Master Year 3 General Pathology with 30 key short answer questions on oncopathology's Hallmarks 1, 2, & 3. Prepare for exams now!
Comprehensive coverage: Molecular Basis of Cancer, Hallmarks of Cancer, and Carcinogenesis --- SECTION A: NORMAL CELL CYCLE & REGULATION (6 Questions) 1. Explain the role of the Cyclin D-CDK4 complex in regulating the G1/S checkpoint. Answer: - Cyclin D synthesized in mid-G1 phase - Binds to CDK4 forming Cyclin D-CDK4 complex - Complex phosphorylates retinoblastoma (RB) protein - Hypophosphorylated RB normally binds E2F transcription factor (inactive state) - Phosphorylated RB releases E2F - Free E2F activates transcription of genes for S phase (Cyclin E, DNA polymerases) - Acts as molecular "on switch" for cell cycle progression 2. Describe the two main families of CDK inhibitors (CKIs) and their mechanisms. Answer: Cip/Kip family: - Components: p21, p27, p57 - Bind and inactivate Cyclin-CDK complexes - p21 controlled by p53 tumor suppressor - Important for DNA damage response INK4/ARF family: - Encodes p16INK4a and p14ARF - p16INK4a competes with Cyclin D for CDK4 binding - Prevents RB phosphorylation → cell cycle arrest in late G1 - Frequently mutated/hypermethylated in cancers - Act as tumor suppressors 3. What happens at the G1/S and G2/M checkpoints? Answer: G1/S checkpoint: - Checks for DNA damage before S phase - S phase is "point of no return" - If damage detected: repair mechanisms activated and cell cycle arrested - If irreparable: apoptosis triggered - Prevents replication of damaged DNA G2/M checkpoint: - Monitors completion of DNA replication - Ensures cell can safely initiate mitosis - Critical after ionizing radiation exposure - Defects lead to chromosomal abnormalities - Prevents mitosis with incomplete/damaged DNA 4. Explain p53's role as "Guardian of the Genome." Answer: - Central monitor of cellular stress - Activated by: DNA damage, anoxia, inappropriate oncogene signaling - Upon activation (by phosphorylation):Drives transcription of CDKN1A (p21) → blocks RB phosphorylation → G1/S arrest - Allows time for DNA repair - If repair fails: induces cellular senescence or apoptosis - Mutated in ~70% of human tumors (biallelic loss) - One defective allele in Li-Fraumeni Syndrome - Can be inactivated by viral oncoproteins (HPV) 5. Describe how Cyclin B-CDK1 initiates mitosis. Answer: - Cyclin A-CDK2 complex forms at G2/M transition - Regulates events at mitotic prophase - Cyclin B-CDK1 complex subsequently formed - Activated by protein phosphatase - Causes nuclear membrane breakdown - Initiates mitosis proper - Essential for M phase entry 6. What is the significance of E2F transcription factor in cell cycle progression? Answer: - Bound and inactivated by hypophosphorylated RB in G1 - Released when RB is phosphorylated by Cyclin D-CDK4 - Activated E2F increases transcription of:Cyclin E (forms complex with CDK2) - DNA polymerases - Genes essential for S phase progression - Drives DNA synthesis - Also induces Cyclin A transcription for G2/M transition - Master regulator of S phase entry --- SECTION B: ONCOGENES & SELF-SUFFICIENCY IN GROWTH (5 Questions) 7. Differentiate between proto-oncogenes and oncogenes. Answer: Proto-oncogenes: - Normal physiologic regulators of cell proliferation and differentiation - Required for normal growth and development - Tightly regulated - Examples: RAS, MYC, growth factor receptors Oncogenes: - Mutated/altered versions of proto-oncogenes - Promote autonomous cell growth even without normal mitogenic signals - Oncoproteins lack important regulatory elements - Constitutively active - Contribute to cancer development 8. Explain how cancer cells achieve growth factor self-sufficiency. Answer: - Normal cells require external growth factors for proliferation - Cancer cells achieve autonomy through: Autocrine stimulation: Synthesize growth factors they can respond to (have receptors for same) - Mutant receptors: Constitutively dimerized and activated without ligand binding - Deliver continuous mitogenic signals - Independence