1. Have a positive role in cell division Have a negative role in cell division Have a role in the maintenance of DNA integrity Genes altered in cancer typically:

2. Tumor Suppressor Genes Not enough of a good thing….

4. 1 / 10 6 1 / 10 6 = 10 12

10. Inactivation of a Tumor Suppressor Gene Change the function of a gene product

11. Inactivating mutation Point mutation Insertion Deletion Frameshift

12. “Second Hit” = 2 nd copy inactivation 1 / 10 6 1 / 10 12

13. Loss of Heterozygosity: Heterozygote becomes homozygous by some mechanism Loss of an allele (i.e., hemizygosity)

14. “Second Hit” = 2 nd copy inactivation LOH by MITOTIC RECOMBINATION 1 / 10 4 – 1 / 10 5

15. “Second Hit” = 2 nd copy inactivation LOH by GENE CONVERSION

16. “Second Hit” = 2 nd copy inactivation LOH by NONDISJUNCTION

17. hemizygosity “Second Hit” = 2 nd copy inactivation LOH by NONDISJUNCTION

18. “Second Hit” not required due to HAPLOINSUFFICIENCY

19. Mutation within the coding region “Second Hit” o Mitotic recombination o Gene conversion o Non-disjunction Haploinsufficiency Decrease protein activity by:

20. Inactivation of a Tumor Suppressor Gene Change gene Expression

21. N C N C N C No TF SP-1 AP-2 Decrease promoter utilization by POINT MUTATION

22. Decrease promoter utilization by HYPER-METHYLATION

24. NormalAdenocarcinomaAdvanced Colon Carcinoma

25. Decrease promoter utilization by HYPERMETHYLATION

27. Decrease protein production by: : Mutation within the promoter region “Second Hit” o Mitotic recombination o Gene conversion o Non-disjunction Haploinsufficiency Hypermethylation

32. Have a positive role in cell division Have a negative role in cell division Have a role in the maintenance of DNA integrity Genes altered in cancer typically: