SN2 SHORT NOTE 5M ★ High-yield

Define oncogenes. Describe the mechanisms of their activation with examples.

Pathology · 2nd Professional — Para-Clinical

Definition

Oncogenes are mutated or overexpressed versions of normal proto-oncogenes, which promote autonomous cell growth. Their products are called oncoproteins.

They act in a dominant fashion — mutation of a single allele is sufficient, which is a "gain of function"
Proto-oncogenes are normal, essential genes governing growth and differentiation; the abnormality is in their regulation or activity, not their existence

Mechanisms of Activation

Mechanism	Explanation	Example
Point mutation	Produces a constitutively active protein	RAS — locked in the GTP-bound form because GTPase activity is lost; present in about 30% of human cancers
Translocation	Places the gene under an active promoter, or creates a fusion gene	T(8;14) MYC in burkitt lymphoma; t(9;22) BCR-ABL in chronic myeloid leukaemia
Amplification	Many extra copies, giving gross overexpression	N-MYC in neuroblastoma; HER2/neu in breast carcinoma
Insertional mutagenesis	A retrovirus integrates beside the gene	Chiefly in animal tumours

Classification BY Function

Category	Examples	Tumour
Growth factors	PDGF-B (SIS), FGF	Astrocytoma, osteosarcoma
Growth factor receptors	EGFR, HER2/neu, RET, kit	Lung, breast, men 2, gastrointestinal stromal tumour
Signal transduction proteins	RAS, ABL, BRAF	Colon, pancreas, lung; CML; melanoma
Nuclear transcription factors	MYC, N-MYC, L-MYC	Burkitt lymphoma, neuroblastoma, small cell lung carcinoma
Cell cycle regulators	Cyclin D1, CDK4	Mantle cell lymphoma, melanoma

CLINICAL PEARL

Every step of the growth-signalling pathway can be hijacked, and the classification above simply follows that pathway. From the growth factor itself, to its receptor, to the signal transducer, to the transcription factor in the nucleus, to the cell cycle machinery — a mutation at any point produces the same result: growth without an external signal.

Applied Aspects

BCR-ABL and imatinib — the first and best example of rational targeted therapy; a tyrosine kinase inhibitor designed against a specific fusion protein transformed chronic myeloid leukaemia from a fatal disease into a manageable one
HER2 amplification and trastuzumab — about 20% of breast cancers overexpress HER2 and respond; testing by immunohistochemistry and fish precedes treatment
EGFR mutation and gefitinib or erlotinib in lung adenocarcinoma, particularly in non-smokers and in Asian populations, where the mutation is commoner
KRAS mutation predicts failure of anti-EGFR antibodies in colorectal cancer, since the pathway is activated downstream of the drug target — a negative predictive marker
Resistance develops through further mutation, which is why combination and sequential therapy are used, and why liquid biopsy is valuable for detecting it
BRAF V600E and vemurafenib in melanoma is another example of a single point mutation defining a treatable subgroup
Oncogene addiction — some tumours depend so completely on one activated oncogene that blocking it causes rapid regression; this is what makes targeted therapy possible at all

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