Cancer

1. Cancer

2. Learning Objectives By the end of this class you should understand: • The steps required for a cell to become cancerous • The link between genes, mutation and cancer • The models of retinoblastoma, breast cancer, and colon cancer • Translocation events that create a risk for cancer • Treatments for cancer including new ones currently under study

3. What is Cancer? • Cancer is the result of a single cell that is undesirably and constantly reproducing • Any cell in the body can become cancerous • But some are more likely candidates than others!

4. Cell Replication • There are molecular mechanisms (checkpoints) that prevent a cell from constantly undergoing mitosis • Occur at G1/S and G2/M • Cells also cannot replicate without an external signal

5. Cancer Checklist • To become cancerous, a cell must: • Have its control genes fail via mutation (fresh or inherited) • Have its go-ahead signal stuck in the “on” position • Develop expression of telomerase if it was not already a stem cell

6. This is a long list! • Typically, to facilitate the checklist being met, cancer cells also have a failure of mutation repair • This begins to prompt many, many mutations

7. Types of Cancer • A cell that has begun to undergo mitosis until it has exhausted all its blood supply forms a tumor • A lump, sometimes hard, sometimes just an outgrowth of flesh • If no further mutation takes place, it is typically benign (not harmful)

8. Dangerous Cancer • For cancer to become malignant, two additional steps must be met: • Angiogenesis (ability to create new blood vessels to feed the tumor) • Metastasis (ability to spread through tissues and blood)

9. Cancer Genes • Cancer genes fall into two major categories: • Tumor-suppressor genes normally block mitosis and must be knocked out for cancer to occur • Proto-oncogenes normally pass on signals to grow, and must be stuck in the “on” mode

10. Tumor-Suppressor Genes • p53 is the classic tumor-suppressor gene • Produces a protein that blocks mitosis when DNA is damaged • Protein also induces apoptosis (cell suicide) if genome is irretrievable • p53 knockouts are nearly universal in cancer

11. Tumor-Suppressor Gene • RB1 is another tumor-suppressor gene found in many cells • Produces a protein called pRB that blocks cell cycle • RB1 failure is linked to retinoblastoma and other cancers

12. Proto-Oncogenes • ras is the classic proto-oncogene • Codes for a protein that passes a growth factor signal to the nucleus • If mutates in amino acid 12 or 61, fails to switch off and cell is permanently stimulated

13. ras Mutations

14. Cancer Categories • There are hundreds of kinds of cancer, but some are clearly more common than others • Epithelial cancers are most common for two reasons: • Epithelial tissue is exposed to the outside more • Epithelial stem cells are very common (e.g. skin)

15. Model Cancers • Model cancers are especially well-studied for their genetics • Often studied due to being relatively common • Models discussed here: • Retinoblastoma • Breast Cancer • Colon Cancer • Leukemia (CML)

16. Retinoblastoma • Familial retinoblastoma is caused by having a bad RB1 gene • Typically individuals are heterozygous • If the “good” allele is deactivated by any mutation, this loss of heterozygosity results in cancer in affected organ

17. Breast Cancer • Breast cancer is very common, so a major study searched for commonly mutated genes in all breast cancer cells • BReast CAncer genes BRCA1 and BRCA2 were isolated • These were patended by Myriad, patent recently overturned

18. BRCA1 and BRCA2 • The BRCA genes are for DNA repair • BRCA1 activates when a break in DNA is discovered • Inactivated BRCA1 protein cannot bind to Rap80 and fix the DNA • Loss of heterozygosity occurs in up to 85% of women with one mutant allele, resulting in most of the heritable breast cancer cases • Still only about 20% of all breast cancer cases

19. Colon Cancer • Two major pathways for colon cancer: • Familial adenomatous polyposis (chromosomal instability) or FAP • Hereditary nonpolyposis colon cancer (failure to repair DNA) or HNPCC

20. FAP Colon Cancer • In FAP, polyps forms much more than usual, increasing mitosis and risk of cancer • Identifying FAP genes helped overall understanding of cancer

21. Sequential Gene Failure

22. HNP Colon Cancer • HNPCC is caused by failed DNA repair enzymes that work during mitosis • Even without polyps, mutation rate in colon is increased and cancer risk increases

23. Leukemia • Chronic Myelogenous Leukemia is often caused by a particular translocation • Chromosomes 9q and 22q • The “Philadelphia Chromosome” • The exact point of translocation creates a hybrid gene • Combination of C-ABL and BCR genes

24. Philadelphia Chromosome

25. Hybrid Gene • The C-ABL gene and the BCR gene produce a single protein that contains properties of both • C-ABL is for signal transduction • BCR activates and deactivates proteins • The hybrid protein signals white blood cells to constantly multiply

26. Cancer Treatments • Two standard treatments today are radiation therapy and chemotherapy • Both work by poisoning cells during mitosis • Since cancer cells are constantly undergoing mitosis they are affected the most • This is why you also lose your hair

27. Targeted Therapy • A new model of cancer treatment is to determine what protein in the cancer is constantly signaling mitosis and block it • The C-ABL/BCR hybrid can be deactivated by a special messenger molecule

28. Targeted Therapy • Works better in earlier stages • Many late-stage cancer cells have so many mutations they will not respond to targeted therapy • Provides promising less-destructive ways to cure cancer in the future

29. Have you picked your genetic disorder yet? Have a good weekend!