2. Genomic Instability and Cancer
Sept 7, 2017

3. Hallmarks of Cancer, 2011

4. 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.”

5. 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.

6. Increased Probability!!

11. Retinoblastoma

14. Tumor Suppressor Genes

17. 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

18. Rb, a Tumor Suppressor

19. 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

20. 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

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

22. Postreplicative Mismatch Repair (MMR)

23. Mismatch Repair in Eukaryotes

24. Hereditary Non-Polyposis Colorectal Cancer

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

26. Polyp vs. Non-polyp
familial adenomatous polyposis

27. Diagnosis of HNPCC

28. Amsterdam and Bethesda Criteria

30. Microsatellite Instability
DNA Strand Slippage Model

31. Microsatellite Instability

32. Microsatellite Instability

33. 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

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

35. Tumor Suppressors vs Oncogenes