Precision Medicine Flashcards
What is the aim of precision medicine?
- To reduce variation by working out which patients will respond to certain therapies and prescribing accordingly.
- Precision medicine ensures the delivery of the right intervention to the right patient at the right time.
- Each patient should benefit from individualised treatment.
What is the mode of inheritance of cystic fibrosis?
Autosomal recessive
Describe the frequency with which cystic fibrosis occurs in the UK.
- Most common fatal inherited disease in Caucasians.
- Incidence of 1 in 2400 in UK.
- Carrier frequency 1 in 23 (Scotland).
How is cystic fibrosis screened for?
- Newborn screening programme - heel-prick immuno-reactive trypsinogen (IRT) level.
- IRT is not specific for CF, it is just a test for trypsinogen (ie. a stressed pancreas).
- Used to identify babies with CF to allow early treatment interventions.
- Raised IRT - then test using CF mutation kit.
- CF suspected if IRT raised and one pathogenic mutation is found.
- CF confirmed if 2 pathogenic mutations found.
What is compound heterozygosity?
Where there are 2 different mutations on different alleles of the same gene.
What is R117H?
- A ‘mild’ mutation.
- R117H is the second mutation in 1.85% of Scottish CF patients.
- But it makes up 9% of CF mutations identified on postnatal screen.
- The majority of R117H compound heterozygotes do not present with CF in childhood.
- Effect of R117H varies according to intron 8 splice site efficiency.
What are the issues for the rest of the family when they receive a diagnosis of cystic fibrosis in the newborn?
- What is the risk for other children (siblings of the child with CF)?
- Cascade testing of relatives.
- Options for any future pregnancy:
- Prenatal diagnosis (PND)
- Chorionic villus sampling
- Amniocentesis
- Pre-implantation genetic diagnosis (PGD)
- Prenatal diagnosis (PND)
Mutations in CF can have a range of effects.
What are they?
- I - No transcription
- II - Protein incorrectly processed
- III - Inappropriately regulated
- IV - Inappropriate function
- V - Reduced transcript number
- VI - Unstable protein
What is Ivacaftor?
- Ivacaftor is the new therapeutic agent that acts at the cystic fibrosis transmembrane conductance regulator (CFTR) channel to alter activity.
- The G551D mutation arises and prevents the dimerisation of the nucleotide binding domain and the chloride channel cannot open properly.
- Ivacaftor binds exclusively to the mutated protein and opens the chloride channel and the defect can be overcome.
What sort of genes are altered in lung cancer?
- To move from normal cells to neoplastic cells:
- Oncogenes must be activated
- Tumor suppressor genes must be inactivated
Describe the inactivation of tumour suppressor genes.
- If you have a mutation in one copy of the gene this is better than having the mutation in both copies because there is still a copy of the gene telling the defective cell NOT to divide.
Describe the action of oncogenes.
- Drivers of neoplastic behaviour.
- Proto-oncogene.
- Mutation is usually an activating mutation - a gain of function mutation which means that the gene is ALWAYS switched on.
Describe a gene’s potential to become oncogenic.
Describe an epidermal growth factor receptor.
Describe the relationship between EGFR expression and prognosis.
What is Gefitinib?
How does it produces its action?
- Gefitinib is a drug used for certain breast, lung and other cancers.
- It is an EGFR inhibitor - it specifically targets EGF receptors.
- It binds very close to the same site as TTP so it inhibits the tyrosine kinase activity of the dimerised receptor.
- So, where there is a tumour that has permanently active EGFR, the drug binds to the ATP binding site which blocks ATP from binding it and it cannot act as a kinase.
Describe driver vs passenger mutations.
