Molecular Basis of Cancer

Oncogenes & Growth Signals - Go-Go Growth Genes

• Oncogenes: Mutated proto-oncogenes; drive uncontrolled cell growth (gain-of-function). "Accelerator ON".
• Activation:
  • Point mutation: RAS (KRAS, HRAS, NRAS).
  • Amplification: HER2/neu (breast), NMYC (neuroblastoma).
  • Translocation: BCR-ABL (CML), MYC-IgH (Burkitt's).
• Pathway Hijack:

• Key Examples by Class:
  • Receptors: EGFR (lung adeno); HER2/neu (ERBB2) (breast, ovary, gastric ca). 📌 "HER 2 much growth".
  • Transducers: RAS (pancreas, colon, lung); BRAF (melanoma); ABL (CML).
  • Nuclear Factors: MYC (Burkitt's, neuroblastoma); drives growth, angiogenesis.

⭐ RAS mutations (KRAS, HRAS, NRAS) affect ~15-20% of human cancers; a key oncogene family.

Tumor Suppressors & Genome Guardians - Stop Signs & Fix-It Crew

• Function: Genes that normally inhibit cell proliferation or promote DNA repair. Loss of function (LOF) → cancer.
  • Knudson's "two-hit" hypothesis: both alleles inactivated for cancer development.
• Key Examples:
  • RB (Retinoblastoma): "Governor". Controls G1/S checkpoint by binding E2F.
    • Inactive when hyperphosphorylated by CyclinD-CDK4/6.
    • Associated: Retinoblastoma, osteosarcoma.
  • TP53 (p53): "Guardian". Responds to DNA damage.
    • Actions: Cell cycle arrest (via p21), DNA repair, Apoptosis (via BAX).
    • Li-Fraumeni syndrome (germline).

-   **APC**: Degrades β-catenin (WNT pathway). Familial Adenomatous Polyposis (FAP).
-   **BRCA1/BRCA2**: DNA repair (homologous recombination). ↑Breast, ovarian cancer risk.
-   **CDKN2A (p16<sup>INK4a</sup>)**: Inhibits CDK4/6 → keeps RB active.

⭐ TP53 is mutated in >50% of human cancers, leading to genomic instability.

Epigenetics & Non-Coding RNAs - Silent Gene Tweaks

• Epigenetics: Heritable gene expression changes without DNA sequence alteration.
  • DNA Methylation:
    • Promoter hypermethylation → silences Tumor Suppressor Genes (TSGs) (e.g., CDKN2A (p16), MLH1).
    • Global hypomethylation → activates oncogenes.
  • Histone Modification: Acetylation (↑activity), deacetylation (↓activity). Dysregulated 'histone code'.
• Non-Coding RNAs (ncRNAs): Regulatory RNAs; not translated.
  • MicroRNAs (miRNAs): ~22 nt. Post-transcriptional gene silencing.
    • OncomiRs (promote cancer): e.g., miR-21, miR-17-92 cluster.
    • Tumor suppressor miRNAs: e.g., let-7, miR-34a.
  • Long Non-Coding RNAs (lncRNAs): >200 nt. Diverse roles. E.g., HOTAIR, MALAT1.

⭐ Promoter hypermethylation of key tumor suppressor genes (e.g., CDKN2A (p16), MLH1, BRCA1) is a common epigenetic event driving carcinogenesis.

Immortality, Angiogenesis, Metastasis - Advanced Aggression

• Immortality (Limitless Replication):
  • Telomerase (hTERT) activation: prevents telomere shortening.
  • Evasion of apoptosis: e.g., p53 mutations, ↑BCL-2 family proteins.
  • Bypass senescence signals.
• Angiogenesis (New Blood Vessel Formation):
  • "Angiogenic switch": balance shifts to pro-angiogenic factors (VEGF, bFGF).
  • Hypoxia (via HIF-1α) is a potent inducer.
  • Tumor vessels are often abnormal: leaky, tortuous.
• Metastasis (Distant Spread):
  • Sequential steps: local invasion → intravasation → systemic transport → extravasation → colonization.
  • Epithelial-Mesenchymal Transition (EMT): crucial for motility; ↓E-cadherin, ↑N-cadherin, ↑vimentin.
  • Matrix Metalloproteinases (MMPs) degrade ExtraCellular Matrix (ECM).

⭐ The "cadherin switch" (loss of E-cadherin, gain of N-cadherin) is a hallmark of EMT, facilitating tumor cell invasion.

High‑Yield Points - ⚡ Biggest Takeaways

• Proto-oncogenes (e.g., RAS, MYC) and Tumor Suppressor Genes (e.g., TP53, RB) are critical.
• TP53 ("guardian of the genome") is the most commonly mutated gene, vital for apoptosis.
• RB gene controls the G1/S checkpoint; its loss drives proliferation.
• RAS mutations cause constitutive activation of growth signaling pathways.
• BRCA1/BRCA2 defects impair DNA repair, predisposing to breast and ovarian cancers.
• Telomerase reactivation enables cancer cell immortality_._