2. Cancer as a genetic chapter 21 pp 627-637 & lecture notes

3.  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

4. Cancer is abnormal cell growth. TUMORS

5. MalignantBenign

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

8. 2009 Estimated US Cancer Deaths* ONS=Other nervous system. Source: American Cancer Society, 2009. Men 292,540 Women 269,800  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 & bronchus30% Prostate9% Colon & rectum 9% Pancreas6% Leukemia4% Liver & intrahepatic4% bile duct Esophagus4% Urinary bladder3% Non-Hodgkin 3% lymphoma Kidney & renal pelvis3% All other sites 25%

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

10. 2 broad groups of cancer causing genes  1. Tumor suppressor genes  2. Oncogenes

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

12. Alfred Knudson: 2 hit model of cancer

13. 1. Loss of Heterozygosity

14. Examples of tumor suppressors  Retinoblastoma gene (rb)  p53 gene

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

16. osteoclastsneutrophils P53 and the bax gene Example

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

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

19. 2.

20. Where do Oncogenes originate?

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

22.  Proto-oncogenes Oncogene virus mutated in virusControl by viral promotermutated by virus In host cell DNA Possible outcomes of recombination

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

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

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

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

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

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

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

30. 6. Genomic Instability Hypomethylation (?)

31. Hypermethylation  Gene repression

32. Let’s summarize some key points

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

34. Cancer : Multi-step process Normal Loss of functionGain of function Cancer Many mutations Multiple mutations

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

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

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

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

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

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

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