7. the molecular basis of cancer Flashcards
what do carcinogens lead to
high rate of mutation in cancer
characteristics of proto oncogenes and tumour supressor genes
promote events leading to cancer
regulate proliferation
gain of function in mutations
inhibit events leading to cancer
regulate apoptosis, immortality and proliferation
loss of function in mutations of cancer
gain of function mutations
- Overexpression: amplification/ regulatory regions change (of promoters to switch on)
- Point mutations/fusions
loss of function mutations
- Point mutation, deletion- frameshift, loss of allele.
- Bits of chromosome lost with the tumour suppressor
- Frameshift- can result in stop codons forming
How to identify key cancer genes
whole genome analysis
P53 expressed differently
Cytogenetics- pick on the marker chromosome that you see over in the same place in lots of tumours- passenger becomes a driver gene
Don’t just randomly get the same gene over and over again
Compare genomes
- Familial syndromes of cancer
- Retinoblastoma (Rb gene found here)
- Colon cancer (few specific genes have high impact)
- Breast cancer (BRCA1, BRCA2)
- Familal cancers are RARE. But - studying these families has helped to identify some important cancer genes (especially TS genes) and then know which mutations to look for in sporadic
Identification of the gene for Retinoblastoma – a rare childhood tumour
First TS
Tumour arises in precursors of photoreceptor cells (cone cells)
Of retina
Treated by radiotherapy or surgery
Stop a flashlight from flashing red (one red eye and the other eye isn’t)
Familial and non-familial forms of retinoblastoma
- Sporadic cases unilateral, familial cases bilateral and assoc with other tumours (mostly osteosarcomas- bone tumour)
- familial shows autosomal dominance
- Familial tumours due to a single random somatic event
- one copy is defective, so the other copy needs to become defective then TS lost
- Sporadic tumours require two random somatic events (lost of both copies) this is enough for this tumour to form
- Rb gene defective
Two hit hypothesis
- Phenotype of the mutant Rb allele is dominant at the level of the whole organism
- However - the phenotype of the mutant allele is recessive at the cellular level
- Characteristic of tumour suppressor genes
TS genes in tumours are associated with loss of
heterozygosity
- Problem - highly unlikely that both gene copies inactivated by two successive mutational events
- Unlikely that second mutation in that same gene in the same cell with the first mutation
- The second mutation occurs by a different mutational process with a higher frequency
- One possibility is mitotic recombination
- Cells lacking functional Rb then gain growth advantage over other cells
- Or become homozygous so both copies identical- good replaced by bad recombination event
- Lose other copy by error in replication
- Associated with loss of heterozygosity (LOH) for region containing the Rb gene
How do the tumour suppressors Rb and P53 act?
- R
- “go – no go” signal, cell requires growth signals to pass this checkpoint
- G1
- DNA damage checkpoint, entrance to S blocked if DNA damaged
- G2
- Is DNA replication completed?
- M
- Are chromatids properly assembled on spindle?
which gene would activate any part of this pathway?
oncogene
Familial forms of cancer are rarely associated with
oncogene mutation
Generally, mutant oncogenes cannot be tolerated in the germ line-their action would be dominant
- Disrupt normal embryonic development
- A few syndromes described but in genes not widely expressed in development
- If inherited drives proliferation- all cells of body would be hyperproliferative
- Oncogenes are dominant
how are oncogenes activated?
- deletions:
- point mutations
E.g. EGFR– activate kinase activity in non-small cell lung cancer
Ligand, binds, signal, proliferation,
Mutations truncate receptor act as if it is bound and signals
- translocations
Functional gene stuck to a promoter that switches on so lots of signals to proliferate
Most of Ig or T cell receptor drives the production of something that stimulates the promoter turning on
- cytogenetics
cytogenetic activation of oncogene
example
Chromosomal rearrangements creating a novel gene
- Common in hematologic tumours and sarcomas
- Philadelphia chromosome in 90% patients with chronic myeloid leukemia
- ABL is a proto-oncogene
- BCR (breakpoint cluster region)
- Produces a novel protein kinase
- This acts on many downstream signalling pathways
- Ph1 stitches half BCR and half ABL hybrid phosphorylates proteins in cell and causes proliferation
translocation in activation of oncogenes
- transcriptionally active chromatin
- Burkitt’s lymphoma
- Activation MYC important
- Also associated with translocations, but doesn’t create a fusion protein
- The MYC gene is placed in a region of chromatin that is transcribed at a high level in antibody-producing B-cells
- regions of chromosomes amplified
kaplan meier plot
Every time line drops patients tumour reappears on this particular plot
