Oncogenes: From Proto-oncogenes to Cancer Drivers

Oncogenes: Mutated Drivers of Cancer

Proto-oncogenes are normal genes regulating cell growth, differentiation, and survival. Oncogenes are their mutated/activated versions driving malignant transformation.

Activation Mechanisms

• Point mutation: Constitutive activation (e.g., RAS G12V)
• Gene amplification: Extra copies → overexpression (HER2, MYC)
• Chromosomal translocation: Fusion protein (BCR-ABL, TMPRSS2-ERG)
• Promoter insertion: Viral enhancer drives overexpression
• Overexpression: Loss of regulatory control

Major Oncogene Families

TP53: The Exception

TP53 is a tumor suppressor (not proto-oncogene). Loss-of-function → genomic instability. Mutated in >50% cancers. "Guardian of genome."

Precision Oncology

• Molecular profiling identifies actionable oncogenes
• Targeted therapies improve outcomes in defined subsets
• Resistance mechanisms drive next-gen drug development

Oncogenes are the accelerators; tumor suppressors are the brakes. Cancer needs both.

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Oncogene	Normal Function	Cancers	Therapeutic Target
MYC	Transcription factor; cell cycle, metabolism	Burkitt lymphoma, SCLC, breast, colon	Indirect (BET inhibitors, CDK)
RAS (HRAS, KRAS, NRAS)	GTPase; growth signal transduction	Pancreas (90%), colon, lung, melanoma	KRAS G12C inhibitors (sotorasib)
EGFR / HER2	Receptor tyrosine kinases	Lung (EGFR), breast/gastric (HER2)	TKIs (osimertinib), ADCs (trastuzumab)
PIK3CA	PI3K catalytic subunit	Breast, endometrial, colon	Alpelisib (PI3Kα)
BCR-ABL	Fusion tyrosine kinase	CML, Ph+ ALL	TKIs (imatinib, dasatinib)
ALK	Receptor tyrosine kinase	NSCLC, anaplastic large cell lymphoma	ALK inhibitors (crizotinib, lorlatinib)