from external growth signals - Examples: PDGF in gliomas, TGF-α in sarcomas 9. Describe the RAS oncogene and its role in cancer. Answer: - RAS = signal-transducing protein - Located under cell membrane - Normal function: receives signals from growth factor receptors, transmits to nucleus - In cancers:Point mutations prevent GTPase activity - RAS locked in active GTP-bound state - Continuous proliferative signaling - No external growth factor needed - Mutations in RAS family (HRAS, KRAS, NRAS) found in ~30% human cancers - Especially common in pancreatic, colon, lung cancers 10. How does the BCR-ABL fusion protein cause cancer? Answer: - Results from t(9;22) Philadelphia chromosome translocation - Occurs in Chronic Myeloid Leukemia (CML) and some ALL - c-ABL gene (chromosome 9) fused to BCR gene (chromosome 22) - BCR-ABL fusion protein produced - Loss of regulatory region controlling tyrosine kinase activity - Constitutively active tyrosine kinase - Continuous proliferative signaling independent of growth factors - Targeted by imatinib (Gleevec) - tyrosine kinase inhibitor 11. Explain the role of MYC oncogene in human cancers. Answer: - Most commonly involved oncogene in human cancers - Nuclear transcription factor - Normal role: regulates cell growth, proliferation, differentiation - In cancer (when overexpressed/amplified):Potent transcriptional activator - Multiple downstream effects on proliferation - Drives cell cycle progression - Inhibits differentiation - Promotes angiogenesis - Examples: Burkitt lymphoma (MYC translocation), breast cancer (amplification) --- SECTION C: TUMOR SUPPRESSORS & GROWTH INHIBITION (5 Questions) 12. Explain Knudson's "Two-Hit Hypothesis" using retinoblastoma as example. Answer: - Both copies of tumor suppressor gene must be lost for cancer - RB gene at chromosome 13q14 Familial retinoblastoma: - First hit: inherited germline mutation (one defective allele) - Second hit: somatic mutation in retinal cell (loss of normal allele) - Earlier onset, bilateral tumors, multiple lesions Sporadic retinoblastoma: - Both hits: somatic mutations in same retinoblast - Later onset, unilateral, single lesion - Both alleles lost randomly 13. How does RB protein act as "Governor of the Cell Cycle"? Answer: - Controls G1/S checkpoint - Active form: hypophosphorylated RB - Binds E2F transcription factor - Prevents transcription of S phase genes (Cyclin E, DNA replication genes) - Blocks cell cycle progression - When phosphorylated by Cyclin D-CDK4:Releases E2F - Cell cycle proceeds - Loss of RB function: uncontrolled progression through G1/S - Almost all cancers have disabled G1 checkpoint (RB mutation or genes affecting RB) 14. Describe how TGF-β pathway inhibits cell proliferation. Answer: - TGF-β is potent growth inhibitor in normal epithelial, endothelial, hematopoietic cells - Binds to TGF-β receptor complex (types I and II) - Receptor dimerization upon ligand binding - Signaling cascade activated - Results:Transcriptional activation of CDKIs (growth suppression) - Repression of growth-promoting genes (MYC, CDK2, CDK4, Cyclins A and E) - Cell cycle arrest - Mutations in pathway components:100% of pancreatic cancers - 83% of colon cancers - Late-stage tumors: TGF-β paradoxically promotes EMT and metastasis 15. Explain the role of APC gene in colon cancer. Answer: - APC = Adenomatous Polyposis Coli tumor suppressor gene - Normal function: regulates destruction of cytoplasmic β-catenin - With APC loss/mutation:β-catenin not destroyed - Accumulates in cytoplasm - Translocates to nucleus - Acts as growth-promoting transcription factor - Activates proliferative genes Clinical significance: - Familial Adenomatous Polyposis (FAP): germline APC mutation + somatic loss - Hundreds of colonic polyps at young age - Inevitably progresses to colon cancer - ~70% sporadic colon cancers: somatic loss of both APC alleles 16. How do E-cadherin and NF2 maintain contact inhibition? Answer: E-cadherin: - Acts as intercellular "glue" - Maintains cell-cell adhesion - Cytoplasmic portion binds β-cat