1. Molecular Pathology – Cell cycle Dr. Leonard Da Silva Senior Lecturer Molecular & Cellular Pathology

2. Molecular Pathology study and diagnosis of disease  molecules  organs, tissues or fluids anatomic pathology, clinical pathology, molecular biology, biochemistry, proteomics and genetics

3. Tissue sources

4. Time Line 1902 Boveri – abnormal chromosomal segregation 1960’s Philadelphia Chromosome 1970’s – oncogenes – 2 hit hypothesis 1980’s cloning of RB 1990’s BRCA1/2 2000 Human genome

6. Grade, Stage & Prognosis

8. Cancer As A Disease Of Genetic Material  Heritable predisposition - Retinoblastoma  Chromosomal Abnormalities - Burkitt’s  Rare genetic disorders have inability to repair DNA e.g. Xeroderma pigmentosa  Many chemical carcinogens are also mutagens  Transfer of DNA from tumour cells to normal cells leads to transformation

9. Cancer Producing Genes Any mutated gene that contributes to neoplastic transformation Oncogenes Tumour suppressor genes Stability/DNA repair genes

10. Dominant Oncogenes  Identified as transforming genes in viruses  Altered forms of normal cellular genes - Proto-oncogenes  Products of oncogenes involved in: - Cell cycle - Cell division - Differentiation  This maintenance is lost in cancer cells

11. Control of normal cellular Growth & Differentiation mediated by: Intracellular pathways activated Activation / Repression of various genes  Growth Factors  Growth Factor Receptors  Cytokines Dominant Oncogenes

12. Examples of Dominant Oncogenes abl CML translocation bcl2Follicular Lymphoma translocation erbB-2 Breast/ovarian carcinoma amplification c-mycBurkitt’s lymphoma translocation ras Thyroid /Colon carcinoma point mutation ret Thyroid carcinoma Rearrangement

13. Tumour Suppressor Genes  Loss of function  Familial Syndromes - Retinoblastoma - Familial Adenomatous Polyposis

14. a bc d a d a c b c b d Retinoblastoma

15. Examples of Tumour Suppressor Genes APCColon Cancer BRCA1 Breast & Ovarian Cancer BRCA2 Breast Cancer NF1Neurofibromatosis (malignant neurofibromas) TP53Brain, Breast, Colon, Liver, Lung carcinomas RB Retinoblastoma, Sarcomas, Bladder WT1Wilm’s tumour

16. Dominant Oncogenes Tumour Suppressor Genes EnhancedReduced Activating Gain in function Dominant Inactivating Loss of function Recessive

17. DNA REPAIR Homologous recombination (HRR) Non-homologous end joining (NEHJ) Nucleotide excision (NER) Base excision (BER) Mismatch Repair (MMR)

18. Mechanism of Mutations  Point Mutations  Amplification  Translocation / Rearrangements  Deletions  Altered Expression

19. Point Mutation Change in single base-pair e.g. G:C to A:T SHE HAD ONE MAD CAT AND ONE SAD RAT SHE HAD ONE BAD CAT AND ONE SAD RAT

20. 8148 C-myc IgH Translocation

21. Amplification N-Myc Gene in Neuroblastoma CerbB2 gene in Breast Cancer

22. HER2 amplified HER2 non-amplified Acquired from Vysis Educational Slide Set

23. Deletions Tumour suppressor genes e.g. retinoblastoma

24. Which cell does cancer arise in?

25. MULTISTEP MODEL OF CARCINOGENESIS

27. Principles of mammographic screening

28. Cell cycle The cell cycle is an ordered set of events

29. The cell cycle

31. Key regulators Cdk (cyclin dependent kinase, adds phosphate to a protein), along with cyclins, are major control switches

32. Master regulators

35. Checkpoints

36. P53 and cell cycle p53 is a protein that functions to block the cell cycle if the DNA is damaged. If the damage is severe this protein can cause apoptosis (cell death). p53 levels are increased in damaged cells. This allows time to repair DNA by blocking the cell cycle. A p53 mutation is the most frequent mutation leading to cancer  Li Fraumeni syndrome, where a genetic a defect in p53 leads to a high frequency of cancer in affected individuals.

37. HPV pathogenesis

39. cell cycle patient care