BIS104 Note15

BIS104 Note15 - Lecture 15 Bio Sci 104 Human Cancers...

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Lecture 15 1 Bio Sci 104 Winter 2010 Human Cancers (continued) I. How about human cancers? We described convergence of study of retroviral oncogenes and characterization of regulatory processes that control normal cell growth and proliferation. A. However, most human cancers are not caused by viruses. A few exceptions though: 1. H epatitis B infection is associated with increased rates of liver cancer. 2. Some human cancers are even associated with bacterial infections . e.g. chronic Helicobacter pylori infections lead to ulcers ; the chronic inflammation and irritation appears to be associated with elevated levels of stomach cancer . B. Virtually all cancers appear to be due to spontaneous mutations : not an infection, but a genetic change in a normal gene (or genes) leading to loss of growth control. 1. Mutations frequently incurred after birth (i.e. somatic mutation)- limited to cancer cells, with remainder of cells in body having wild-type sequence. Chemicals (natural and man-made: e.g. cigarette smoke, oxygen), radiation (cosmic X-rays), physical insults (asbestos fibers) can lead to alterations in gene sequence. Most mutations either neutral (no phenotypic effects) or are so detrimental to cell that it dies; only rarely does mutation lead to loss of control of proliferation. 2. Notably, however, some families have inherited genetic pre-disposition to cancer (breast cancer, colon cancer, retinoblastomas). Here, a genetic change is passed on in gametes, and all cells contain mutation (although only some cell types may proliferate to cause the cancer). These forms of mutations usually elevate the chances of developing cancer, but typically these cancers do not have a rapid onset. II. What is going on in typical human cancers? A. What is the most likely set of candidates for the somatic mutations involved in clinical cancers? Same set of proto-oncogenes previously discussed ! 1. First proof of this hypothesis demonstrated by use of a powerful approach to identify these mutated, cancer-causing genes: cell transfection. a. Take DNA from human cancers, introduce it into normal cells growing in culture. b. If mutated gene is dominant, would expect some cells in culture to now become cancer-like (can be selected by proper growth conditions). c. First success- obtained DNA from human bladder cancer , could make normal mouse cells become cancer-like. Isolated gene involved, sequenced it c-Ras ! d. The c-Ras from the bladder cancer had a single point mutation, converting Val 61 to Glycine, and therefore lowering GTPase activity leading to hyperactive Ras . e. Just like v-Ras, the mutant c-Ras in bladder cancer was activated as a oncogene because of a genetic change, leading to hyperactivity. Note, however, that in the case of bladder cancer, no virus involved.
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Lecture 15 2 2. This activating mutation could have been either somatic mutation or an inherited predisposition. Therefore researchers isolated and sequenced DNA from other, normal cells in same cancer patient, and from their father and mother- found only wild-type c-Ras;
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BIS104 Note15 - Lecture 15 Bio Sci 104 Human Cancers...

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