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!
Have you picked your genetic disorder yet?