Oncogene – Definition, Function and Significance

What is an Oncogene?

An oncogene is a gene that, when mutated or overexpressed, drives uncontrolled cell growth and division, potentially leading to cancer. Oncogenes originate from normal, healthy genes called proto-oncogenes, which play essential roles in regulating cell growth, differentiation, and survival. When a proto-oncogene undergoes a genetic alteration, it can become a permanently active oncogene that continuously sends growth signals to the cell.

Causes and Mechanisms of Activation

Proto-oncogenes can be converted into oncogenes through several molecular mechanisms:

• Point mutation: A single change in the DNA sequence that produces a constitutively active protein, regardless of external signals.
• Gene amplification: Multiple copies of the gene are produced, leading to an excessive amount of the growth-promoting protein.
• Chromosomal translocation: Two chromosomal regions are abnormally joined, creating a fusion gene with altered function. A classic example is the BCR-ABL fusion gene in chronic myeloid leukemia (CML).
• Viral integration: Certain viruses insert their genetic material near or within proto-oncogenes, causing inappropriate activation.

Function and Mechanism of Action

Under normal circumstances, proto-oncogenes encode proteins that tightly regulate cell proliferation, differentiation, and survival. These proteins include:

• Growth factors and their receptors (e.g., HER2/ERBB2)
• Signal transduction proteins such as RAS proteins
• Transcription factors such as MYC
• Cell cycle regulators such as cyclins

When a proto-oncogene mutates into an oncogene, the associated proteins lose their regulatory controls. The result is a persistently active growth signal, causing cells to divide uncontrollably and potentially forming a tumor.

Well-Known Oncogenes and Their Clinical Relevance

Several oncogenes are of major importance in clinical oncology:

• RAS oncogenes (KRAS, NRAS, HRAS): Frequently mutated in colorectal, lung, and pancreatic cancers.
• HER2 (ERBB2): Overexpressed in certain breast and gastric cancers; targeted by therapies such as trastuzumab.
• BCR-ABL: Fusion oncogene in CML; the primary target of imatinib therapy.
• MYC: A transcription factor overexpressed in lymphomas, lung carcinomas, and other cancers.
• BRAF: Commonly mutated in malignant melanoma and thyroid cancer.

Diagnosis and Molecular Testing

Identifying oncogene mutations is a cornerstone of modern cancer diagnostics. Key methods include:

• Next Generation Sequencing (NGS): Comprehensive genomic profiling to detect relevant mutations across the entire tumor genome.
• Fluorescence In Situ Hybridization (FISH): Detection of gene amplifications or translocations at the chromosomal level.
• Immunohistochemistry (IHC): Detection of overexpressed proteins in tumor tissue, such as HER2.
• Liquid biopsy: Analysis of circulating tumor DNA in blood for non-invasive monitoring of disease progression.

Therapeutic Implications

Knowledge of specific oncogene mutations has enabled the development of targeted therapies that selectively block the dysregulated signaling pathways. Unlike conventional chemotherapy, these drugs act on specific mutated proteins while largely sparing healthy tissue. Key examples include:

• Tyrosine kinase inhibitors (e.g., imatinib for BCR-ABL, erlotinib for EGFR mutations)
• Monoclonal antibodies (e.g., trastuzumab for HER2 overexpression, cetuximab for EGFR)
• BRAF and MEK inhibitors (e.g., vemurafenib, trametinib in melanoma)

The field of precision oncology uses the molecular profile of a tumor to select the most effective treatment for each individual patient.

Oncogenes vs. Tumor Suppressor Genes

Oncogenes are often discussed alongside tumor suppressor genes. While oncogenes act like an accelerator pedal by promoting cell growth, tumor suppressor genes such as TP53 and RB1 act as brakes in the cell cycle. Cancer typically arises when both control mechanisms are disrupted: an oncogene is overactive while a tumor suppressor gene is inactivated.

References

1. Hanahan D, Weinberg RA. Hallmarks of Cancer: The Next Generation. Cell. 2011;144(5):646-674. doi:10.1016/j.cell.2011.02.013
2. Weinberg RA. The Biology of Cancer. 2nd ed. Garland Science; 2013.
3. World Health Organization (WHO). Cancer – Key Facts. Available at: https://www.who.int/news-room/fact-sheets/detail/cancer (accessed 2024).