Chapter 5: Precision Oncology: Driver Mutations, Oncogenes & Tumor Suppressors
Chapter 5: Precision Oncology: Driver Mutations, Oncogenes & Tumor Suppressors
Cancer is an evolutionary disease driven by somatic mutations that confer selective growth and survival advantages to neoplastic cells. Precision oncology identifies these specific driver mutations to match cancer patients with targeted kinase inhibitors, antibody-drug conjugates, or immunotherapies.
Oncogenes vs. Tumor Suppressor Genes
- Proto-Oncogenes (Activating Drivers): Require only a single activating hit (dominant). Mutations cluster at specific amino acid hotspots (e.g. KRAS G12D/V, BRAF V600E, PIK3CA H1047R) or cause focal copy-number amplifications (e.g. ERBB2 / HER2 amplification).
- Tumor Suppressor Genes (Loss of Function): Follow Knudson's two-hit hypothesis (recessive). Mutations are distributed across the entire gene body (frameshifts, nonsense mutations, deletions, or epigenetic silencing in TP53, PTEN, RB1, BRCA1/2).
1. The AMP/ASCO/CAP Somatic Variant Tiers
Unlike the ACMG germline 5-tier system, somatic oncology classifies variants based on clinical actionability:
# Somatic Clinical Actionability Tiers (AMP/ASCO/CAP):
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# Tier Clinical Significance Therapeutic Actionability
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# Tier I Strong Clinical Significance FDA-approved therapy (Level A) or
# well-powered professional guideline (Level B)
# Tier II Potential Clinical Significance FDA-approved in another cancer type (Level C)
# or ongoing clinical trials (Level D)
# Tier III Uncertain Clinical Significance (VUS) Unknown functional or clinical impact
# Tier IV Benign or Likely Benign High population frequency; non-actionable
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