1. Cancer as a genetic
chapter 21 pp & lecture notes

2. How cancer genes do alter a cell’s phenotype?
What is cancer?
Epidemiology statistics
Phenotype of the cancer cell
Cancer genes
Tumor suppressor genes
oncogenes
How cancer genes do alter a cell’s phenotype?
Molecular multi-step process and cancer
P53 and Rb genes: specific example

3. Cancer is abnormal cell growth.
TUMORS

4. TUMORS
Malignant
Benign

5. Most cancers fall into one of these groups
Carcinomas
Sarcomas
Leukemias
Lymphomas

7. 2009 Estimated US Cancer Deaths*
Men 292,540
Women 269,800
Lung & bronchus 30%
Prostate 9%
Colon & rectum 9%
Pancreas 6%
Leukemia 4%
Liver & intrahepatic 4% bile duct
Esophagus 4%
Urinary bladder 3%
Non-Hodgkin % lymphoma
Kidney & renal pelvis 3%
All other sites %
26% Lung & bronchus
15% Breast
9% Colon & rectum
6% Pancreas
5% Ovary
4% Non-Hodgkin lymphoma
3% Leukemia
3% Uterine corpus
2% Liver & intrahepatic bile duct
2% Brain/ONS
25% All other sites
Lung cancer is, by far, the most common fatal cancer in men (30%), followed by prostate (9%), and colon & rectum (9%). In women, lung (26%), breast (15%), and colon & rectum (9%) are the leading sites of cancer death.
ONS=Other nervous system.
Source: American Cancer Society, 2009.

8. Characteristics of Cancer
Loss of contact inhibition
Loss of apoptosis
Growth in soft agar
Tumor growth “in vivo”

9. 2 broad groups of cancer causing genes
1. Tumor suppressor genes
2. Oncogenes

10. 1. Tumor Suppressors Normally requires 2 “hits”
Mutations cause loss of function
haploinsufficiency

11. Alfred Knudson: 2 hit model of cancer

12. 1.
Loss of Heterozygosity

13. Examples of tumor suppressors
Retinoblastoma gene (rb)
p53 gene

14. Retinoblastoma: Rb gene and Retinal tumor
P53 gene and breast cancer

15. Example
osteoclasts
neutrophils
P53 and the bax gene

16. Nobel Prize in 2002 for their discovery of apoptosis
Brenner
Horvitz
Sulston

17. 2. Oncogenes ■ Second group of cancer causing genes
■ Mutations cause a gain of activity
■ Requires only one “hit”

18. 2.

19. Where do Oncogenes originate?

20. Hypothesis of origin of oncogenes
Viruses recombine with proto-oncogenes
Michael Bishop and Harold Varmus

21. Oncogene Possible outcomes of recombination Proto-oncogenes virus
Control by viral promoter
mutated in virus
mutated by virus
In host cell DNA

22. Here are some examples of how tumor suppressors and oncogenes stimulate cell growth.

23. 1. Genes controlling the cell cycle
For example: cyclic dependent kinases

24. 2. Genes controlling DNA repair
Colon cancer
For example: HNPCC: colon cancer and DNA repair mutations

25. Breast cancer susceptibility genes (BRCA1 and BRCA2) & DNA repair
Breast Cancer Tumors

26. 3.Genes affecting chromosome segregation
metaphase
apc gene and p53 gene required for proper chromosomal separation

27. 4. GENES that promote vascularization
Van Hippel-Landau disease
▪ Extensive vascularization
▪ Dominant mutation

28. 5. Telomerase may with cancer
Genes that regulate telomerase

29. 6. Genomic Instability
Hypomethylation (?)

30. Hypermethylation
Gene repression

31. Let’s summarize some key points

32. These Cancer Causing Genes may affect
The cell cycle
DNA repair
Chromosome segregation
Changes in chromosome number
Telomerase regulation
Vascularization
Genomic Instability
DNA hypomethylation (?)

33. Cancer : Multi-step process
Normal
Many mutations
Multiple mutations
Gain of function
Loss of function

36. The relationship of p53 and Rb to the cell cycle

37. Cyclins are the control proteins that keep the cell cycle moving.
But how??

38. Cell cycle & cyclins
I get it!
(and late G1)

39. Rb mutations prevent E2F binding
Wt Rb protein are changed by cyclins.
Release of
Rb mutations prevent E2F binding

40. Another look at the cell cycle
Requires E2F
(and late G1)

41. But you said p53 is also involved in the cell cycle
But you said p53 is also involved in the cell cycle. Where is it in the picture?!

42. 1 4 2 3 Under normal (wt) conditions P53 and Rb communicate
p21 inhibits phosphorylation step by
Preventing cyclin/Cdk complex 1 4 2 3