Genetic Basis of Cancer

Cancer Genes - The Prime Suspects

• Proto-oncogenes (Accelerators):
  • Promote normal cell growth/division.
  • Mutation (gain-of-function) → Oncogenes (e.g., RAS, MYC, EGFR).
• Tumor Suppressor Genes (TSGs) (Brakes):
  • Inhibit proliferation, induce apoptosis.
  • Mutation (loss-of-function, Knudson's "two-hit" hypothesis).
  • E.g., TP53, RB1, APC, BRCA1/2.
• Apoptosis Regulating Genes:
  • Control programmed cell death.
  • Imbalance (e.g., ↑BCL-2 anti-apoptotic, ↓BAX pro-apoptotic) → uncontrolled cell survival.
• DNA Repair Genes (Caretakers):
  • Maintain genomic integrity.
  • Defects → ↑mutation rates, genomic instability (e.g., MSH2, MLH1, BRCA).

⭐ TP53, "guardian of the genome," is the most commonly mutated gene, found in >50% of sporadic human cancers.

Oncogenes - Pedal to Metal

• Mutated or overexpressed versions of normal proto-oncogenes; they drive uncontrolled cell proliferation via gain-of-function mutations.
• Dominant: one mutated allele sufficient.
• Activation Mechanisms:
  • Point Mutation: RAS (pancreatic, colon, lung Ca).
  • Gene Amplification: N-MYC (neuroblastoma), ERBB2/HER2 (breast Ca).
  • Chromosomal Translocation:
    • BCR-ABL (t(9;22), Philadelphia chr.): CML.
    • MYC (t(8;14)): Burkitt lymphoma.
• Examples & Roles:
  • RAS: GTP-binding protein, signal transduction.
  • MYC: Transcription factor, cell cycle progression.
  • ERBB2 (HER2): Receptor tyrosine kinase.
  • ABL: Non-receptor tyrosine kinase.

⭐ BCR-ABL fusion in CML results in constitutively active tyrosine kinase, a prime target for imatinib.

Tumor Suppressors - Guardians Down!

• Act as cellular "brakes"; normally prevent uncontrolled cell growth.
• Loss-of-function mutations promote cancer.
• Typically require inactivation of both alleles (Knudson's "two-hit" hypothesis).
  • First hit: often germline (inherited).
  • Second hit: somatic (acquired).
• Key Examples & Associations:
  • RB1: Retinoblastoma, osteosarcoma (G1/S checkpoint).
  • TP53: Li-Fraumeni syndrome ("Guardian of the Genome").
  • APC: Familial adenomatous polyposis (FAP), colorectal cancer.
  • BRCA1/BRCA2: Hereditary breast and ovarian cancer.
  • NF1/NF2: Neurofibromatosis 1 & 2.
  • WT1: Wilms tumor.

⭐ TP53 is the most frequently mutated gene in human cancers, implicated in over 50% of sporadic tumors.

System Sabotage - Repair, Death, Epigenetics

• DNA Repair Defects (Genomic Instability):
  • Mismatch Repair (MMR): HNPCC/Lynch (MSH2, MLH1). Microsatellite Instability (MSI).
  • Nucleotide Excision Repair (NER): Xeroderma Pigmentosum (XP). UV sensitivity, skin cancers.
  • Homologous Recombination (HR): BRCA1/2 mutations. Breast, ovarian cancer risk. Fanconi Anemia.
  • ATM gene: Ataxia-Telangiectasia. Defective DNA damage sensing.
• Evasion of Apoptosis (Resisting Cell Death):
  • BCL-2 family: ↑Anti-apoptotic BCL-2 (follicular lymphoma t(14;18)).
  • TP53 mutations: Loss of p53-mediated apoptosis.
  • IAPs: Upregulation blocks caspases.
• Epigenetic Alterations (Gene expression changes without DNA sequence alteration):
  • DNA Methylation: TSG promoter hypermethylation (CDKN2A, MLH1). Global hypomethylation.
  • Histone Modification: Altered acetylation, methylation (EZH2).
  • Non-coding RNAs: Dysregulated miRNAs (oncomiRs) & lncRNAs.

⭐ Follicular Lymphoma's t(14;18) translocation constitutively activates BCL-2 by placing it near the IgH enhancer, promoting cell survival via apoptosis evasion.

High‑Yield Points - ⚡ Biggest Takeaways

• Proto-oncogenes (e.g., RAS, MYC) drive cancer via gain-of-function mutations.
• Tumor suppressor genes (e.g., TP53, RB1) require loss-of-function (Knudson's two-hit hypothesis).
• TP53 is the most commonly mutated gene in human cancers, crucial for cell cycle control.
• Defects in DNA repair genes (e.g., BRCA1/2, MSH/MLH) lead to ↑ genomic instability.
• Epigenetic alterations like hypermethylation can silence tumor suppressor genes.
• Chromosomal translocations (e.g., BCR-ABL in CML) create oncogenic fusion proteins.
• Telomerase reactivation allows limitless replicative potential, a hallmark of cancer.