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

3. Cancer is abnormal cell growth. TUMORS

4. MalignantBenign

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

7. Scientists have also defined characteristics of a cancer cell.

8. Normal Fibroblasts Transformed Fibroblasts

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  Mutations cause loss of function  Normally requires 2 “hits”  Haploinsufficiency

12. 1. Loss of Heterozygosity

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

14. Retinoblastoma: Retinal tumor

15. Alfred Knudson: 2 hit model of cancer

16. Breast cancer and p53

17. osteoclastsneutrophils P53 and the bax gene Example

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

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

20. 2.

21. Where do Oncogenes originate?

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

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

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

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

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

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

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

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

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

31. 6. Genomic Instability Hypomethylation (?)

32. Hypermethylation  Gene repression

33. Let’s summarize some key points

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

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

36. Cancer : Multi-step process  Initiation  Clonal expansion  Progression  Expansion

37. Now, Let’s look more closely at 2 cancers & their multi-step progression Colon CancerRetinoblastoma

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

41. Brief overview: The cell cycle

42. Mitosis prophase metaphase anaphase telophase

43. Interphase

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

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

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

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

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

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