subunit Unfortunately, heterogeneity can greatly confound pedigree analysis Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-26
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Genetic testing refers to the use of tests to discover if an individual has a genetic abnormality Genetic screening refers to population-wide genetics testing Refer to Table 22.4 for examples of testing methods Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Genetic Testing 22-27
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22-28
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In many cases, single-gene mutations that affect proteins, can be examined at the protein level Biochemical assays may be available for enzymes Consider Tay-Sachs disease (TSD) An enzymatic assays exist to test for the enzyme HexA The artificial substrate 4-methylumbellifreone (MU) is covalently linked to N-acetylglucosamine (GlcNAc) Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-29 MU (fluorescent) MU–GlcNAc (nonfluorescent) + GlcNAc Individuals that are homozygous for the normal allele, produce a high level of fluorescence Those that are affected with TSD produce little fluorescence Heterozygotes produce intermediate levels of fluorescence
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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 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-30
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In the U.S., genetic screening for certain disorders has become common medical practice For example Pregnant women over 35 years of age are screened routinely to see if they are carriers of chromosomal abnormalities Widespread screening for phenylketonuria 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 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-31
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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 Refer to Figure 22.5 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-32
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22-33 Figure 22.5
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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 This may be easier said than done! Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-34
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Prions are proteinaceous infectious particles The term was coined by Stanley Prusiner in 1982 Prusiner was the first to propose that prions act as infectious agents composed entirely of proteins Prions cause several types of neurodegenerative diseases of humans and livestock Refer to Table 22.5 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Prions 22-35
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Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-36
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Prion-related diseases arise from the ability of the prion protein to exist in two conformational states: Normal form, designated PrPC Does not cause disease Abnormal form, designated PrPSc Does cause disease The gene encoding the prion protein is expressed at low levels in certain cell types, such as nerve cells The abnormal protein can come from two sources 1. By “infection” through direct contact or consumption of contaminated meat 2. By “inheritance” Some alleles of the PrP gene cause the spontaneous conversion of PrPC into PrPSc Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-37
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22-38 Figure 22.6 A proposed molecular mechanism of prion diseases
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22-39 Figure 22.6 A proposed molecular mechanism of prion diseases PrPSc proteins are deposited as dense aggregates in the cells of the brain and peripheral nervous tissues PrPSc proteins are also excreted from infected cells and taken up by the bloodstream Thus, a prion disease can spread throughout the body, just like many viral diseases
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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 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22.2 GENETIC BASIS OF CANCER 22-40
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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 Refer to Figure 22.7 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) Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-41
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22-42 Figure 22.7 Progression of cellular growth leading to cancer
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~ 1 million Americans are diagnosed with cancer each year About 500,000 will die from the disease 5-10% of cancers are inherited 90-95% 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 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-43
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A few viruses are known to cause cancer in plants, animals and humans Many of these viruses can also infect lab-grown cells and convert them into malignant cells The process of converting a normal cell into a malignant cell is termed transformation Most cancer-causing viruses are not very potent at inducing cancer In addition, most viruses are inefficient at transforming or are unable to transform normal cells grown in the lab Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-44 Certain Viruses Can Cause Cancer
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A few types of viruses can rapidly induce tumors in animals and efficiently transform cells in culture These are called acutely transforming viruses (ACVs) About 40 ACVs have been isolated The first ACV virus, the Rous sarcoma virus (RSV), was isolated from chicken by Peyton Rous in 1911 During the 1970s, RSV research led to the discovery of oncogenes (genes that promote cancer) Mutant RSV strains did not transform chicken fibroblast cells These RSV strains contained a defective viral gene designated src For sarcoma, the type of cancer it causes The src gene is also designated v–src (for viral src) It is the first example of a viral oncogene Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-45
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The v–src gene is not important for viral replication So researchers wondered why should the virus carry it? Harold Varmus and Michael Bishop discovered that viral oncogenes had a cellular origin! A normal copy of the src gene is found in the host cell’s chromosome It is designated c–src (for cellular src) Once incorporated into the viral genome, c–src can now cause cancer There are two possible explanations 1. Viral replication leads to overexpression of the src gene 2. The v–src gene may accumulate additional mutations that convert it into an oncogene Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-46
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RSV acquires the src gene during its life cycle RSV is a retrovirus It uses reverse transcriptase to make a DNA copy of its RNA genome The DNA becomes integrated as a provirus in the host genome The integration may occur next to a proto-oncogene During transcription of the proviral DNA, the proto-oncogene may be included in the RNA transcript This RNA transcript can then recombine with an RNA retroviral genome within the cell This results in a retrovirus that contains an oncogene Since the early studies on RSV, several cancer-causing viruses have been identified Refer to Table 22.6 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-47
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Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-48
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In 1979, Robert Weinberg and his colleagues wanted to determine if chromosomal DNA from malignant cells can transform normal cells into malignant cells Let’s first consider how malignant cells are identified A widely used assay relies on the differential growth pattern of normal vs. malignant cells Normal cells grow to form a monolayer Malignant cells pile up to form a mass of cells called a focus (Fig. 22.8) At the microscopic level, the malignant cells also have altered shapes Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Experiment 22A: Cellular DNA Can Cause Transformation 22-49
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The Hypothesis Cellular DNA isolated from malignant cells will be taken up by normal cells and transform them into malignant cells Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Testing the Hypothesis Refer to Figure 22.9 22-50
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22-51 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Figure 22.9
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Figure 22.9 22-52 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display
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The Data Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-53 *In this experiment, 2 of the plates were contaminated, so this is 48 foci on 10 plates
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Interpreting the Data Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-54 *In this experiment, 2 of the plates were contaminated, so this is 48 foci on 10 plates DNA isolated from these malignant cells could transform normal mouse cells DNA isolated from normal cells did not cause significant transformation It is not clear why there was no transformation here It could be that some oncogenes act in a dominant fashion, while others act recessively
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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 Figure 22.10 shows its mechanism of action Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-55 Oncogenes and Their Effects on Cell Division
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22-56 Figure 22.10 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Binds to two EGF receptors causing them to dimerize and phosphorylate each other This leads to the activation of an intracellular signaling pathway GTPase Protein kinase Transcription factors are activated This leads to transcription of genes involved in promoting cell division
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22-57
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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 E.g., c-myc gene is amplified about 10-fold in a human promyelocytic leukemia cell 2. The oncogene may produce an aberrant protein E.g., Mutations that alter the amino acid sequence of the Ras protein, keep the cell division signaling pathway turned on Refer to Figure 22.11 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-58
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22-59 Figure 22.11 Functional cycle of the Ras protein Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Mutations that convert normal ras into an oncongenic ras either/or Decrease the GTPase activity of the Ras protein Increase the rate of exchange of bound GDP for GTP This results in greater amounts of the active Ras/GTP complex Signaling pathway stays ON
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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 Refer to Table 22.8 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-60 Proto-Oncogenes Can Be Converted into Oncogenes
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Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-61
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Missense mutations can convert ras genes into oncogenes The human genome contains four different but evolutionary related ras genes rasH, rasN, rasK-4a, and rasK-4b Missense mutants in these genes are associated with certain cancers For example Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-62 Experimentally, chemical carcinogens have been shown to cause these missense mutations and thereby lead to cancer
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Many human cancers are associated with the amplification of particular oncogenes Amplification of N-myc in neuroblastom and erbB-2 in breast carcinoma Specific types of chromosomal translocations have been identified in certain types of tumors In 1960, Peter Nowell discovered that chronic myelogenous leukemia was correlated with the presence of a shortened chromosome 22 He called this the Philadelphia chromosome after the city where it was discovered The cause is not a deletion; Rather a translocation between chromosomes 9 and 22 Refer to Figure 22.12 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-63
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22-64 Figure 22.12 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display A proto-oncogene An oncogene that encodes an abnormal fusion protein
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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 tumor-suppressor gene involved studies of retinoblastoma A tumor of the retina of the eye Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-65 Tumor-Suppressor Genes and Their Effects on Cell Division
