Chapter 18: Genetics of Cancer and Cell-Cycle Regulation

1. Chapter 18: Genetics of CancerandCell-Cycle Regulation

2. What is Cancer? • Large number of complex diseases • Behave differently depending upon cell type from which originate • Age on onset, invasiveness, response to treatment • Common general properties • Abnormal cell growth/division (cell proliferation) • If only this is a benign tumor • When grow in culture without contact inhibition are referred to as transformed • Spread to other regions of body (metastasis) • Malignant tumors

3. Cancer • Second leading cause of disease in Western Countries • 1 million new cases per year in U.S. • 500,000 per year die • War “declared” on cancer approximately 30 years ago • Slowly treatments are changing/improving based upon better genetic understanding of the varieties

4. Cancer Rates in US

6. Age and Cancer • Note log scale for incidence rate

7. Abnormal Cell Growth

8. Cancer is a Genetic Disease • Genome alterations • One nucleotide to large-scale chromosome rearrangements, amplifications and deletions • Mostly in somatic cells (unless associated with inherited risk—about 1% of total) • Alter cellular functions • DNA repair, cell division , apoptosis, cellular differentiation and cell-cell contact/communication

9. Molecular Biology of Neoplasia Retroviral oncogenes: Abl, akt, erbB, ets, fos, kit, myb, myc, raf, ras, rel, src, yes Proto-oncogene: normal gene that can undergo a genetic change to become cancerous. Oncogene: a gene that causes a normal gene to become cancerous. Mutant overactive form of a proto-oncogene. Tumor suppressor gene: a recessive mutation in an inhibitory gene, thus inactivating the gene. Loss of function causes tumorigenesis.

10. Functions of Cancer Causing Genes/Alleles • Many disrupt control of cell cycle • Oncogenes • Proto-oncogenes • Normal genes that if mutated may act to make a cell cancerous • Recessive, cancer causing forms active and stimulates cell division • C-oncogenes and v-oncogenes • Tumor suppressors • Genes whose products act to regulate cell cycle • Loss of gene product function contributes to cancer process • Recessive, commonly involved with inherited risk • About 200 proto-oncogenes and tumor suppressor genes

11. Oncogenes are identified through their dominant transforming effects

12. Changes observed when a normal tissue culture cell is transformed by a tumor virus or an expression vector carrying the oncogene 1. Alterations in the nucleus 2. Plasmamembrane related abnormalities 3. Adherence abnormalities 4. Growth and division abnormalities 5. Defective differentiation 6. Inability to undergo apoptosis following DNA damage

13. Normal and Cancer Karyotypes • Chromosome painting (a) is a normal cell (b) is a “very messed up” cancer cell

14. Clonal Origin of Tumors • Tumor arises from a single cell • Burkitt’s lymphoma • Translocation involving chromosome 8 (myc) and either chromosomes 2, 14, or 22 (near an immunoglobulin gene • All cells from a patient have breakpoints at exactly the same points as shown by DNA sequence analysis • Cancer cells in tumors of females all use same X chromosome (same one in Barr body)

15. Multistep Process • Cancer requires mutation of multiple genes • Age relationship with cancer consistent with this • If one mutation caused cancer then rate would be constant independent of age • It increases dramatically with age… • Delay between carcinogen exposure and onset • 5-8 year delay between carcinogen exposure (Hiroshima and Nagasaki) and onset of leukemia • 15 year delay between tuberculosis X-ray treatment and onset of breast cancer

16. Multistep Process…Continued • Cancers often develop in progressive steps • From mildly aberrant cells to malignant • See figure 18-3 • Process called tumorigenesis

17. Tumorigenesis of Cervical Cancer

18. Properties of Cancer Cells • Genetic instability • Mutator phenotype • Duplicating, losing and translocating chromosomes or portions of them common • Chronic myelogenous leukemia (CML) • Chromosome 9/chromosome 22 translocation • BCR gene fused to ABL (protein kinase) • Mutant signal transduction protein stimulates cells constantly to proliferate

19. Genome Instability • Double minutes (DMs) • Miniature chromosomes giving many copies of rgion • Homogeneous staining regions (HSRs) • Tandem gene duplications

20. Chromosomal Translocation in CML

21. Xeroderma Pigmentosum • Failure to remove pyrimidine dimers from DNA • Excision repair defect • Patients often develop skin cancer and must stay out of sunlight

22. HFNPCC • Hereditary nonpolyposis colorectal cancer • Higher than normal rates of colon (first noted) but also elevated rates of ovary, uterine and kidney cancers • 1/200 persons, autosomal dominant • Eight genes associated and four involve mismatch repair systems

23. HNPCC Pedigree • Colon, Stomach endometiral, pancreatic, bladder • Orange also other cancers, multiple slashes unknown cause of death

24. Role of cell division in tumor progression Tumors arise from cells with DNA damage or mutant DNA that divide uncontrollably. Cancer cells lose normal restraints for replication of damaged DNA and G1/S progression of cells with damaged DNA. Increased probability of tumor progression by further genetic change.

25. Proto-oncogenes can be converted into oncogenes

26. Proteins that control cell growth (proto-oncogenes and cell cycle checkpoints) 1. Growth factors and receptors: (EGF/EGFR, IGF/IGFR, PDGF/PDGFR) 2. Intracellular transducers: GTP binding proteins: Ras Protein kinases: Src, Raf 3. Intracellular receptors: ER, RAR 4. DNA repair proteins: BRCA1 5. Cell cycle control proteins: cyclins, cdkis, Rb, p53 6. Transcription factors: myc, jun. fos, myb 7. Anti apoptotic proteins: Akt, Bcl-2 Proto-oncogene may become converted to an oncogene by a mutation that results in increased intrinsic activity of the protein product

27. Defects in Cell Cycle Regulation • Cell cycle • G1, S, G2, M phases • Progression through cycle is regulated and specific blocks or checkpoints exist • Nondividing cell (quiescent) is in an extended G1 phase called G0 • Cancer cells never enter G0

28. Cell Cycle

30. Cell Cycle Checkpoints • G1/S • Monitors cell size and for DNA damage • G2/M • Replication complete, DNA damage? • M • Spindle fibers connected, etc.? • G0 • Does body require more of my type of cell?

31. Regulators of Cell Cycle • Cyclins and cyclin-dependent kinases (CDKs) • Cyclins synthesized and destroyed in a precise pattern • A cyclin bind to a specific CDKs, activating it • Other proteins phosphorylated/activated • CDK4/cyclinD activate transcription factors for genes such as DNA polymerase delta and DNA ligase • CDK1/cyclinB trigger events of early mitosis (chromosome condensation, nuclear membrane breakdown, etc.)

32. Cell cycle regulatory genes can be oncogenes or tumor suppressors

33. Cyclin dependent kinase regulation

36. Cyclins as oncogenes

37. 2. Oncogenes that encode growth factors or their receptors

38. Tel/PDGFR Oncogene activation Translocation of Tel transcription factor onto PDGF causes dimerization (activation) in the absence of correct ligand. Found in leukemias

39. mutant receptor – always active even without binding ligand • mutant Gsα – always active – always signaling to adenylate cyclase

40. Steroid hormone receptors as oncogenes: ER, AR, myl (RAR) Steroid hormone receptors can act as nuclear transcription factors and activate transcription of other oncogenes such as cyclins, myc, myb

44. Cyclin Levels

45. Activation of CDKs