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1、16 遗传与肿瘤发生 Cancer Genetics,The ancient Greeks believed that cancer was caused by too much body fluid they called “black bile.“,Doctors in the seventeenth and eighteenth centuries suggested that parasites caused cancer. Today, doctors understand more about the link between cancer and genetics.,Viruse
2、s, ultraviolet (UV) radiation, and chemicals can all damage genes in the human body. If particular genes are affected, a person can develop cancer. Understanding how genes cause cancer, though, first requires a basic understanding of several genetic terms and concepts.,1. General,Cancer is a very co
3、mmon disease, affecting about 1 in 3 individuals, and about half the people that contract cancer will die as a direct result of their disease.,For the most part, cancer arises from a single cell, that is, cancer is a clonal disease. The average human being contains about 1014 cells (i.e., 100,000,00
4、0,000,000 cells), any one of which could, in principle, become a cancer cell, if it acquired the right sort of mutations while it still had the potential to proliferate.,Therefore, the cancer cell arises and progresses once out of a possible 1014 cellular targets. That only happens in 1 in 3 people.
5、 Even then it usually takes 60 or 70 years to occur.,Tumors are hereditary Hereditary retinoblastoma is an autosomal dominant trait in which susceptibility to retinoblastoma is inherited. This is an unusual “dominant“ trait in that a mutation in one RB gene is not sufficient to cause symptoms, but m
6、utations in the second allele often arise during development.,Offspring have a 50% chance of receiving the mutant gene from a heterozygous parent, and 90% of carriers will develop retinoblastoma, usually in both eyes. The hereditary form is also associated with a high risk for other cancers especial
7、ly of the bone and fibrous tissues (osteosarcomas and fibrosarcoma.,Sporadic retinoblastoma is a trait in which the affected individual has not inherited any mutant alleles of the retinoblastoma gene.,The mutations occur after birth and result in tumor formation. Tumors usually develop in only one e
8、ye and patients are not at high risk for other cancers. Both alleles need to be mutated in a single cell, and that is why this form typically occurs only in one eye.,Chromosome and tumors Detailed studies of the Philadelphia chromosome show that most of chromosome 22 has been translocated onto the l
9、ong arm of chromosome 9. In addition, the small distal portion of the short arm of chromosome 9 is translocated to chromosome 22. This translocation, which is found only in tumor cells, indicates that a patient has chronic myelogenous leukemia (CML). In CML, the cells that produce blood cells for th
10、e body (the hematopoietic cells) grow uncontrollably, leading to cancer.,The connection between this chromosomal abnormality and CML was clarified by studying the genes located on the chromosomes at the sites of the translocation breakpoints.,In one of the translocated chromosomes, part of a gene ca
11、lled abl is moved from its normal location on chromosome 9 to a new location on chromosome 22. This breakage and reattachment leads to an altered abl gene. The protein produced from the mutant abl gene functions improperly, leading to CML.,2. oncogene,Oncogenes are mutated forms of genes that cause
12、normal cells to grow out of control and become cancer cells. They are mutations of certain normal genes of the cell called proto-oncogenes.,Proto-oncogenes are the genes that normally control how often a cell divides and the degree to which it differentiates (or specializes). When a proto-oncogene m
13、utates (changes) into an oncogene, it becomes permanently “turned on“ or activated when it is not supposed to be. When this occurs, the cell divides too quickly, which can lead to cancer.,It may be helpful to think of a cell as a car. For it to work properly, there need to be ways to control how fas
14、t it goes. A proto-oncogene normally functions in a way that is similar to a gas pedal - it helps the cell grow and divide. An oncogene could be compared to a gas pedal that is stuck down, which causes the cell to divide out of control.,The pathway for normal cell growth starts with growth factor, w
15、hich locks onto a growth factor receptor. The signal from the receptor is sent through a signal transducer. A transcription factor is produced, which causes the cell to begin dividing. If any abnormality is detected, the cell is made to commit suicide by a programmed cell death regulator.,More than
16、100 oncogenes are now recognized, and undoubtedly more will be discovered in the future. Scientists have divided oncogenes into the 5 different classes.,Growth factors These oncogenes produce factors that stimulate cells to grow. The best known of these is called sis. It leads to the overproduction
17、of a protein called platelet-derived growth factor, which stimulates cells to grow.,Growth factor receptors These are normally turned “on“ or “off“ by growth factors. When they are “on,“ they stimulate the cell to grow. Certain mutations in the genes that produce these cause them to always be “on.“
18、In other cases, the genes are amplified.,This means that instead of the usual 2 copies of the gene, there may be several extras, resulting in too many growth factor receptor molecules. As a result, the cells become overly sensitive to growth-promoting signals.,The best known examples of growth facto
19、r receptor gene amplification are erb B and erb B-2. These are sometimes known as epidermal growth factor receptor and HER2/neu. HER2/neu gene amplification is an important abnormality seen in about one third of breast cancers. Both of these oncogenes are targets of newly developed anti-cancer treat
20、ments.,Signal transducers These are the intermediate pathways between the growth factor receptor and the cell nucleus where the signal is received. Like growth factor receptors, these can be turned on or off. When they are abnormal in cancer cells, they are turned on.,Transcription factors These are
21、 the final molecules in the chain that tell the cell to divide. These molecules act on the DNA and control which genes are active in producing RNA and protein.,The best known of these is called myc. In lung cancer, leukemia, lymphoma, and a number of other cancer types, myc is often overly activated
22、 and stimulates cell division.,Two well known signal transducers are abl and ras. Abl is activated in chronic myelocytic leukemia and is the target of the most successful drug for this disease, imatinib or Gleevec. Abnormalities of ras are found in many cancers.,Programmed cell death regulators Thes
23、e molecules prevent a cell from committing suicide when it becomes abnormal. When these genes are overactive they prevent the cell from going through the suicide process.,This leads to an overgrowth of abnormal cells, which can then become cancerous. The most well described one is called bcl-2. It i
24、s often activated in lymphoma cells.,3. Tumor Suppressor Genes,Tumor suppressor genes are normal genes that slow down cell division, repair DNA mistakes, and tell cells when to die (a process known as apoptosis or programmed cell death).,When tumor suppressor genes do work properly, cells can grow o
25、ut of control, which can lead to cancer. About 30 tumor suppressor genes have been identified, including p53, BRCA1, BRCA2, APC, and RB1. Some of these will be described in more detail later on.,A tumor suppressor gene is like the brake pedal on a car it normally keeps the cell from dividing too qui
26、ckly just as a brake keeps a car from going too fast. When something goes wrong with the gene, such as a mutation, cell division can get out of control.,An important difference between oncogenes and tumor suppressor genes is that oncogenes result from the activation (turning on) of proto-oncogenes,
27、but tumor suppressor genes cause cancer when they are inactivated (turned off).,Another major difference is that while the overwhelming majority of oncogenes develop from mutations in normal genes (proto-oncogenes) during the life of the individual (acquired mutations), abnormalities of tumor suppre
28、ssor genes can be inherited as well as acquired.,Types of Tumor Suppressor Genes Genes that control cell division Genes that repair DNA Cell “suicide“ genes,Genes that control cell division Some tumor suppressor genes help control cell growth and reproduction. The RB1 (retinoblastoma) gene is an exa
29、mple of such a gene. Abnormalities of the RB1 gene can lead to a type of eye cancer (retinoblastoma) in infants, as well as to other cancers.,Genes that repair DNA A second group of tumor suppressor genes is responsible for repairing DNA damage. Every time a cell prepares to divide into 2 new cells,
30、 it must duplicate its DNA.,This process is not perfect, and copying errors sometimes occur. Fortunately, cells have DNA repair genes, which make proteins that proofread DNA. But if the genes responsible for the repair are faulty, then the DNA can develop abnormalities that may lead to cancer.,When
31、DNA repair genes do work, mutations can slip by, allowing oncogenes and abnormal tumor suppressor genes to be produced. The genes responsible for HNPCC (hereditary nonpolyposis colon cancer) are examples of DNA repair gene defects. When these genes do not repair the errors in DNA, HNPCC can result.
32、HNPCC accounts for up to 5% of all colon cancers and some endometrial cancers.,Cell “suicide“ genes If there is too much damage to a cell DNA to be fixed by the DNA repair genes, the p53 tumor suppressor gene is responsible for destroying the cell by a process sometimes described as “cell suicide.“,
33、Other names for this process are programmed cell death or apoptosis. If the p53 gene is not working properly, cells with DNA damage that has not been repaired continue to grow and can eventually become cancerous.,Abnormalities of the p53 gene are sometimes inherited, such as in the Li-Fraumeni syndr
34、ome (LFS). People with LFS have a higher risk for developing a number of cancers, including soft-tissue and bone sarcomas, brain tumors, breast cancer, adrenal gland cancer, and leukemia.,Many sporadic (not inherited) cancers such as lung cancers, colon cancers, breast cancers as well as others ofte
35、n have mutated p53 genes within the tumor.,Inherited Abnormalities of Tumor Suppressor Genes Inherited abnormalities of tumor suppressor genes have been found in several cancers that tend to run in families.,In addition to mutations in p53, RB1, and the genes involved in HNPCC, several other mutatio
36、ns in tumor suppressor genes can be inherited.,A defective APC gene causes familial polyposis, a condition in which people develop hundreds or thousands of colon polyps, some of which may eventually acquire several sporadic mutations and turn into colon cancer.,Abnormalities of the BRCA genes accoun
37、t for 5% to 10% of breast cancers. There are also many other examples of inherited tumor suppressor gene mutations, and more are being discovered each year.,Non-inherited mutations of tumor suppressor genes Mutations of tumor suppressor genes have been found in many cancers,For example, abnormalitie
38、s of the p53 gene have been found in over 50% of human cancers. Acquired mutations (those which happen during a person life) of the p53 gene appear to be involved in a wide range of cancers, including lung, colorectal, and breast cancer, as well as many others.,The p53 gene is believed to be among t
39、he most frequently mutated genes in human cancer. However, acquired changes in many other tumor suppressor genes also contribute to the development of sporadic (not inherited) cancers.,4. Multi-stage Carcinogenesis,Multi-stage carcinogenesis starts with the development of initiated cells after inter
40、actions of acarcinogenic agent with normal (target) cells. The initiated cells have the ability to clonally expand and act as precursors for additional alterations. In different model systems initiated cells have shown some of the following characteristics. 1. Increased proliferative capabilities 2. Resistance to apoptotic stimuli 3. Resistance to other inducers of cell toxicity 4. Increased life-span,