Gene Mutations, Oncogenes & Tumour Suppressors

Genes consist of coding (exons) and non-coding (introns) regions.
Following transcription, RNA is spliced to remove introns.
Spliced RNA provides the genetic code for protein translation.
- The process involves transcription of DNA into RNA, followed by splicing to remove introns, and then translation of the spliced mRNA into a polypeptide.

Codons define amino acids.
Each codon, a sequence of three nucleotides, corresponds to a specific amino acid or a stop signal during protein synthesis.
The genetic code includes:
- Amino acids
- Stop codons that signal the termination of translation

Mutagens alter the DNA code at specific sites within the genome.
This alteration can lead to changes in the mRNA sequence and, consequently, in the amino acid sequence of the protein.

Synonymous (silent): No change to the amino acid.
Non-Synonymous: Could be pathogenic as it alters the amino acid, potentially regulating function.
- Missense: Can result in conservative or non-conservative amino acid substitution.
- Nonsense (truncation): Introduces a STOP codon, which alters protein length, often causing damage.
Example: Leucine codons CUU/CUC/CUA/CUG.

Non-Synonymous mutations may alter gene function, resulting in:
- Activating (Pathogenic).
- Inactivating (Pathogenic).
- Neutral (Benign).
- Variant of Unknown Significance (VUS).
Some variants in cancer genes may be "Clinically Actionable," meaning there is evidence that approved drugs may act effectively against the targeted protein; this is referred to as "precision medicine."

Gene amplification (copy number gain).
Gene deletion (copy number loss).
Inversions (reverse orientation in the same chromosome).
Translocations (attaches to a different chromosome).
Highly complex DNA rearrangements (e.g., chromothripsis).
Focal changes copy number variants of limited size (e.g., ERBB2 amplification in breast cancer, EGFR amplification in colon cancer).
Entire chromosomes (aneuploidy) or chromosomal arms.

Proto-oncogenes are required for normal cell function but can cause normal cells to become cancerous when mutated.
Oncogenes are mutated genes that have the potential to cause cancer.
Oncogenes result in a gain of function, often involving enzymes associated with signaling pathways.
Copy number amplification can cause oncogene activation.
Notable oncogenes:
- Ras (KRas, NRas, HRas).
- c-myc.
- ErbB1 (EGFR).
- ErbB2 (Her2).
- Braf
H-Ras oncogene is an example of point mutation activation.

TSGs regulate normal cell growth and division.
Loss of function (LOF) of TSGs removes the ‘gatekeeper’ function, leading to uncontrolled cell division or failure to initiate apoptosis.
TSGs can be considered “anti-oncogenes.”
Mutations in TSGs may lead to cancer.
Both alleles of TSGs must be inactivated for LOF.
Loss of TSGs in cancer occurs more frequently than activation of proto-oncogenes.