ONCOPATHOLOGY - 30 KEY SHORT ANSWER QUESTIONS Hallmarks 1,2 & 3

**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 regulat