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Published byFelicia Marshall Modified over 8 years ago
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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:
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Tumor Suppressor Genes Not enough of a good thing….
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1 / 10 6 1 / 10 6 = 10 12
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Inactivation of a Tumor Suppressor Gene Change the function of a gene product
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Inactivating mutation Point mutation Insertion Deletion Frameshift
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“Second Hit” = 2 nd copy inactivation 1 / 10 6 1 / 10 12
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Loss of Heterozygosity: Heterozygote becomes homozygous by some mechanism Loss of an allele (i.e., hemizygosity)
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“Second Hit” = 2 nd copy inactivation LOH by MITOTIC RECOMBINATION 1 / 10 4 – 1 / 10 5
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“Second Hit” = 2 nd copy inactivation LOH by GENE CONVERSION
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“Second Hit” = 2 nd copy inactivation LOH by NONDISJUNCTION
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hemizygosity “Second Hit” = 2 nd copy inactivation LOH by NONDISJUNCTION
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“Second Hit” not required due to HAPLOINSUFFICIENCY
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Mutation within the coding region “Second Hit” o Mitotic recombination o Gene conversion o Non-disjunction Haploinsufficiency Decrease protein activity by:
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Inactivation of a Tumor Suppressor Gene Change gene Expression
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N C N C N C No TF SP-1 AP-2 Decrease promoter utilization by POINT MUTATION
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Decrease promoter utilization by HYPER-METHYLATION
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NormalAdenocarcinomaAdvanced Colon Carcinoma
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Decrease promoter utilization by HYPERMETHYLATION
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Decrease protein production by: : Mutation within the promoter region “Second Hit” o Mitotic recombination o Gene conversion o Non-disjunction Haploinsufficiency Hypermethylation
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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:
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