Cancer Genetics: Understanding the Link Between Genetics and Cancer

1. 16 遗传与肿瘤发生Cancer Genetics

2. The ancient Greeks believed that cancer was caused by too much body fluid they called "black bile."

3. Doctors in the seventeenth and eighteenth centuries suggested that parasites caused cancer. Today, doctors understand more about the link between cancer and genetics.

4. Viruses, 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.

5. 1. General Cancer is a very common disease, affecting about 1 in 3 individuals, and about half the people that contract cancer will die as a direct result of their disease.

6. Tumors are hereditary Hereditary retinoblastomais 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 mutations in the second allele often arise during development.

8. The mutations occur after birth and result in tumor formation. Tumors usually develop in only one eye 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.

10. Chromosome and tumors Detailed studies of the Philadelphia chromosome show that most of chromosome 22 has been translocated onto the long 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 the body (the hematopoietic cells) grow uncontrollably, leading to cancer.

13. In one of the translocated chromosomes, part of a gene called 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 ablgene functions improperly, leading to CML.

14. 2. oncogene Oncogenes are mutated forms of genes that cause normal cells to grow out of control and become cancer cells. They are mutations of certain normal genes of the cell called proto-oncogenes.

15. 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 mutates (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.

16. The pathway for normal cell growth starts with growth factor, which 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.

17. myc. In lung cancer, leukemia, lymphoma, and a number of other cancer types, myc is often overly activated and stimulates cell division.

18. abl and ras. Abl is activated in chronic myelocytic leukemia. Abnormalities of ras are found in many cancers.

19. This leads to an overgrowth of abnormal cells, which can then become cancerous. The most well described one is called bcl-2. It is often activated in lymphoma cells.

20. 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).

21. When tumor suppressor genes dowork properly, cells can grow out 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.

22. Types of Tumor Suppressor Genes Genes that control cell division Genes that repair DNA Cell "suicide" genes

23. Genes that control cell division Some tumor suppressor genes help control cell growth and reproduction. The RB1(retinoblastoma) gene is an example 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.

24. 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, it must duplicate its DNA.

25. 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.

26. Cell "suicide" genes If there is too much damage to a cellDNA 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."

27. Many sporadic (not inherited) cancers such as lung cancers, colon cancers, breast cancers as well as others often have mutated p53 genes within the tumor.

28. Inherited Abnormalities of Tumor Suppressor Genes Inherited abnormalities of tumor suppressor genes have been found in several cancers that tend to run in families.

29. In addition to mutations in p53, RB1, and the genes involved in HNPCC, several other mutations in tumor suppressor genes can be inherited.

30. 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.

31. Abnormalities of the BRCA genes account 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.

33. 4. Multi-stage Carcinogenesis Multi-stage carcinogenesis starts with the development of initiated cells after interactions 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