Genomic Instability and Cancer Sept 7, 2017

Hallmarks of Cancer, 2011

Theodor Boveri Two major accomplishments: 1900, Redisocvery of Mendel’s work led Boveri to formulate the chromosomal theory of inheritance. Mendal’s “factors” were hereditary units found on chromosomes Theorized that a tumor could develop from a single cell. He also developed the concept of a “Two-hit hypothesis.”

Autosomal recessive disorders Phenotype Normal Diseased Genotype Heterozygote Homozygote Unknown The affected phenotype of an autosomal recessive disorder is inherited as a recessive allele; hence, the corresponding unaffected phenotype must be inherited as the corresponding dominant allele. For example, the human disease phenylketonuria (PKU), discussed earlier, is inherited in a simple Mendelian manner as a recessive phenotype, with PKU determined by the allele p and the normal condition determined by P.

Increased Probability!!

Retinoblastoma

Tumor Suppressor Genes

Rb, a Tumor Suppressor -Rb functions in the G1 Checkpoint -If both copies are lost then growth is unregulated and can transition into S phase

Rb, a Tumor Suppressor

Control of Mutation Rates Important concepts: Errors in DNA Replication Correction of Replication Errors (Proofreading) Exposure to External chemicals and Normal Metabolism DNA Repair Mechanisms

Mechanisms of Genomic Stability and Instability Fidelity of DNA Replication Postreplicative Mismatch Repair Prevention of Oxidative DNA Damage Repair of DNA Damage Cell Cycle Checkpoints Maintenance of Chromosome Ploidy Inherited Human Chromosome Instability Syndromes Recombination Epigenetic DNA Modification

Results of Genomic Instability BRCA 1 and 2 are breast cancer associated genes

Postreplicative Mismatch Repair (MMR)

Mismatch Repair in Eukaryotes

Hereditary Non-Polyposis Colorectal Cancer

HNPCC is the result of Genomic Instability caused by a second mutation in a Tumor Suppressor Gene

Polyp vs. Non-polyp familial adenomatous polyposis

Diagnosis of HNPCC

Amsterdam and Bethesda Criteria

Microsatellite Instability DNA Strand Slippage Model

Microsatellite Instability

Microsatellite Instability

Cases of HNPCC have been identified with no detectable mutations. Increased methylation in the promoter region of genes were detected, resulting in epigenetic silencing of the gene

Oncogene A gene when mutated results in higher levels of its protein product or its protein is more active resulting in tumor formation

Tumor Suppressors vs Oncogenes