the molecular basis of cancer Flashcards
mutations caused by carcinogens
‘driver mutations’- mutations that affect function of genes that regulate proliferation, apoptosis, immortality etc.
all other mutations that are not relevant to the promotion of cancer are ‘passenger’ mutations
gain-of-function mutations
- overexpression: amplification/ changes to regulatory regions
- point mutations
- fusions
loss-of-function mutations
- point mutations
- deletion- with frameshift
- loss of allele
how to identify key cancer genes
- cellular and biochemical studies of normal cells and tumours.
- find genes commonly damaged in cancers
- best approach is whole-genome analysis
identification of the gene for retinoblastoma
- retinoblastoma is a rare childhood tumour
- tumour arises in precursors of photoreceptor cells
- treated by radiotherapy or surgery
- familial cases are bilateral
- sporadic cases are unilateral
- familial is associated with other tumours (mostly osteosarcomas)
two-hit hypothesis for retinoblastoma
Knudson (1970s) proposed “2-hit hypothesis” based on tumour-formation timescales:
- Familial: caused by single random somatic event
- Sporadic: require two random somatic events
theory later confirmed and RB gene identified through genetic-linkage studies
familial retinoblastoma shows autosomal dominant inheritance
- retinoblastoma phenotype is dominant at the level of the whole organism
- however the phenotype of the mutant allele is recessive at the cellular level .
- both Rb and Rb- need to be nutated for cancer to form.
TS genes associated with loss of heterozygosity in tumours
Highly unlikely for sporadic mutation to inactivate both copies by two successive mutational events (p = 1 in ~1012-14)
The second mutation occurs by a different mutational process with a higher frequency
-one possibility is mitotic recombination
-associated with loss of heterozygosity (LOH) for region containing the Rb gene
how do the tumour suppressors Rb and P53 act?
• Restriction point: ‘go-no go’ signal, cell requires growth signals to pass this checkpoint (beyond this cells are committed to division)
- G1: DNA damage checkpoint, entrance to S blocked if DNA damaged
- G2: Is replication complete?
- M: Are chromatids properly assembled on spindle?
tumour suppressors and apoptosis
proteins such as p53 can trigger cells to enter apoptosis if cell cycle/DNA synthesis fails to complete correctly
upstream activators of p53
- DNA damage
- aberrant growth signals, oncogene activation
- cell stress: hypoxia, nucleotide depletion.
downstream cell effects of p53
- cell cycle arrest or senescence
- DNA repair
- apoptosis
- inhibition of angiogenesis
what are oncogenes
Oncogenes are mutated (or occasionally viral) forms of genes involved in a range of processes:
Secreted growth factors (e.g. PDGF-B)
Cell surface receptors (e.g. EGFR)
Signal transduction components (e.g. ras)
Transcription factors (e.g. myc)
These proto-oncogenes undergo dominant-activating mutations in tumours (i.e. gain of function)
deletions or point mutations in the EGFR can result in constitutively-active receptor
Bcr-Abl
- ABL on chromosome 9 fuses with the BCR (breakpoint-cluster region) locus on chromosome 22
- produces a novel protein kinase (3 variants) acting on multiple downstream signalling pathways
translocation into transcriptionally-active chromatin: Burkitt’s lymphoma
- Also associated with DNA translocations, but doesn’t create a fusion protein
- Activation of myc important in oncogenesis
- The MYC gene is placed in a region of chromatin that is transcribed at a high level in antibody-producing B-cells
