pharmacogenomics

Question 1

what is pharmacogenomics?

Answer 1

is the study of how variations in the human
genome dictate a person’s response to medications
Assess the ‘GENOTYPE’ of a patient to determine response to a
therapy/medication
* Gene alterations can be used to predict increased or decreased effect of a
medication

Question 2

what is the outcome for pharmacogenomics?

Answer 2

• Maximize the intended use of a medication or treatment
• Reduce adverse drug reactions
• Accelerate the time to achieving the therapeutic benefit of a drug
• Decrease the chance of side effects or dependency

Question 3

why is pharmacogenomics important?

Answer 3

WE ARE ALL DIFFERENT
* Profile patients prior to treatment
* Identify patients with altered biochemistry
* Altered enzymes implicated in drug metabolism
* Presence/absence of markers of targeted
treatment

Question 4

define pharmacogenetics

Answer 4

the study of single gene-drug interactions, e.g. where a gene exerts a strong effect on drug response

Question 5

define pharmacogenomics

Answer 5

the study of more complex relationships between the genome and drug response, e.g. using Genome Wide Association Studies (GWAS) to determine how variants influence
response

Question 6

what are the technologies emploted in PGx?

Answer 6

• Single Nucleotide Variant (SNV) arrays – single base changes
• Microarray Gene Chips – panels of many genes
• Quantitative Polymerase Chain Reaction – single gene
• DNA Sequencing – mutational analysis
• Next Generation Sequencing – whole genome

Question 7

what can preform PGx?

Answer 7

genechips

Question 8

what are gene probe sets?

Answer 8

• 11 probes per gene
• Also contains mismatch probes to
  detect non-specific signals
• Mismatch probes should NOT be
  detected on chip
• They contain an altered base that
  the true RNA sequence would not
  hybridise to

Question 9

what are the 3 ways in which pharmacogenetics work?

Answer 9

1. Targeted drugs - identifying patients who will respond
   a. Herceptin (breast cancer)
2. Drug metabolism and predicting patient response
   a. Tamoxifen (breast cancer)
   b. 6-mercaptopurine (leukaemia)
   c. Warfarin (prevention of stroke)
3. Predicting adverse reaction
   a. Abacavir (HIV)

Question 10

how can breast tumours be classified?

Answer 10

by expression of proteins that promote
growth of the tumour:
1. Estrogen receptor (ER)
2. Progesterone receptor (PR)
3. Human epidermal growth
factor receptor 2 (HER2)

Question 11

how does pharmacogenomics help?

Answer 11

• Modelling of:
• Drug exposure and clinical response variability
• Risk for adverse events
• Genotype-specific dosing
• Mechanisms of drug action
• Polymorphic drug target / genes
• Trial design features

Question 12

why is metabolism important?

Answer 12

know what an effective dose is and to limit toxic effects
How well a drug is taken up into cells
How long a drug survives in the body before it is broken down
Some drugs are prodrugs: will they be metabolised in the body to
an active form IF a crucial enzyme is missing
Will a drug be metabolised faster/slower if a gene variation is
present

Question 13

where are the CYP450 genes commonly expressed?

Answer 13

in the liver and comprise 70-80% of all the
enzymes implicated in drug metabolism

Question 14

what happens in tamoxifen metabolism?

Answer 14

• Tamoxifen targets ER-positive breast cancer
• Metabolised to 4 Hydroxy TAM by CYP enzymes
• this has 100x more affinity for ER

Question 15

what can variants within the CYP2D6 gene cause?

Answer 15

can reduce its efficacy in drug metabolism, resulting in reduced production of 4-OHT.

Question 16

how does the genotype of CYP2D6 effect its phenotype?

Answer 16

two functional allels= ultrarapid metaboliser
one functional alleles- intermediate met
no functional allels- poor metaboliser

Question 17

what is a minaturisation?

Answer 17

• Miniature DNA sequencer that connects to a PC
• Already on the market but High error rates (10-15%)
• Sequence up to 2mb
• RNA and DNA