Cancers are Genetic Diseases; Mutations Flashcards
What is the difference between mutation and epimutation?
Mutation; changes in DNA sequence
Epimutation; DNA/protein modifications passed on to daughter cells (e.g. methylation of histone proteins)
How many mutations are required to initiate cancer?
- At least two; e.g. a RAS-like oncogene (cytoplasmic; signalling protein) and a MYC-like oncogene (nuclear; transcription factor)
- Once initiated by two, tumour progression is accelerated by tumour promoters and further mutations (5 or 6 in total to ‘kick off’ process
What is the mutator phenotype hypothesis?
- Cancer cells contain thousands of mutations; 200 times more than we’d expect
(Spontaneous mutation rate of human cells is approximately 1.4 × 10^−10 per base pair per cell generation) - > 100 genes contribute to DNA repair (protecting against accumulation of mutations, initiating apoptosis if irreparable)
- Mutations in any of those could predispose to a higher mutation rate
- Vicious circle of mutations (in DNA repair genes) allowing further mutation = tumour progresses
»> Cell less able to protect itself, positive feedback loop
»> Results in chromosome instability
What causes oncogenic changes in gene expression?
- Mutations in proto-oncogenes and tumour suppressor genes; change how they behave (normally implicated in controlling cell division, differentiation and death - causes of cancer if malfunctioned)
- Increase/decrease in activity e.g. changing AA sequence influences ligand-binding domain/active site mutation, promoters, UTRs
- Lack of response to proper regulation
Why are p53 mutations important in cancer?
- TP53 gene (encodes p53) is the most mutated in human cancers; > 70% cancers have mutant p53
- Over 29,000 mutations have been identified in the TP53 gene
What are ‘hotspot residues’ WRT TP53?
- 30% of TP53 mutation falls within 6 hotspot residues; residues that are more susceptible to infection.
e. g. nucleotides exposed/liable to modification by mutagens - R175 (Arginine 175)
- G245
- R248
- R249
- R273
- R282
What are the types of mutation that occur to the TP53 gene to produce an oncogenic p53?
- Loss of function mutation; p53 loses tumour suppressor activity
- Gain of function mutation; gains oncogene activity e.g. antagonises unmutated p53 function by aberrant binding to DNA or proteins (transcription factor; tumour suppressing/antagonising normal functions instead)
What does INK4 deletion entail? Why is it detrimental?
- Whole gene deletion
- Normally inhibits cyclin dependent kinases (e.g. Cyclin D-CDK4s; required for cell cycle to proceed as they phosphorylate RB1)
- INK4 is a tumour suppressor
»> Frequently deleted in cancers
»> Removing the safety net/blockage of Cyclin D-CDK4; which will now readily phosphorylate RB1 and allow cell cycle to continue regardless
What does MDM2 amplification entail, and how often does it occur?
- Errors in DNA replication and repair lead to the copying of MDM2 gene multiple times; loads of MDM2s are produced
- MDM2 is amplified in 7% of all cancers
What is the impact of a mutation resulting in MDM2 amplification?
- MDM2 is an oncoprotein; an ubiquitin ligase
- Normally results in ubiquitylation of the tumour suppressor p53, marking it for degradation
- Amplification of MDM2 would result in a big decrease of p53 levels as a result; more MDM2 to ubiquitylate p53, more degradation of vital tumour suppressor
What is the Philadelphia chromosome, and what kind of mutation is it an example of?
- Chromosomal rearrangement
- BCR is a serine threonine kinase and GTPase
- ABL is a signalling TK
»> Reciprocal translocation of chromosomes 9 and 22 occurs, fusing BCR and ABL
(genes for BCR and ABL are normally found in different chromosomes; Philadelphia chromosome is half BCR, half ABL) - Fusion has TK activity, but is NO longer regulated
What cancers is the Philadelphia chromosome mutation often found in, and what therapies are availible?
- Frequently associated w/CML (Chronic Myeloid Leukaemia)
- Imatinib (Gleevec), Nilotinib (Tasigna) and Dasatinib (Sprycel) are TKIs that target BCR/ABL
»> ATP analogues, so protein no longer has phosphate source
What is EGFRvIII (EGFR variant III), and what mutation is it an example of?
- Variant of EGFR; but lacks most of its extracellular domain (ligand-binding domain)
- Constitutively active as a result; continues to phosphorylate downstream proteins despite no ligand-docking (RAS-RAF-MEK-ERK, PI3K-)
- Mutation (deletion) of 801 base pairs (267 AAs); a partial deletion
Which cancer is EGFRvIII prevalent in?
- Present in 20-60% glioblastoma multiforme
What is RAS, and what does a point mutation of RAS result in? Where does the mutation occur?
- GTPase regulating pathways (RAF-MEK-ERK) for proliferation and survival
- Mutations affecting codons 12, 13, or 61 leads constitutively active RAS protein; active downstream pathways as a result
- GTP binding favoured over GDP binding (active conformation of RAS protein favoured over inactive)
