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:

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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:

Tumor Suppressor Genes Not enough of a good thing….

1 / / 10 6 = 10 12

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

Inactivating mutation Point mutation Insertion Deletion Frameshift

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

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

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

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

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

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

“Second Hit” not required due to HAPLOINSUFFICIENCY

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

Inactivation of a Tumor Suppressor Gene Change gene Expression

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

Decrease promoter utilization by HYPER-METHYLATION

NormalAdenocarcinomaAdvanced Colon Carcinoma

Decrease promoter utilization by HYPERMETHYLATION

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

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: