1.7.3 Oncogene Definition

Oncogene Definition is the description of a gene that, as a result of mutation, amplification, chromosomal rearrangement, or epigenetic alteration, drives abnormal, excessive, or unregulated promotion of cell growth, division, or survival, contributing directly to the development of cancer. An oncogene arises from the alteration of a normal cellular gene, referred to as a proto-oncogene, and it is distinguished from its normal counterpart by producing a protein product or an expression level that is no longer subject to the regulatory constraints that govern the corresponding proto-oncogene under ordinary physiological conditions.

Conceptual Basis of the Oncogene

A Gain-of-Function Category of Alteration

An oncogene represents a gain-of-function alteration, meaning that its abnormal activity arises from an increase or dysregulation of a pre-existing cellular function, in contrast to alterations that instead eliminate the function of a gene that would otherwise restrain cell growth.

Origin From a Normal Cellular Gene

An oncogene does not arise as an entirely foreign genetic element but originates from a proto-oncogene already present within the normal genome, meaning that the abnormal protein or abnormal expression pattern associated with an oncogene typically retains substantial similarity to the normal gene product from which it derives, differing specifically in the properties altered by the activating event.

Mechanisms by Which Oncogenes Arise

Mutation of the Coding Sequence

An oncogene can arise through a mutation affecting the coding sequence of a proto-oncogene, producing an altered protein that remains constitutively active or that no longer requires the upstream signal ordinarily needed to trigger its function.

Amplification of Gene Copy Number

An oncogene-like driver effect can arise through amplification of a proto-oncogene, in which additional copies of the gene are generated within the cancer cell genome, resulting in overproduction of an otherwise normal protein and a correspondingly amplified growth-promoting signal.

Chromosomal Rearrangement

An oncogene can arise through a chromosomal rearrangement that repositions a proto-oncogene under the control of a different gene's regulatory elements, or that fuses its coding sequence to that of a separate gene, in either case producing abnormal expression or an abnormally active fusion protein.

Epigenetic Activation

An oncogene-like effect can arise through epigenetic alteration that removes the chromatin marks normally maintaining a proto-oncogene in a silenced or low-expression state, resulting in inappropriate activation of the gene without any change to its underlying sequence.

Functional Behavior of Oncogenes

Dominant Action at the Cellular Level

Because a single altered allele is generally sufficient to produce the abnormal gain-of-function effect characteristic of an oncogene, oncogenes typically behave as dominant alterations, exerting their abnormal effect even in the presence of a remaining normal, unaltered copy of the gene.

Sustained Promotion of Abnormal Cell Growth

The unifying functional consequence of an oncogene, regardless of the specific mechanism by which it arose, is the generation of a signal that promotes cell growth, division, or survival in a manner that is stronger, more persistent, or less dependent on normal regulatory input than the corresponding signal generated by the unaltered proto-oncogene.

Significance of Oncogenes Within Cancer Cell Biology

A Recurrent Driver of Malignant Cellular Behavior

Oncogenes affecting specific, recurrently identified genes are observed across a wide range of independent cancers, indicating that activation of these particular genes confers a substantial and reproducible proliferative advantage to the cells that acquire them, distinguishing such oncogenes from incidental alterations that do not confer a comparable advantage.

A Target for Molecular Characterization

Because an oncogene frequently produces a specific, identifiable abnormal protein product or an abnormally elevated expression level, the identification of oncogenes within a tumor provides a basis for molecular characterization of that tumor and for understanding the specific abnormal signaling pathways driving its growth.