Precision medicine

Question 1

Cystic fibrosis

Answer 1

Autosomal recessive disorder
Most common fatal inherited disease
Mutated chloride channel - lungs clogged up with mucous, susceptibility to infections
Incidence 1 in 2400 but carrier 1 in 23

Question 2

Newborn screening programme

Answer 2

Identification of babies with CF to allow early treatment interventions
based on heel prick immuno-reactive trypsinogen (IRT) level
Raised IRT - test using CF mutation kit
CF suspected of IRT raised and one pathogenic mutation found
CF confirmed if 2 pathogenic mutations found

Question 3

Mutations in CF

Answer 3

G551D is main mutation
R117H is mild mutation - found commonly in postnatal screening - more show up on screen that are actually present - majority do not present with CF in childhood
Effect of R117H varies according to intron 8 splice site efficiency - depends on T’s - if 5T’s then this makes mutation pathogenic or if two mutations then pathogenic

Question 4

Mutations can have a range of effects - what are they?

Answer 4

No transcription
Protein incorrectly processed
Inappropriately regulated
Inappropriate function
Reduced transcipt number
Unstable protein

Question 5

What does ivacaftor do?

Answer 5

Drug that targets specific mutation on specific transmembrane receptor - binds to G551D and causes dimerisation to allow chloride to be released from the cell and thus overcome the defect

Question 6

What are the main types of lung cancer?

Answer 6

Small-cell lung cancer

Large cell lung cancer (adenocarcinoma, squamous cell carcinoma, large cell carcinoma)

Question 7

Tumour supressor genes

Answer 7

Recessive mutation so have to have mutations affecting both copies of TSG - function is to stop cells from dividing

Question 8

Oncogenes

Answer 8

Mutation in one cell in order to drive cell to be tumourogenic - gain of function mutation
Potential to become oncogenic can be by mutation in coding sequence, gene amplification or chromosome rearrangement

Question 9

How does gefitinib act?

Answer 9

EGFR receptor
Binds to similar site to ATP and inhibits TK activity as it blocks ATP binding and stops EGFR pathway
Not all respond to the drug though

Question 10

What are compensating mutations?

Answer 10

Following tx with gefitinib some patients develop resistance to it by developing a second mutation within the same protein - this mutation again is in catalytic cleft - blocks the binding site of gefitinib (this compensating mutation is T790M)

Question 11

What are driver and passenger mutations?

Answer 11

A driver mutation is mutated protein essential for tumour transformation/growth
Essential passenger mutation is protein containing mutation essential for tumour survival
Passenger mutation is mutated protein non-essential for tumour growth/survival

Question 12

Other examples where genetic info can be used to influence prescribing - indirect effects

Answer 12

• CYP2D6 variation in metabolism - required for activation of some drugs from pro-drug to drug e.g. tamoxifen
• Thiopurine methyltransferase (TPMT) - required for inactivation of some drugs e.g. azathioprine
• HLA-B*5801 - immune system e.g. allopurinol