T5: Pharmacogenetics

Question 1

What is pharmacogenetics?

Answer 1

• The study of inherited genetic differences in drug metabolic pathways which can affect an individuals response to drugs.
• These differences may result in a positive response to a drug therapy or an adverse drug reaction.
• Plays an important role in offering a stratified medicine approach to improve patient care.

Question 2

What genetic variations affect drug metabolism?

Answer 2

• Altered outcome to treatment
• Gene amplification
• Promoter polymorphisms
• Translocations
• Deletions, Insertions
• Single Nucleotide Polymorphism

Question 3

What effects can genetic variation have?

Answer 3

• Absorption
• Activation
• Altered target
• Catabolism (breakdown)
• Excretion

Question 4

What patients can benefit from Trastuzumab?

Answer 4

20% of breast cancers have over-expression of HER2 (human epidermal growth factor receptor 2)

These patients benefit significantly from trastuzumab (Herceptin) – a monoclonal antibody to the HER2 receptor.

Question 5

What patients can benefit from BRAF targeted therapy?

Answer 5

• Melanoma is notoriously resistant to chemotherapy treatment
• ~50% of melanomas have a somatic mutation in the BRAF gene
• A new targeted therapy Vemurafenib recently showed a 48% reponse rate compared with 5% for standard chemotherapy

Question 6

Other examples of use of pharmacogenetics.

Answer 6

• Thiopurine methyltransferase (TPMT) – enzyme that inactivates certain drugs e.g. Azathioprine
• Ivacaftor - Cystic Fibrosis (CFTR gene variants)
  Succinylcholine - Muscle relaxant used in anaesthesia (to stop breathing)
• Aminoglycoside induced hearing loss - (MT-RNR1 gene variants)
• Warfarin – anti-coagulant (affected by VKOR gene variants)