Oncogenes and Cancer Development

Oncogenes

• Oncogenes are mutated or overexpressed versions of normal cellular genes, also known as proto-oncogenes.
• Proto-oncogenes regulate essential cellular processes, such as growth, proliferation, and survival.
• Under normal conditions, proto-oncogenes help control cell division and differentiation.
• Oncogenes drive continuous cell growth and division, overriding normal regulatory mechanisms.
• Activation of oncogenes is a crucial step in cancer development.
• Oncogenes can be activated through various processes, including point mutations (a single DNA change), gene amplification (increasing gene copies), and chromosomal translocations (rearranging DNA).
• Oncogenes such as RAS, MYC, and HER2/neu play roles in cell growth and regulation.
• Growth factors, acting as oncogenes, result from abnormal expression, self-stimulating growth factor production, ultimately causing abnormal cell proliferation in tumor development.
• Growth factor receptors, encoded by oncogenes, such as protein tyrosine kinases, can be altered activating oncogene proteins.
• Some examples include the PDGF receptor activation by chromosome translocations featuring transcription factor sequences.
• Additional oncogenes such as erbB-2 and others encode non-receptor protein-tyrosine kinases activated by mutations or deletions of regulatory sequences.
• Ras proteins play a key role in mitogenic signaling by coupling growth factor receptors to Raf protein kinase, which activates ERK MAP kinase.
• Raf genes, similarly, can be converted to oncogenes by deletions affecting their regulatory domains, leading to unregulated protein kinase and MAP kinase activation.
• Transcription factors like Fos and Jun, components of the AP-1 transcription factor, respond to growth factor-induced transcription in stimulated cells.
• Myc transcription factors are regulated by mitogenic stimuli and their abnormal expression can contribute to tumor development.
• Oncogenes, activated through various chromosome translocations, are involved in leukemias and lymphomas.

Mechanisms of Oncogene Activation

• Oncogene activation is facilitated by genetic changes to proto-oncogenes leading to growth advantage for the cell.
• Three primary mechanisms are responsible: mutations, gene amplification, and chromosome rearrangements.
• These mechanisms either alter proto-oncogene structure or increase expression, contributing to tumor development.
• Typically, multiple cancer-associated gene alterations are involved in full expression of a tumor's phenotype including its capacity for metastasis. Proto-oncogene activation and tumor suppressor gene loss or inactivation are often involved.

Types of Oncogene Mutations

• Mutations can affect critical protein regulatory regions, often causing uncontrolled activity of the mutated protein.
• Mutations can include base substitutions, deletions, and insertions.
• Retroviral oncogenes frequently exhibit deletions contributing to activation.
• Examples of mutation effects include alterations in the amino-terminal ligand-binding domains of oncogenes like erbB, kit, ros, met, and trk.
• Most characterized oncogene mutations, commonly referred to as point mutations, involve single amino acid changes within the protein.

Gene Amplification

• Gene amplification represents an increase in the copy number of a gene within a cell's genome.
• This mechanism is a crucial factor for tumor cells to develop resistance to anti-tumor drugs.
• The process involves repetitive replication of genomic DNA generating karyotypic abnormalities like double-minute chromosomes (DMs) and homogeneous staining regions (HSRs).
• Large regions of amplified genomic DNA, often encompassing numerous copies of a gene, are associated with increased gene expression, conferring a selective advantage for cell growth.

Significance in Cancer Development

• Oncogenes are central to cancer development and progression.
• They promote tumor formation by increasing cell division.
• Oncogenes affect cell adhesion and movement, facilitating metastasis.
• Activation of oncogenes triggers blood vessel formation (angiogenesis) supporting tumor sustenance and nutrient/oxygen supply.
• Some oncogenes induce genomic instability, increasing mutation probability, further fueling genetic chaos within cancer cells.
• Tumor clonality, a key feature of cancer, involves the proliferation of a single cell's aberrant growth. X-chromosome inactivation is involved in tumor clonality studies.
• During embryonic development, one X chromosome within female cells is inactivated by being converted to heterochromatin. This process can influence the expression of specific genes on that chromosome in distinct cells, hence explaining the use of X-chromosome inactivation analysis.

Clinical Implications

• Oncogene studies have significantly advanced cancer diagnosis and treatment strategies.
• Diagnostic markers, like HER2, are used to diagnose cancer types and predict prognosis.
• Understanding oncogenes facilitates the development of targeted therapies.
• Drugs like trastuzumab target specific oncogenes such as HER2 in breast cancer, while imatinib targets the BCR-ABL fusion protein in chronic myeloid leukemia.
• Despite advancements, cancers can develop resistance to these treatments, emphasizing the need for combination therapies and further research.