VALIDATION CRITERIA Decision What are the critical criteria

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VALIDATION CRITERIA Decision: What are the critical criteria and how many have to be

VALIDATION CRITERIA Decision: What are the critical criteria and how many have to be satisfied to be considered a valid model?

PREDISPOSITION 1. Cancer predisposition models: Genetic modification must involve the same gene modified in

PREDISPOSITION 1. Cancer predisposition models: Genetic modification must involve the same gene modified in humans 2. Total knock-out or mutations similar to those in humans must be mimicked

INITIATION AND PROGRESSION • Initiation models might involve genes specific for a tumor type

INITIATION AND PROGRESSION • Initiation models might involve genes specific for a tumor type (e. g. Apc) • Progression models might involve genes that are generic to many tumor types (e. g. Ras)

TISSUE SPECIFIC MODIFICATION • Tissue specific KO to mimic sporadic tumors must also involve

TISSUE SPECIFIC MODIFICATION • Tissue specific KO to mimic sporadic tumors must also involve genes modified in human tumors • It is desirable to have only a few cells carry the modification

COMBINATIONS In combinations of genetic changes all genes must be those found to be

COMBINATIONS In combinations of genetic changes all genes must be those found to be modified in human tumors

LARGE SCALE MODIFICATIONS Large scale modifications (LOH or Amplification) similar to those found in

LARGE SCALE MODIFICATIONS Large scale modifications (LOH or Amplification) similar to those found in human tumors should be mimicked

TUMOR INCIDENCE AND MOLECULAR PATHOLOGY • Timing of tumors must be comparable to that

TUMOR INCIDENCE AND MOLECULAR PATHOLOGY • Timing of tumors must be comparable to that seen in patients • Incidence/Penetrance must be comparable to that seen in humans • Nature of progression must be similar to that in humans • Molecular pathology (e. g. karyotype and expression profiles) must be similar to human tumors

ADDITIONAL EFFORTS REQUIRED • Large scale modification models need to be contemplated • Utilize

ADDITIONAL EFFORTS REQUIRED • Large scale modification models need to be contemplated • Utilize BAC or Chromosome specific gene arrays to identify LOH and amplification • Standard mouse and human gene arrays with homologous genes at comparable positions • Standard methods for comparing array results • Set of genes for Taqman assay

Genetic criteria for validation • Genes mutated in humans • Null or point mutation

Genetic criteria for validation • Genes mutated in humans • Null or point mutation similar to those in humans • Combinations must mimic those in human tumors • In tissue specific modifications only a few cells will be modified to mimic sporadic cases • Timing, penetrance and progression must be comparable to human tumors • Equivalent molecular pathology (genomic changes and expression profiles)

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