STEPTRACKERGENERAL PRINCIPLES | PATHOLOGY + GENETICS | HIGH-YIELD REVIEW

Oncogenes

Growth-promoting genes stuck in the "on" position — one mutated allele is enough.

FOCUS ON
Place each gene on the growth-signal chain: factor → receptor → RAS → BRAF → nucleus (MYC) → cyclin D/CDK4. Then learn how it is activated (mutation, amplification, translocation), its tumor, and its targeted drug.
GENE
PROTEIN · ACTIVATION
TUMOR(S)
TARGETED DRUG
ERBB2 (HER2)
receptor tyrosine kinase
Amplification
Breast, gastric carcinoma
Trastuzumab, pertuzumab
EGFR (ERBB1)
receptor tyrosine kinase
Activating mutation
Lung adenocarcinoma (non-smokers, women, Asian)
Erlotinib, osimertinib; cetuximab in colon (if KRAS wild-type)
ALK
receptor tyrosine kinase
Rearrangement (EML4-ALK)
Lung adenocarcinoma (young non-smokers); anaplastic large cell lymphoma
Crizotinib, alectinib
RET
receptor tyrosine kinase
Point mutation (germline) · RET/PTC rearrangement
MEN2A, MEN2B, medullary thyroid · papillary thyroid
Prophylactic thyroidectomy in carriers
KIT (CD117)
receptor tyrosine kinase
Activating mutation
GIST, systemic mastocytosis, seminoma
Imatinib
KRAS / NRAS / HRAS
GTPase
Point mutation → can't hydrolyze GTP → always on
Pancreatic (KRAS ~90%), colorectal, lung adenocarcinoma; most common mutated oncogene
KRAS mutation → anti-EGFR antibodies fail
BRAF
serine/threonine kinase
V600E point mutation
Melanoma, papillary thyroid, hairy cell leukemia, colorectal
Vemurafenib, dabrafenib
ABL (BCR-ABL)
non-receptor tyrosine kinase
t(9;22) Philadelphia chromosome
CML; subset of ALL (worse prognosis)
Imatinib, dasatinib
JAK2
non-receptor tyrosine kinase
V617F point mutation
Polycythemia vera, essential thrombocythemia, myelofibrosis
Ruxolitinib
MYC family
transcription factor
c-MYC: t(8;14) · N-MYC: amplification · L-MYC: amplification
Burkitt lymphoma · neuroblastoma (poor prognosis) · small cell lung cancer
—
CCND1 (cyclin D1)
cell-cycle regulator
t(11;14)
Mantle cell lymphoma
CDK4/6 inhibitors exist (breast)
BCL2
anti-apoptotic
t(14;18) → overexpression
Follicular lymphoma
Venetoclax (BCL-2 inhibitor, CLL)
MDM2 · CDK4
p53/Rb opponents
Amplification
Well-differentiated and dedifferentiated liposarcoma
MDM2 degrades p53

Mechanism — the growth-signal chain

Growth factorPDGF
→
Receptor TKHER2, EGFR, RET, KIT, ALK
→
RAS-GTPKRAS
→
RAF → MEK → ERKBRAF
→
NucleusMYC
→
Cyclin D / CDK4Phosphorylates Rb → S phase

Proto-oncogene → oncogene is a gain of function, so a single mutated allele is enough (dominant at the cell level).

How oncogenes switch on

MECHANISM
EXAMPLES
Point mutation
RAS, BRAF V600E, RET, KIT, JAK2 V617F, EGFR
Amplification
HER2, N-MYC, L-MYC, MDM2
Translocation
BCR-ABL t(9;22), MYC t(8;14), cyclin D1 t(11;14), BCL2 t(14;18), EML4-ALK
Overexpression
PDGF (gliomas), BCL2

How it's tested

COMMON CONFUSIONOncogenes need one hit (gain of function). Tumor suppressors need two hits (loss of function) — page 3.04.
THE TRAPA colon cancer patient with a KRAS mutation won't respond to cetuximab, because RAS signals downstream of EGFR no matter what.
YOUR APPROACHGene → place it on the chain → name the activation route → match the tumor → name the drug.

If you see… think…

t(9;22) in a patient with very high WBC and basophilia → BCR-ABL (CML) — imatinib
HER2-amplified breast cancer → trastuzumab
Lung adenocarcinoma in a young non-smoking woman → EGFR mutation or ALK rearrangement
Spindle-cell gastric tumor, CD117 ⁺ → KIT (GIST) — imatinib
Medullary thyroid carcinoma + pheochromocytoma → RET (MEN2)
Pancreatic adenocarcinoma → KRAS
Neuroblastoma with poor prognosis → N-MYC amplification
"Starry sky" B-cell lymphoma → t(8;14) c-MYC
CD5⁺ lymphoma in an older man → t(11;14) cyclin D1 (mantle cell)
Hairy cell leukemia or melanoma → BRAF V600E
Polycythemia vera → JAK2 V617F