3. Cancer Genetics Is Cancer a Genetic Disease? Cancer is not a classic genetic disease, instead, Genetic background (set-up) has a definite role in cancer progression

4. Cont’D Oncogenes Tumor Suppressor Genes Regulatory Genes Cancer Genetics Abnormalities in at least 3 categories of genes are identified:

5. Abnormal regulation of angiogenesis and Avoidance of host-immune mechanisms Cont’D Cancer Genetics Other Mechanisms for Cancer Progression:

6. Quantitative changes: e.g., Gene amplification and/or overexpression Qualitative changes: e.g., Gene mutations Cont’D Cancer Genetics The genetic abnormalities are:

7. During transition from benign in situ invasive cancer Cancer Progression Basement membrane organization Continuous Vs interrupted Cellular heterogeneity Loss of cell/cell and cell/matrix interactions Neovascularization The angiogenic phenotype Gradual changes in:

8. Oncogenes Growth factors and their receptors Signal transduction molecules Transcription factors Apoptotic regulators Viral Oncogenes: Retroviral transforming genes Cellular Oncogenes: Activated proto-oncogenes Proto-oncogenes: Normal cellular homologues

9. Gene amplification Viral insertion Chromosomal rearrangement Oncogenes: Activation Cont’D Point, Deletion/insertion Mutations: Inappropriate Expression:

10. Overexpressed in breast cancer Oncogenes: RAS Cont’D Prognostic significance Farnesyl transferase inhibitors RAS oncogene: Therapeutic implications:

11. Breast, lung and ovarian cancers Oncogenes: HER-2/NEU Cont’D Chemoresistance Monoclonal antibody therapy Gene therapy Therapeutic potentials: Encodes EGFR Prognostic value Mutated or altered expression:

12. Tumor Suppressor Genes They encode proteins that normally Cause cell-cycle arrest, e.g., pRB Induce apoptosis, e.g., APC Or both e.g., p53 The two-hit model of tumorigenesis: Single mutation usually insufficient Additional mutation (second hit)

13. Inherited Basis of Cancer No direct vertical transmission Some families are genetically prone: Defects in DNA repair genes: XP and HNPCC The p53 mutations: Li-Fraumeni Families: Early-onset leukemias, sarcomas, breast and brain malignancies

14. Risk Factors: Multiple affected relatives, esp., First degree relatives Family history of both breast and ovarian cancers Family history of bilateral breast cancer Early-onset breast cancer Inherited Basis of Cancer: Hereditary Breast Cancer Cont’D Several affected subjects/family by: Statistical chance Environmental effects Incidence: 5-10%

15. BRCA1: Chromosome 17q21 50% of inherited cancer Both breast and ovarian cancers BRCA2: Chromosome 13q12-13 Breast but not ovarian cancers Inherited Basis of Cancer: Hereditary Breast Cancer Cont’D

16. Apoptosis Programmed cell death, cell suicide Morphologial changes: Membrane blebbing, Cytoplasmic & nuclear condensation DNA fragmentation (apoptotic ladder) Apoptotic bodies Nicely-packaged, easily-engulphed cells

17. Pro-survival (anti-apoptotic): e.g., Bcl-2 Pro-apoptotic (agonist): e.g., Bax Apaf-1: Apoptotic protease and activation factor Caspases: Initiator: e.g., Caspase-9 Effector: e.g., Caspase-3 Apoptosis: Regulation

18. Activation of Apaf-1: ATP and cytochrome C Release of mitocondrial Cyt C: By apoptotic/anti-apoptotic mediators Active Apaf-1: binds to and activate caspase-9 Caspase-9: activates caspase-3 Caspase-3: activates other caspases and proteins Morphological changes of apoptosis Apoptosis: Regulation Cont’D

19. Conclusions The identification and better understanding of genes and their encoded-proteins that are involved in carcinogenesis would be useful: Follow-up tools of cancer patients Prognostic markers for cancer progression Target for new therapeutic modalities