AMED3001 Cancer
Gene Mutations, Oncogenes & Tumour-Suppressor Genes
Week 6 is the genetic core of the unit. It works through mutation types (point, frameshift, splicing, structural), then the central dichotomy: proto-oncogenes that become gain-of-function oncogenes with a single hit, versus tumour-suppressor genes that need both alleles inactivated (Knudson's two-hit hypothesis). The guardians p53 and Rb anchor the story. This is dense MCQ and short-answer territory in the mid-semester quiz and the final (50%, confirm on Canvas), and the Module 2 poster assignment (10%) builds on it.
What this chapter covers
- 01Point mutations: synonymous/silent, missense (amino-acid substitution), nonsense (premature stop → truncated protein)
- 02Frameshift indels and splicing mutations (exon skipping, intron retention); variant of unknown significance (VUS)
- 03Structural/copy-number variants: amplification (HER2 in breast, EGFR in colon), deletion, translocation
- 04BCR-ABL1: t(9;22) Philadelphia chromosome → constitutively active tyrosine kinase → inhibited by imatinib
- 05Oncogenes: gain-of-function, a single activating hit; RAS, MYC, EGFR, HER2, BRAF
- 06Tumour-suppressor genes: loss-of-function, both alleles hit; p53, Rb, APC, BRCA1/2
- 07Knudson's two-hit hypothesis; retinoblastoma — bilateral (familial) vs unilateral (sporadic)
- 08p53 the guardian of the genome (mutated in ~50% of cancers); Rb, hypo- vs hyper-phosphorylation and E2F
Oncogene vs tumour-suppressor gene, and the two-hit hypothesis in retinoblastoma
- +1Oncogene: a gain-of-function change in a proto-oncogene; a SINGLE activating hit (point mutation, amplification or translocation) is sufficient because the effect is dominant at the cellular level. Example: KRAS (also MYC, EGFR, HER2, BRAF).
- +1Tumour-suppressor gene: a loss-of-function change; BOTH alleles must be inactivated (the two-hit hypothesis) because one functional copy is usually enough to maintain the restraining function. Example: Rb (also p53, APC, BRCA1/2).
- +1Retinoblastoma is caused by loss of both RB alleles. In FAMILIAL cases the person inherits one defective RB allele in every cell (the first hit is already present), so only one further somatic hit is needed in any retinal cell.
- +1Because that single remaining hit is likely to occur independently in more than one cell and in both eyes, familial retinoblastoma tends to be MULTIFOCAL and BILATERAL, and often presents earlier.
- +1In SPORADIC cases both hits must occur somatically in the SAME cell, which is a rare double event, so disease is usually a single tumour in one eye — UNILATERAL.
Key terms
- Oncogene
- A mutant, gain-of-function version of a proto-oncogene that drives proliferation; a single activating hit (mutation, amplification or translocation) is sufficient. Examples: RAS, MYC, EGFR, HER2, BRAF.
- Tumour-suppressor gene (TSG)
- A gene whose normal product restrains division or triggers repair/apoptosis; cancer requires loss of function, and both alleles must be inactivated. Examples: p53, Rb, APC, BRCA1/2.
- Two-hit hypothesis
- Knudson's model that a tumour-suppressor gene needs both alleles inactivated to lose function; an inherited first hit (familial cases) means only one further somatic hit is required.
- Missense vs nonsense mutation
- A missense mutation substitutes one amino acid; a nonsense mutation introduces a premature stop codon, producing a truncated, usually non-functional protein.
- Translocation (BCR-ABL1)
- A chromosomal rearrangement fusing two genes; the t(9;22) Philadelphia chromosome fuses BCR and ABL1 into a constitutively active tyrosine kinase driving chronic myeloid leukaemia, targeted by imatinib.
- p53
- The ‘guardian of the genome’, a stress-activated transcription factor that halts the cell cycle for repair or triggers apoptosis; it is mutated in about 50% of all cancers, the most frequent of any gene.
Gene Mutations, Oncogenes & Tumour-Suppressor Genes FAQ
How many mutations activate an oncogene versus inactivate a tumour-suppressor gene?
An oncogene needs only a single activating (gain-of-function) hit, because the effect is dominant. A tumour-suppressor gene needs both alleles inactivated (the two-hit hypothesis) before its restraining function is lost. Mixing these up is the most common genetics error in the exam.
Why is p53 so important in cancer?
p53 is the master stress sensor: when DNA is damaged it halts the cell cycle for repair or triggers apoptosis. It is mutated in roughly half of all cancers — the single most frequently mutated gene — so its loss removes a key safeguard, which is why it is heavily examined.
How does the Philadelphia chromosome cause leukaemia?
The t(9;22) translocation fuses BCR and ABL1 to form a constitutively active tyrosine kinase that signals continuously through RAS-MAPK and JAK-STAT, driving chronic myeloid leukaemia. The drug imatinib inhibits that fusion kinase — a classic targeted-therapy example.
Can AI help me keep oncogenes and tumour-suppressors straight?
Yes — Sia can quiz you on which genes are oncogenes versus TSGs, the single-hit-versus-two-hit rule, and the retinoblastoma logic, re-explaining any point a different way. It checks your reasoning; it does not complete your poster or exam.
Exam move
Build one two-column sheet — oncogene versus tumour-suppressor gene — with mutation type, number of hits and examples, and rehearse it until the single-hit/two-hit rule is reflexive, because that dichotomy underlies many MCQs. Learn the mutation types with their functional consequences and the BCR-ABL1/imatinib and retinoblastoma stories as worked examples. This material feeds the Module 2 poster (10%) as well as the exams. Ask Sia to quiz the contrasts and confirm assessment details on Canvas.
Working through Gene Mutations, Oncogenes & Tumour-Suppressor Genes in AMED3001? Sia is AskSia’s AI Biology tutor — ask any AMED3001 Gene Mutations, Oncogenes & Tumour-Suppressor Genes question and get a clear, step-by-step explanation grounded in how AMED3001 is taught and assessed. Read this chapter free, then take your hardest questions to Sia.
