ug-Molecular Basis of Cancer part 1.pptx

Cancer

1. Molecular Basis of Cancer

2. A neoplasm is a genetic disorder of cell growth, that is trigerred by acquired or less commonly inherited mutations affecting a single gene and its clonal progeny

3. METASTASIS “Spread of a tumor to sites that are physically discontinuous with the primary tumor Pathways of spread of neoplasms?

4. Benign v/s Malignant Characteristics Benign Malignant Differentiation Well-diff. Lack of diff. Anaplasia Absent Present Rate of growth Slow Rapid Capsule Present Absent Mitosis Rare, Numerous, normal abnormal Local invasion Absent Present Metastasis Absent Present

5. Natural History Of Malignant Tumors TRANSFORMATION PROGRESSION LOCAL INVASION DISTANT METASTASIS

6. Natural History Of Malignant Tumors TRANSFORMATION PROGRESSION LOCAL INVASION DISTANT METASTASIS

7. Nonlethal genetic damage lies at the heart of carcinogenesis

8. A tumor is formed by the clonal expansion of a single precursor cell that has incurred genetic damage (i.e., tumors are clonal ). Alterations in DNA are heritable All cells within an individual tumor share the same set of mutations that were present at the moment of transformation DNA sequencing chromosomal analyses

9. Principal targets of cancer causing mutations

10. Proto- oncogenes & Oncogenes A proto- oncogene is a normal gene which promotes normal growth An oncogene is a mutant version of protooncogene An oncogene is dominant over a protooncogene Mutation- gain of function - increase in function of encoded gene product -appearance of completely new function

11. Normal role of Tumor Supressor genes Haploinsufficiency loss of only a single tumor suppressor gene allele reduces the quantity of the encoded protein enough to release the brakes on cell proliferation and survival.

12. Genes that regulate “Apoptosis” Pro- apoptotic genes Bak Bax Bim Anti- apoptotic genes BCL-2 BCL-X Mutations result in less cell death and enhanced survival gain-of-function mutations in anti apoptotic genes loss-of-function mutations in proapoptotic genes

13. Defects in DNA repair genes Loss-of-function mutations With mutation in repair genes errors accumulate in other genes including The cell fails to recognize and repair nonlethal genetic damage in other genes Proto-oncogenes Tumor supressor genes Apoptosis genes

14. Cellular and molecular hallmarks of cancer Self- sufficiency in growth signals - Insensitivity to growth inhibitory signals - Evasion of apoptosis Defects in DNA repair Unlimited replicative potential - Sustained angiogenesis Escape from Immune surveillence Ability to invade and metastasize

15. Carcinogenesis results from the accumulation of complementary mutations in a stepwise fashion over time Driver mutation

16. Driver mutation Passenger mutation Once established, tumors evolve genetically during their outgrowth and progression under the pressure of Darwinian selection (survival of the fittest)

17. Protooncogene & Oncogene Protooncogene is converted to Oncogene Inherited mutations Environmental factors Chemicals, Radiation, Viruses

18. How are RET ABL MYC Conversion of proto- oncogenes to oncogenes

19. Activation of protooncogene to oncogene Point mutation - RET in medullary ca thyroid Gene amplification MYC in Neuroblastoma Translocation ABL in CML

20. What do Protooncogenes & Oncogenes code for?

21. Oncogene products (Oncoproteins) Similar functions Devoid of regulatory elements Endow cells with self sufficiency of growth

22. Growth factors & Oncogenes

23. Oncogenes coding for Growth factors Autocrine stimulation GF GFR

24. Growth factors

25. Growth factor Receptor

26. Growth Factor Receptors

27. Normal ERB B2 Mutant ERB B2 ERB B2 - 50% Ca Breast - 25% Ovarian Ca ERB B1 - >80% Ca Lung - 59% Gliomas Her 2 / Neu

28. Growth factor receptors Oncogene GFR Tumors ERB- B1 ERB- B2 EGF receptor Sq cell ca lung Glioma Ca-Breast, ovary PDGF-R PDGF receptor Gliomas RET Neurotropic factor receptor MEN-2 Medullary ca -thyroid KIT Stem cell receptor GIST ALK Alk receptor Adenoca lung

29. Breast carcinoma HER 2 / Neu

30. Signal Transduction gone wrong?!

31. The RAS Proto- oncogene Point mutation RAS oncogene Single most common mutation of dominant oncogene

32. RAS mutation H- RAS - Ca Colon, Pancreas K- RAS - Ca Bladder N- RAS - Leukemia

33. RAS oncoprotein

34. RAS / RAF / MAPK cascade RAF 1

35. Mutant RAS GTP- ase activity not augmented RAS remains activated in the GTP bound form Continuous activation of MAPK mitogenic pathway Scope for targeted therapy

36. ABL activation in CML

37. Philadelphia chromosome

38. Transcription factors

39. Burkitt Lymphoma

40. t (8:14) in Burkitt lymphoma MYC activation

41. Neuroblastoma

42. PCR- N myc amplification

43. CELL CYCLE REGULATORS

44. Normal cell cycle

45. Normal CELL CYCLE Phases INHIBITORS: Cip/Kip, INK4/ARF Tumor (really growth) suppressor genes: p53

46. Cyclins & CDK ases Over expression of Cyclin D Ca Breast Cyclin D1 gene translocation Mantle cell Lymphoma Cyclin dependent kinase activation-CDK4 activation Glioblastoma,melanoma ,sarcoma