Cancer as a genetic

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

2. 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* Men292,540 Women269,800 Lung & bronchus 30% Prostate 9% Colon & rectum 9% Pancreas 6% Leukemia 4% Liver & intrahepatic 4%bile duct Esophagus 4% Urinary bladder 3% Non-Hodgkin 3% lymphoma Kidney & renal pelvis 3% All other sites 25% • 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 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. Possible outcomes of recombination virus Oncogene • Proto-oncogenes 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 Cancer 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. 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. Where is it in the picture?!

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