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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 Retinoblastoma requires two mutation to occur People with the inherited form have already received one mutation from one of their parents It is not unlikely that a second mutation occurs in one of the retinal cells at an early age, leading to disease People with the noninherited form, must have two mutations in the same retinal cell to cause the disease Two rare events are much less likely to occur than a single event Therefore, the noninherited form occurs much later in life, and only rarely Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-66
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Since Knudson’s original hypothesis in 1971, molecular studies have confirmed the “two-hit” hypothesis The rb gene (for retinoblastoma) is on the long arm of chromosome 13 Most individuals have two normal copies of this gene Persons with hereditary retinoblastoma have inherited one functionally defective copy In nontumorous cells of the body, they have one normal copy and one defective copy of rb In retinal tumor cells, the normal rb gene has also suffered the second hit, rendering it defective More recent studies have revealed how the Rb protein prevents the proliferation of cancer cells Refer to Figure 22.13 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-67
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22-68 Figure 22.13 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Thus, when both copies of the Rb protein are defective, the E2F protein is always active This leads to uncontrolled cell division Transcription factor Genes required for cell cycle progression Rb is phosphorylated by cyclin-dependent kinases when the cell is about to divide
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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 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-69 The p53 Gene: The Master Tumor-Suppressor Gene
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22-70 Figure 22.14 Central role of p53 in preventing the proliferation of cancer cells p53 contains a DNA-binding domain and a transcriptional activation domain It can Induction of the p53 gene leads to the synthesis of the p53 protein, which functions as a transcription factor
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Apoptosis is a process that involves cell shrinkage, chromatin condensation and DNA degradation It is facilitated by proteases known as capsases These are sometimes referred to as the cell’s executioners In apoptosis, the cell is broken down into small vesicles These are eventually phagocytosized by cells of the immune system Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-71
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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 Refer to Table 22.9 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-72 Other Types of Tumor-Suppressor Genes
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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 Cyclins and cyclin-dependent kinases (Cdks) are responsible for advancing a cell in the cell cycle There are several checkpoints in the cell cycle of human cells Figure 22.15 shows three of the major checkpoints Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-74
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22-75 Figure 22.15 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Both the G1 and G2 checkpoints involve proteins that can sense DNA damage If so, these checkpoint proteins can prevent the formation of active cyclin/Cdk complexes The M checkpoint is monitored by proteins that can sense if a chromosome is not correctly attached to the spindle apparatus
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It should also be mentioned that the genes encoding DNA repair enzymes are inactivated in some cancers In these cancers, it is more likely for a cell to accumulate mutations that Create an oncogene Eliminate the function of a tumor-suppressor gene Some geneticists do not consider DNA repair genes as tumor-suppressor genes Because the encoded proteins do not play a role in the regulation of cell division Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-76
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The function of tumor-suppressor genes can be lost in three main ways: 1. A mutation in the tumor-suppressor gene itself The promoter could be wrecked An early stop codon could be introduced in the coding sequence 2. DNA methylation The methylation of CpG islands near the promoters of tumor-suppressor genes, inhibits transcription 3. Aneuploidy Chromosome loss may contribute to the progression of cancer if the lost chromosome carries one or more tumor-suppressor genes Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-77
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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 In 1990, Eric Fearon and Bert Vogelstein proposed a series of genetic changes that leads to colorectal cancer The second most common cancer in the US Refer to Figure 22.16 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-78 Most Cancers Involve Multiple Genetic Changes
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22-79 Figure 22.16 APC is a tumor-suppressor gene
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22-80 Figure 22.16 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display Note that the order of mutations is not absolute It is the total number of genetic changes, not their exact order, that is important
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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 Familial adenomatous polyposis Most inherited forms of cancer involve a defect in tumor-suppressor genes Refer to Table 22.10 Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-81 Inherited Forms of Cancers
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Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-82
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Some inherited forms of cancer are due to the activation of an oncogene E.g., Multiple endocrine neoplasia type 2 Other inherited forms of cancer are associated with defect in DNA repair enzymes E.g., The genes MSH2 and MLH1 are associated with nonpolyposis colorectal cancer Copyright ©The McGraw-Hill Companies, Inc. Permission required for reproduction or display 22-83 Inherited Forms of Cancers