Cancer occurs when there is a loss in the control of the cell cycle.

1. Cancer occurs when there is a loss in the control of the cell cycle. There are many controls of the cell cycle. There are many types of cancer.

2. Up to 100 different genes are cancer related genes.

3. These genes are found on all but two (22 and Y) human chromosomes.

4. In 1999, 173,000 cancers were caused by tobacco. 20,000 cancers were caused by excessive alcohol consumption.

5. Cancer cell characteristics uncontrolled proliferation abnormal cell shape ignore normal tissue territory rules increased uptake of sugar increased anaerobic (without oxygen) respiration production of specific antigen (e.g., carcino- embryonic hormone) loss of contact inhibition and colony formation (i.e., cells can lose contact with each other and move elsewhere to start colonies) secrete DNA into the bloodstream

6. Genes Involved in Cancer Oncogenes: Genes associated with the stimulation of cell division. Cancers result from only one mutant allele of gene. Tumor Suppressor Genes: Genes associated with inhibition of cell division. Cancers require both alleles of the gene to be altered.

7. Genes Involved in Cancer DNA Repair Genes Example: ATM ("ataxia telangiectasia mutated") gets its name from a human disease of that name, whose patients - among other things - are at increased risk of cancer. The ATM protein is also involved in detecting DNA damage and interrupting the cell cycle when damage is found.

8. Growth factor G protein Transcription factor Growth factor receptor (tyrosine kinase activity)

9. Detecting Oncogenes in Culture: • Take a tumor cell. Isolate and fragment the DNA, and transfer the DNA into normal cells. • See if you can get transformation. If there is a dominant mutation, it will transform another cell in the culture. • Isolate the new DNA gained from the cancerous cells. • You can distinguish human -vs- mouse DNA by looking at Alu repeats (which are not found in mice). • Only 10-20% of spontaneous human tumors will transform cells in culture. Interestingly, nearly all of these are Ras mutations.

10. FOUR WAYS TO GET CANCER FROM PROTO-ONCOGENES • Virus-Specific Genes • Retroviruses • Mutation • Chromosome Rearrangements

11. How Oncogenes Cause Cancer Example: Deletions of the ligand binding domain of the epidermal growth factor receptor (EFGR) oncogene, located on human chromosome 7, result in continuous signal transduction by the epidermal growth factor receptor it encodes.

12. Transforming Viruses: The virus itself provides the proto-oncogene. The virus uses the host cellular machinery to cause cellular proliferation. • The genes conferring oncogenesis are specific to the viral genome. They are not human and do not resemble human genes. • Adeno Virus = common-cold / flu virus found to cause cancer in mice (but not humans) • These contain the E1A and E1B transcription-factor proteins (BZip Proteins). • E1A gives the host-cell the Immortalizing Function. • E1B gives the host-cell the Transforming Function (for example: confers anchorage-independence).

13. Retroviruses: A proto-oncogene gets captured by a retrovirus and made to be overexpressed. Causes cancer by capturing host-cells containing protooncogenes (inherent to the cell not the virus) and making the host over express them. • Fos protein can be captured by a retrovirus and overexpressed. It was via retroviruses that the fos gene was classified as a protooncogene. Fos was a component of the AP1 (bzip) dimer... a transcription factor. • c-onc = the cellular proto-oncogene. v-onc = the mutated viral oncogene. • In the case of Fos, the sequence homology between the two approaches 99%. But a small mutation renders the gene overexpressed.

14. Mutation: Simple mutation of a proto-oncogene resulting in over expression. • Ras GENES: CANCER CAUSED BY POINT-MUTATIONS. There are three of them. They are all GTPase's, which have signal transduction activity. They hydrolyze GTP ------> GDP and thereby turn off signal transduction. • Mutation in Ras = It loses its GTPase function and hence can't shut off signal transduction. • H-Ras, K-Ras, N-Ras are all mutations of the normal proto-oncogene, c-Ras. There are a wide variety of these mutations. • Most Ras mutations occur at three discrete sites on the c-Ras protein.

15. Gene Amplification The N-Myc gene has been found duplicated up to 1000 times in Retinoblastoma.

16. Chromosomal rearrangements/ Translocations: Chorionic Myelogenous Leukemia. Another method of activating proto-oncogenes. • abl proto-oncogene becomes under control of the bcr locus when it is translocated from #22 to #9. The new regulation causes over expression of abl and hence cancer.

17. How Mutations in DNA Repair Genes can Cause Cancer The BRCA2 gene acts as a "caretaker," that is, it plays an important role in fixing DNA if it is broken -- a process that is constantly occurring as cells divide.

18. How Mutations in DNA Repair Genes can Cause Cancer Another type of DNA repair is a form of nucleotide excision repair known as transcription-coupled repair. Transcription-coupled repair, or TCR, occurs mostly in genes that are actively functioning. Without TCR, a cell has difficulty removing damage. Cells with a damaged TCR system can accumulate other mutations that lead to malignancy.

19. Eleven case examples: Breast Cancer Hereditary Non-polyposis Colerectal Cancer Ataxia Telangiectasia Multiple Endocrine Neoplasias Retinoblastoma Malignant Melanoma Prostate Cancer Familial Colon Cancer Ovarian Cancer Neurofibromatosis Type 1 Li-Fraumeni Syndrome

21. It takes 5-6 mutations in one cell to cause cancer to occur. Those who develop cancer from 30-40 years of age probably inherited a pre-disposition to cancer that allows the cells to develop cancerous conditions with fewer mutations.

22. Benign tumors vs. malignant cancers • Benign tumors are: • usually surrounded by a fibrous capsule • stay in place, can easily be surgically removed • example: warts • Malignant tumors: • cells are less differentiated • have chromosomal abnormalities • are invasive and can spread

23. http://www.ultranet.com/~jkimball/BiologyPages/C/CellCycle.htmlhttp://www.ultranet.com/~jkimball/BiologyPages/C/CellCycle.html

24. http://www.people.virginia.edu/~rjh9u/cdk.html

25. In 1999, the U.S. biotechnology industry employed 153,000 people, up 48.5 percent from 1995, according to Ernst & Young.