Promotion mechanisms of oncogenes and role in carcinogenesis

1. Concepts

• Proto-oncogene — normal gene promoting growth/proliferation.
• Oncogene — mutated/overexpressed proto-oncogene with cancer-causing potential; acts via gain of function and is dominant (one allele suffices).
• A gene has a promoter (control unit) and exons (coding sequence).

2. Activation mechanisms

Mechanism	Effect	Example
Point mutation (coding sequence)	Constitutively active protein, promoter-independent	RAS (MAPK/PI3K); mutant EGFR
Translocation (promoter swap)	Strong promoter drives overexpression	t(14;18) → BCL-2 ↑ (follicular lymphoma); t(8;14) → MYC ↑ (Burkitt)
Translocation (fusion gene)	Hybrid protein with new activity	t(9;22) → BCR-ABL (CML)
Gene amplification	More copies → more protein	HER2/ERBB2 (breast), N-MYC (neuroblastoma)

3. By protein function

• Growth factors / receptors — EGFR/HER2 amplification → ligand-independent signaling; therapy blocks the receptor (antibodies).
• Signal transducers — RAS point mutation → constitutive MAPK/PI3K; ABL in BCR-ABL (CML) → abnormal cytoplasmic tyrosine kinase + impaired apoptosis (activates JAK-STAT, SRC, RAS).
• Transcription factors — MYC (Burkitt t(8;14)) → ↑ cell-cycle entry.
• Cell-cycle regulators — Cyclin D1 (CCND1) via t(11;14) mantle cell lymphoma → pushes G1→S.
• Anti-apoptotic — BCL-2 (t(14;18)) → blocks Bax/Bak → prolonged B-cell survival → lymphadenopathy/marrow infiltration.

💡 High-yield: Proto-oncogene → oncogene by point mutation, translocation (promoter swap or fusion), or amplification (gain of function, dominant). Classics: RAS (point mutation), t(9;22) BCR-ABL (CML), t(8;14) MYC (Burkitt), t(14;18) BCL-2 (follicular), t(11;14) cyclin D1 (mantle), HER2 amplification (breast).