Proto-oncogenes & Oncogenes in Tumorigenesis

Introduction

Cancer is a genetic disease caused by accumulation of mutations affecting cell growth, division, and death.

There are 2 main classes of regulatory genes are involved which prevent these changes that can cause cancer:

1. Proto-oncogenes – These promote normal cell growth.
2. Tumor suppressor genes which inhibit excessive growth.

Mutation or dysregulation of these genes leads to uncontrolled cell proliferation that leads to tumor formation.

Proto-oncogenes regulate cell growth and differentiation.

These gened encode proteins that stimulate cell cycle progression, signal transduction, or growth factors.
These proto-oncogenes are normally tightly regulated.

Function	Example Gene	Protein Product
Growth factors	sis	PDGF (Platelet-derived growth factor)
Growth factor receptors	erbB1, erbB2 (HER2/neu)	Receptor tyrosine kinases
Signal transducers	ras, abl	GTP-binding proteins, tyrosine kinases
Transcription factors	myc, fos, jun	Regulate gene expression
Cell cycle regulators	cyclin D, CDK4	Promote G1 → S phase transition

Oncogenes are mutated or abnormally activated proto-oncogenes that cause uncontrolled cell proliferation, leading to cancer.

Proto-oncogene → (mutation/overexpression) → Oncogene → Uncontrolled cell growth → Tumor formation.

Mechanism	Description	Example
Point mutation	Alters protein function (constitutive activation)	ras in colon, pancreas, thyroid cancers
Gene amplification	Multiple copies → overexpression	HER2/neu in breast carcinoma, myc in neuroblastoma
Chromosomal translocation	Brings gene under control of strong promoter or creates fusion gene	t(8;14) c-myc in Burkitt’s lymphoma; t(9;22) BCR-ABL in CML
Insertional mutagenesis (viral)	Viral genome activates cellular proto-oncogene	HTLV-1 in adult T-cell leukemia

Oncogenes act as dominant mutations that means only one allele needs to be affected to cause the disease.

Oncogenes cause continuous cell signaling for growth even without external stimuli.

This leads to:

Oncogene	Mechanism	Associated Tumor
ras	Point mutation	Colon, lung, pancreatic carcinoma
myc	Translocation	Burkitt’s lymphoma
HER2/neu	Amplification	Breast carcinoma
BCR-ABL	Translocation (Philadelphia chromosome)	Chronic myeloid leukemia
sis	Overproduction of growth factor	Glioma, sarcoma

Tumor markers: Oncogene expression can be used diagnostically or prognostically.
- HER2/neu overexpression → poor prognosis in breast cancer; targeted by Trastuzumab (Herceptin).
- BCR-ABL fusion → diagnostic for CML, targeted by Imatinib (Gleevec).
Molecular therapy: Understanding oncogenes enables development of targeted cancer therapies.

Concept	Proto-oncogene	Oncogene
Function	Normal cell growth & differentiation	Causes uncontrolled growth
State	Normal gene	Mutated or overexpressed form
Type of mutation	Gain of function	Gain of function
Dominance	Dominant at cellular level	Dominant
Example	ras, myc, HER2	BCR-ABL, c-myc